DRUG INTERACTIONS
Abciximab: Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Acarbose: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Acetaminophen; Aspirin, ASA; Caffeine: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Butalbital; Caffeine; Codeine: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Acetaminophen; Caffeine; Dihydrocodeine: Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Codeine: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Acetaminophen; Dextromethorphan: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Dextromethorphan; Doxylamine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Dextromethorphan; Phenylephrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Dextromethorphan; Pseudoephedrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Acetaminophen; Hydrocodone: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Acetaminophen; Oxycodone: Fluoxetine is a relatively potent inhibitor of CYP2D6 resulting in increased concentrations of opiate agonists metabolized via this same pathway including oxycodone. Clinicians should be alert for an exaggerated opiate response if fluoxetine is given with oxycodone.
Acetaminophen; Pentazocine: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions
Acetaminophen; Propoxyphene: Fluoxetine may inhibit the metabolism of propoxyphene. Clinicians should be alert for an exaggerated opiate response if propoxyphene is given with fluoxetine.
Acetaminophen; Tramadol: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as fluoxetine and paroxetine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite.] Patients receiving tramadol in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Albiglutide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Albuterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Albuterol; Ipratropium: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Alfentanil: Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme present in the liver. Inhibitors of CYP3A4, such as fluoxetine, may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Close monitoring for oversedation and respiratory depression is warranted if a CYP3A4 inhibitor is used with alfentanil.
Alfuzosin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include alfuzosin.
Aliskiren; Amlodipine: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Aliskiren; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Almotriptan: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of SNRIs or SSRIs with serotonin-receptor agonists. Of the 27 cases reviewed by the FDA, 2 were considered life-threatening and 13 required hospitalization. Some patients had used the combination previously without incident. Eight of 27 cases involved a recent dose increase or addition of another serotonergic drug to the regimen, with a median onset of 1 day (range: 10 minutes to 6 days). It is thought that the interaction between SNRIs or SSRIs and serotonin-receptor agonists is the result of increased serotonergic activity by each of the drug classes. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 6 patients taking an SSRI antidepressant are known to have received sumatriptan for migraine where no apparent adverse effects were seen. In another case report, the addition of fluoxetine lead to loss of migraine control with sumatriptan. Careful monitoring for serotonin syndrome and neuroleptic malignant syndrome-like reactions is recommended if combination therapy is required.
Alogliptin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Alogliptin; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Alogliptin; Pioglitazone: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Alosetron: Alosetron is metabolized by the hepatic cytochrome P450 isoenzymes CYP1A2, CYP2C9, and CYP3A4. Fluoxetine inhibits both hepatic CYP2C9 and CYP3A4 isoenzymes, and thus may decrease alosetron metabolism.
Alpha-glucosidase Inhibitors: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Alprazolam: Clinical study results suggest that the interaction between alprazolam, a CYP3A4 substrate fluoxetine, a CYP3A4 inhibitor may be of clinical significance, and caution is recommended during co-administration. Concurrent use of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased the half-life by 17%, and decreased measured psychomotor performance. Monitor patients closely for excessive alprazolam-related side effects.
Alteplase, tPA: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Ambrisentan: In vitro studies indicate ambrisentan is a substrate of CYP2C19, although in vivo studies with omeprazole, a CYP2C19 inhibitor, did not demonstrate a clinically significant drug-drug interaction. Although data are lacking, significant CYP2C19 inhibitors, such as fluoxetine, could potentially increase ambrisentan plasma concentrations via CYP2C19 inhibition. Monitor for increased toxicity as well as increased therapeutic effect during times of coadministration
Amiloride: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Amiloride; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Amiodarone: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include amiodarone. In addition, amiodarone inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
Amitriptyline: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Amitriptyline; Chlordiazepoxide: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life. Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Amlodipine: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Amlodipine; Atorvastatin: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Amlodipine; Benazepril: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Amlodipine; Olmesartan: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Amlodipine; Telmisartan: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Amlodipine; Valsartan: Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
Amoxapine: Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6, the isoenzyme partially responsible for the metabolism of amoxapine. CYP2D6 is inhibited most by fluoxetine and least by citalopram and escitalopram. Norfluoxetine, the metabolite of fluoxetine, is also an inhibitor of CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when the structurally related tricyclic antidepressants were co-administered with an SSRI. At least one case report exists of a death thought to be due to impaired clearance of the tricyclic antidepressant amitriptyline by fluoxetine. Patients receiving amoxapine should be monitored closely for toxicity if an SSRI is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7 to 9 days).
Amoxicillin; Clarithromycin; Lansoprazole: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include clarithromycin.
Amoxicillin; Clarithromycin; Omeprazole: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include clarithromycin.
Amphetamine; Dextroamphetamine Salts: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. The MAOI activity of amphetamines may also be of concern with SSRI use. Monitor for adverse effects, such as anger, irritability, insomnia, and headache when treatments are combined. The safe and effective use of SSRIs with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and SSRIs. If serotonin syndrome is suspected, concurrent use should be discontinued.
Anagrelide: Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include fluoxetine. In addition, platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Antithrombin III: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like antithrombin III. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
Apixaban: The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
Apomorphine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include apomorphine.
Aprepitant, Fosaprepitant: Use caution if fluoxetine and aprepitant are used concurrently and monitor for an increase in fluoxetine-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Fluoxetine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. Fluoxetine is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
Ardeparin: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
Arformoterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Aripiprazole: Because both fluoxetine and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of atypical antipsychotics that are CYP2D6 and CYP3A4 substrates including aripiprazole. Decreased metabolism of aripiprazole may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. The manufacturer recommends that the oral aripiprazole dose be reduced by one-half when co-administered with potent inhibitors of CYP3A4 or inhibitors of CYP2D6. In adult patients receiving 300 mg or 400 mg of the extended-release injection, dose reductions to 200 mg or 300 mg, respectively, are recommended if a potent CYP2D6 inhibitor or CYP3A4 inhibitor is used for more than 14 days. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their extended-release intramuscular dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Because fluoxetine and its metabolite norfluoxetine inhibit both CYP3A4 and CYP2D6, a further reduction in aripiprazole dosage may be clinically warranted in some patients. It should be noted that aripiprazole dosage adjustments are not required when it is added as adjunctive treatment to antidepressants for major depressive disorder, provided that the manufacturer's dosing guidelines for this indication are followed. Currently available data indicate no clinically significant pharmacokinetic changes to fluoxetine with coadministration. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Armodafinil: Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluoxetine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
Arsenic Trioxide: Avoid coadministration of fluoxetine and arsenic trioxide. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
Artemether; Lumefantrine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including artemether; lumefantrine. In addition, artemether is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. Lumefantrine is an inhibitor and fluoxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased fluoxetine concentrations. Additionally, lumefantrine is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
Asenapine: According to the manufacturer of asenapine, the drug should not be used with other drugs known to cause QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during post-marketing use of fluoxetine. In addition, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of CYP2D6 and CYP3A4 substrates including asenapine. However, because asenapine is a primary substrate for CYP1A2, a clinically significant pharmacokinetic interaction is less likely to occur. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Aspirin, ASA: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Butalbital; Caffeine: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Butalbital; Caffeine; Codeine: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine. The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine; Dihydrocodeine: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
Aspirin, ASA; Carisoprodol: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Carisoprodol; Codeine: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine. The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Dipyridamole: Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Omeprazole: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Oxycodone: Fluoxetine is a relatively potent inhibitor of CYP2D6 resulting in increased concentrations of opiate agonists metabolized via this same pathway including oxycodone. Clinicians should be alert for an exaggerated opiate response if fluoxetine is given with oxycodone. The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Pravastatin: The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Atazanavir; Cobicistat: Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Atenolol; Chlorthalidone: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Atomoxetine: QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and fluoxetine are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, atomoxetine is primarily metabolized by CYP2D6 and fluoxetine is a strong inhibitor of CYP2D6. In extensive metabolizers (EMs) taking atomoxetine who are treated concurrently with fluoxetine, the atomoxetine AUC is roughly 6-8 fold and Cmax 3-4 fold greater than if atomoxetine is given alone. In children and adolescents up to 70 kg receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If concurrent use is necessary, monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation) during concurrent use.
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Atropine; Difenoxin: Concurrent administration of diphenoxylate/difenoxin with fluoxetine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Atropine; Diphenoxylate: Concurrent administration of diphenoxylate/difenoxin with fluoxetine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Axitinib: Use caution if coadministration of axitinib with fluoxetine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. According to the manufacturer, the inhibition of CYP3A4 by fluoxetine is not clinically significant; reported in vivo studies have been single-dose. However, active metabolite norfluoxetine is a moderate inhibitor of CYP3A4, and the possibility of clinically relevant drug interactions cannot be excluded. Fluoxetine is also a CYP2C19 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Azilsartan; Chlorthalidone: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Azithromycin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include azithromycin.
Bedaquiline: Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with bedaquiline include fluoxetine.
Belladonna Alkaloids; Ergotamine; Phenobarbital: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Belladonna; Opium: Fluoxetine may inhibit the metabolism of opium. Clinicians should be alert for an exaggerated opiate response if opium is given with fluoxetine.
Benazepril; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Bendroflumethiazide; Nadolol: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Benzphetamine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI activity of amphetamines may also be of concern with SSRI use. The safe and effective use of SSRIs with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and SSRIs. Patients receiving an SSRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SSRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Bepridil: Fluoxetine may decrease the clearance of calcium-channel blockers, including bepridil, via inhibition of CYP3A4 metabolism.
Bicalutamide: Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as fluoxetine, decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine.
Bismuth Subsalicylate: The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bismuth Subsalicylate; Metronidazole; Tetracycline: Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine. The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bisoprolol; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Boceprevir: Close clinical monitoring is advised when administering fluoxetine with boceprevir due to an increased potential for boceprevir-related adverse events. If fluoxetine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of fluoxetine and boceprevir. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may be elevated.
Bortezomib: Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluoxetine is not known.
Bosentan: Bosentan is metabolized by CYP2C9 and CYP3A4. Fluoxetine may inhibit both of these isoenzymes and thereby increase the plasma concentrations of bosentan. It is prudent to monitor for potential adverse effects of bosentan during coadministration with fluoxetine; excessive dosage may result in hypotension or elevated hepatic enzymes.
Brexpiprazole: Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
Brimonidine; Timolol: Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
Brompheniramine; Dextromethorphan; Guaifenesin: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Brompheniramine; Guaifenesin; Hydrocodone: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Brompheniramine; Hydrocodone; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Budesonide: Use caution when budesonide is coadministered with drugs that inhibit CYP3A enzymes, such as fluoxetine, and consider dose reduction. Toxicity may occur, particularly excessive HPA-axis suppression. Inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide as well.
Budesonide; Formoterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists. Use caution when budesonide is coadministered with drugs that inhibit CYP3A enzymes, such as fluoxetine, and consider dose reduction. Toxicity may occur, particularly excessive HPA-axis suppression. Inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide as well.
Bumetanide: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Bupivacaine Liposomal: Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine: Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Lidocaine: Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4. Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Buprenorphine: Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Fluoxetine also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as fluoxetine, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as fluoxetine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Buprenorphine; Naloxone: Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Fluoxetine also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as fluoxetine, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as fluoxetine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Bupropion: Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluoxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added.
Bupropion; Naltrexone: Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluoxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added.
Buspirone: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as buspirone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. The addition of fluoxetine to a regimen consisting of buspirone and trazodone was reported to result in an increase in anxiety-type symptoms in one patient. Another patient developed a grand mal seizure while receiving the combination of buspirone and fluoxetine. CYP3A4 inhibitors such as fluvoxamine may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is to be administered concurrently with significant CYP3A4 inhibitors, a low dose of buspirone (i.e., 2.5 mg PO twice daily) is recommended initially. Subsequent dosage adjustments should be based on clinical response. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Cabazitaxel: Fluoxetine is a mild CYP3A4 inhibitor. Cabazitaxel is a CYP3A4 substrate. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if cabazitaxel is coadministered with a mild or moderate CYP3A4 inhibitor; closely monitor patients for cabazitaxel-related toxicities.
Cabergoline: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as cabergoline. Patients receiving cabergoline with an SSRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Caffeine; Ergotamine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Canagliflozin: Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Canagliflozin; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Candesartan; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Cangrelor: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cangrelor). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Capecitabine: Use caution if coadministration of capecitabine with fluoxetine is necessary, and monitor for an increase in fluoxetine-related adverse reactions. Fluoxetine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
Captopril; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Carbamazepine: Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Fluoxetine inhibits CYP3A4 and may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Carbinoxamine; Hydrocodone; Phenylephrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Carbinoxamine; Hydrocodone; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Cariprazine: The metabolite of fluoxetine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as cariprazine. Decreased metabolism of cariprazine may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Carisoprodol: Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Carvedilol: Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as fluoxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
Ceritinib: Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with ceritinib include fluoxetine. Periodically monitor electrocardiograms (EGCs) and electrolytes; therapy interruption, dose reduction, or discontinuation may be required.
Cevimeline: Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Inhibitors of either of these isoenzymes, such as the SSRIs, would be expected to lead to an increase in cevimeline plasma concentrations.
Chlordiazepoxide: Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Chlordiazepoxide; Clidinium: Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Chloroquine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including chloroquine. In addition, chloroquine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
Chlorothiazide: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Chlorpheniramine; Codeine: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Chlorpheniramine; Dextromethorphan: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Chlorpheniramine; Dextromethorphan; Phenylephrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Chlorpheniramine; Hydrocodone: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Chlorpheniramine; Hydrocodone; Phenylephrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Chlorpromazine: Fluoxetine is associated with a possible risk of QT prolongation and torsade de pointes (TdP) and chlorpromazine also has an established risk of QT prolongation and TdP. Combination therapy with these agents should be avoided if possible. Fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum phenothiazine concentrations, which may lead to phenothiazine-related side effects such as cardiac side effects, hypotension, CNS sedation, or extrapyramidal symptoms. The effects of fluoxetine on hepatic metabolism of interacting drugs may persist for a time after discontinuation of fluoxetine because of its long elimination half-life.
Chlorthalidone: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Chlorthalidone; Clonidine: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Choline Salicylate; Magnesium Salicylate: The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Cilostazol: Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, including fluoxetine. These agents have been shown to increase both cilostazol AUC and Cmax when administered concurrently. When significant CYP3A4 inhibitors, such as fluoxetine, are administered concomitantly with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
Cimetidine: Although no clinical data are available, it is possible that inhibitors of hepatic enzymes such as cimetidine may decrease the metabolism of fluoxetine. Until more data are available, cimetidine should be used cautiously in patients receiving fluoxetine.
Cinacalcet: Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
Ciprofloxacin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ciprofloxacin.
Cisapride: Cisapride is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit, and may inhibit the clearance of and potentiate the toxicity of cisapride. QT prolongation and ventricular arrhythmias, including torsade de pointes and death, have been reported when inhibitors of CYP3A4 are coadministered with cisapride. Due to the serious nature of cisapride toxicity, fluoxetine should be avoided in these patients.
Citalopram: Due to the similarity in pharmacology of fluoxetine and citalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both fluoxetine and citalopram have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Clarithromycin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include clarithromycin.
Clobazam: A dosage reduction of clobazam and/or fluoxetine may be necessary during co-administration of clobazam and fluoxetine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluoxetine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluoxetine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam. It should be noted that because fluoxetine is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
Clomipramine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Clonazepam: Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including clonazepam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Clopidogrel: Use clopidogrel and fluoxetine together with caution and monitor for reduced clopidogrel effectiveness. Consider alternative therapy to fluoxetine, if possible. Fluoxetine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. In a large cohort study of clopidogrel and concomitant CYP2C19-inhibiting selective serotonin reuptake inhibitors (SSRIs) (n = 9,281) vs. non-inhibiting SSRIs (n = 44,278), patients receiving concurrent CYP2C19-inhibiting SSRIs, such as fluoxetine, had an increased risk of composite ischemic events. This risk was more pronounced in patients 65 years and older. Additionally, because SSRIs affect platelet activation, concomitant use with clopidogrel may increase the risk of bleeding. In this study, bleeding events did occur in both groups; however, there were no meaningful differences in bleeding events between groups. Monitor for signs and symptoms of bleeding.
Clorazepate: Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including clorazepate. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Clozapine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Clozapine is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of CYP2D6 and CYP3A4 substrates including clozapine. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Decreased metabolism of clozapine may lead to clinically important adverse reactions such as seizures or orthostatic hypotension. According to the manufacturer of clozapine, concomitant use of clozapine and substrates or inhibitors of CYP2D6 may require lower doses of either drug. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Cobicistat: Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Cobimetinib: If concurrent use of cobimetinib and fluoxetine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and fluoxetine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Codeine: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Codeine; Guaifenesin: The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Codeine; Phenylephrine; Promethazine: Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine. The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Codeine; Promethazine: Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine. The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
Conjugated Estrogens: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Bazedoxifene: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Medroxyprogesterone: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Crizotinib: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including crizotinib. In addition, concomitant use of crizotinib and fluoxetine may result in increased crizotinib concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (PGP) substrate, while fluoxetine may be a CYP3A4 inhibitor. Monitor patients for toxicity with coadministration.
Cyclobenzaprine: Cyclobenzaprine is structurally similar to tricyclic antidepressants, which have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage). Because QT prolongation has been reported with both cyclobenzaprine and fluoxetine, concurrent use should be approached with caution. In addition, serotonin syndrome has been reported during concurrent use of cyclobenzaprine and SSRIs (e.g., fluoxetine) due to the serotonin-enhancing properties of both drugs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because of the potential risk and severity of serotonin syndrome, cautious use is recommended, particularly during initiation of treatment and dose increases. If serotonin syndrome occurs, cyclobenzaprine and fluoxetine should be discontinued immediately and supportive symptomatic treatment should be initiated.
Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with fluoxetine, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Fluoxetine is a moderate CYP2C19 inhibitor, as well as a weak inhibitor of CYP3A4 and 2C9; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
Cyclosporine: Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of cyclosporine.
Cyproheptadine: Cyproheptadine is an antagonist of serotonin in the CNS, and this pharmacologic action opposes the pharmacologic actions of sertraline. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine. Clinically, cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine, an agent related to sertraline, but more data are needed to confirm a direct drug-drug interaction. Ondansetron, granisetron, and methysergide also antagonize serotonin (5-HT) receptors, although no drug-drug interactions have been reported with sertraline.
Dabigatran: Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
Dalteparin: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
Danaparoid: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like danaparoid. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
Dapagliflozin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Dapagliflozin; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Darifenacin: Fluoxetine inhibits CYP2D6 and CYP3A4. Serum concentrations of darifenacin, a CYP2D6 and CYP3A4 substrate, may increase when used in combination with fluoxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered.
Darunavir; Cobicistat: Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Because both ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring for adverse effects is prudent. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration.
Dasatinib: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include dasatinib.
Daunorubicin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Degarelix: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include degarelix.
Delavirdine: Delavirdine is metabolized by CYP2D6 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This interaction can result in substantial increases in the trough levels of delavirdine, up to a 50% increase.
Desflurane: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
Desipramine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Desmopressin: Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including SSRIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
Desvenlafaxine: Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like desvenlafaxine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Discontinuation symptoms have been reported when switching from other antidepressants to desvenlafaxine. It may be advisable to taper the previous antidepressant to minimize discontinuation symptoms. If serotonin syndrome is suspected, desvenlafaxine and concurrent serotonergic agents should be discontinued. Dosage adjustments of fluoxetine may be necessary during concurrent use of desvenlafaxine; the dose of CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dexmethylphenidate: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dexmethylphenidate. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Although data are lacking for dexmethylphenidate, racemic methylphenidate may decrease the metabolism of the SSRIs; interactions have been reported in the literature. Dosage adjustments may be necessary during concurrent use. Patients receiving dexmethylphenidate in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as methylphenidate. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Methylphenidate may decrease the metabolism of the SSRIs; interactions have been reported in the literature. Dosage adjustments may be necessary during concurrent use. Patients receiving methylphenidate in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan; Diphenhydramine; Phenylephrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan; Guaifenesin: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan; Guaifenesin; Phenylephrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan; Guaifenesin; Pseudoephedrine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Dextromethorphan; Promethazine: Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects. Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine.
Dextromethorphan; Quinidine: Concurrent use of either quinidine or dextromethorphan; quinidine and fluoxetine is considered a contraindication. Quinidine and dextromethorphan; quinidine are contraindicated for use in patients taking drugs that prolong the QT interval and are metabolized by CYP2D6. Fluoxetine is a primary substrate of CYP2D6, and is associated with a risk of QT prolongation and torsade de pointes (TdP). Because citalopram, escitalopram, fluoxetine, sertraline, and dextromethorphan are associated with QT prolongation, these combinations should be used cautiously and with close monitoring. The manufacturers of dextromethorphan and citalopram recommend an ECG in patients taking dextromethorphan in combination with other drugs known to cause QT prolongation. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Fluoxetine and paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles the serotonin syndrome. Patients receiving dextromethorphan in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Diazepam: Diazepam is metabolized by CYP2C19 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This can result in substantial increases in the half-life of diazepam, and the psychomotor and physiological response may be altered.
Dienogest; Estradiol valerate: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Diethylpropion: Phentermine and diethylpropion have a similar mechanism of action. When phentermine was given with fluoxetine, adrenergic excess and dyskinesia were observed. Thus, diethylpropion may interact with fluoxetine similarly. It is unclear, however, if all SSRIs would be affected as fluoxetine has the longest half-life of the group.
Dihydrocodeine; Guaifenesin; Pseudoephedrine: Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
Dihydroergotamine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Diltiazem: Fluoxetine may decrease the clearance of calcium-channel blockers via inhibition of CYP3A4 metabolism.
Diphenhydramine; Hydrocodone; Phenylephrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Dipyridamole: Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Disopyramide: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including disopyramide. In addition, CYP3A4 inhibitors, such as fluoxetine may increase serum plasma concentrations of disopyramide, a CYP3A4 substrate. Monitor clinical response and serum disopyramide concentrations.
Diuretics: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Docetaxel: Docetaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of docetaxel.
Dofetilide: QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Because of the potential for TdP, use of fluoxetine with dofetilide is contraindicated.
Dolasetron: Taking these drugs together may increases the risk for serotonin syndrome. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include dolasetron.
Donepezil: Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. SSRIs with a possible risk for QT prolongation that should be used cautiously and with close monitoring during donepezil therapy include fluoxetine, sertraline, citalopram, and escitalopram. In addition, there is the potential for inhibition of donepezil metabolism via CYP2D6 and/or CYP3A4 by certain SSRIs, which may necessitate dosage adjustments or selection of alternative therapy should side effects occur. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, and concurrent use of these drugs with donepezil may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur. At least 2 case reports of an interaction with paroxetine have been published; the patients exhibited cholinergic-induced GI side effects and/or the appearance of insomnia, agitation, confusion and combativeness when paroxetine was added to donepezil therapy. The side effects subsided with the downward titration of the donepezil dosage or the discontinuation of both treatments. Both fluvoxamine and the metabolite of fluoxetine are moderate inhibitors of CYP3A4, and have the potential to reduce the metabolism of donepezil. Sertraline, citalopram, and escitalopram are milder inhibitors of CYP2D6, and are not likely to interact pharmacokinetically with donepezil.
Donepezil; Memantine: Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. SSRIs with a possible risk for QT prolongation that should be used cautiously and with close monitoring during donepezil therapy include fluoxetine, sertraline, citalopram, and escitalopram. In addition, there is the potential for inhibition of donepezil metabolism via CYP2D6 and/or CYP3A4 by certain SSRIs, which may necessitate dosage adjustments or selection of alternative therapy should side effects occur. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, and concurrent use of these drugs with donepezil may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur. At least 2 case reports of an interaction with paroxetine have been published; the patients exhibited cholinergic-induced GI side effects and/or the appearance of insomnia, agitation, confusion and combativeness when paroxetine was added to donepezil therapy. The side effects subsided with the downward titration of the donepezil dosage or the discontinuation of both treatments. Both fluvoxamine and the metabolite of fluoxetine are moderate inhibitors of CYP3A4, and have the potential to reduce the metabolism of donepezil. Sertraline, citalopram, and escitalopram are milder inhibitors of CYP2D6, and are not likely to interact pharmacokinetically with donepezil.
Dorzolamide; Timolol: Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
Doxepin: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Doxercalciferol: Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including selective serotonin reuptake inhibitors (SSRIs), may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if SSRIs are coadministered with doxercalciferol.
Doxorubicin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Dronabinol, THC: Use caution if coadministration of dronabinol with fluoxetine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; fluoxetine is a weak inhibitor of CYP2C9 and 3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. A hypomanic episode was reported in a 21 year old female with depression and bulimia receiving fluoxetine 20 mg per day for 4 weeks after smoking marijuana. Her symptoms resolved in 4 days. Because dronabinol, THC is a synthetic analog of a naturally occurring substance found in marijuana, interactions with fluoxetine may also occur with dronabinol.
Dronedarone: QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dronedarone administration is associated with a dose-related increase in the QTc interval. The concomitant use of dronedarone with fluoxetine may induce TdP and is contraindicated.
Droperidol: Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with droperidol include fluoxetine.
Drospirenone; Estradiol: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Drospirenone; Ethinyl Estradiol; Levomefolate: Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Dulaglutide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Duloxetine: Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Dutasteride; Tamsulosin: Plasma concentrations of tamsulosin may be increased with concomitant use of fluoxetine. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as fluoxetine, should be avoided.
Edoxaban: Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with edoxaban; however, the absolute risk is not known. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
Efavirenz: Coadministration of efavirenz and fluoxetine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Fluoxetine administration is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while fluoxetine is a mild CYP3A4 inhibitor.
Efavirenz; Emtricitabine; Tenofovir: Coadministration of efavirenz and fluoxetine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Fluoxetine administration is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while fluoxetine is a mild CYP3A4 inhibitor.
Elbasvir; Grazoprevir: Administering elbasvir; grazoprevir with fluoxetine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluoxetine is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eletriptan: Eletriptan is contraindicated for use within 72 hours of usage of any drug that is a potent CYP3A4 inhibitor, including fluvoxamine. Fluoxetine, another CYP3A4 inhibitor, may interact similarly. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering citalopram with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) with serotonin-receptor agonists. Of the 27 cases reviewed by the FDA, 2 were considered life-threatening and 13 required hospitalization. Some patients had used the combination previously without incident. Eight of 27 cases involved a recent dose increase or addition of another serotonergic drug to the regimen, with a median onset of 1 day (range: 10 minutes to 6 days). It is thought that the interaction between SNRIs or SSRIs and serotonin-receptor agonists is the result of increased serotonergic activity by each of the drug classes. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 6 patients taking an SSRI antidepressant are known to have received sumatriptan for migraine where no apparent adverse effects were seen. In another case report, the addition of fluoxetine lead to loss of migraine control with sumatriptan. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required.
Eliglustat: In poor CYP2D6 metabolizers (PMs), coadministration of fluoxetine and eliglustat is not recommended. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), concurrent use of these agents requires dosage reduction of eliglustat to 84 mg PO once daily; monitor patients closely and consider reducing the dosage of fluoxetine and titrating to clinical effect. Coadministration of eliglustat with both fluoxetine and a strong or moderate CYP3A inhibitor is contraindicated in all patients. Fluoxetine is a substrate and strong inhibitor of CYP2D6 and a weak inhibitor of CYP3A that is independently associated with QT prolongation and torsade de pointes (TdP). Eliglustat is a substrate and inhibitor of CYP2D6 and a CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of fluoxetine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with even weak CYP3A inhibitors, such as fluoxetine, in this population may significantly increase eliglustat exposure and, hence, concurrent use is not recommended.
Empagliflozin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Empagliflozin; Linagliptin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
Empagliflozin; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including rilpivirine. In addition, close clinical monitoring is advised when administering fluoxetine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including rilpivirine. In addition, close clinical monitoring is advised when administering fluoxetine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Enalapril; Felodipine: Fluoxetine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism.
Enalapril; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Encainide: Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including encainide. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias.
Enflurane: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
Enoxaparin: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
Epirubicin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Eprosartan; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Eptifibatide: Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Ergoloid Mesylates: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Ergonovine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Ergot alkaloids: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Ergotamine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
Eribulin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include eribulin.
Erlotinib: Use caution if coadministration of erlotinib with fluoxetine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both fluoxetine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with fluoxetine may also increase erlotinib exposure.
Erythromycin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include erythromycin.
Erythromycin; Sulfisoxazole: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include erythromycin.
Escitalopram: Due to the similarity in pharmacology of fluoxetine and escitalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both fluoxetine and escitalopram have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Esomeprazole: In the hepatic oxidative system, esomeprazole is metabolized primarily by CYP2C19 and secondarily by the CYP3A4 isoenzyme. Theoretically, esomeprazole metabolism could be inhibited if combined with drugs that inhibit CYP2C19, leading to increased plasma levels of esomeprazole. Drugs that are inhibitors of the CYP2C19 isozyme include fluoxetine.
Esomeprazole; Naproxen: In the hepatic oxidative system, esomeprazole is metabolized primarily by CYP2C19 and secondarily by the CYP3A4 isoenzyme. Theoretically, esomeprazole metabolism could be inhibited if combined with drugs that inhibit CYP2C19, leading to increased plasma levels of esomeprazole. Drugs that are inhibitors of the CYP2C19 isozyme include fluoxetine.
Esterified Estrogens: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Esterified Estrogens; Methyltestosterone: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Estradiol Cypionate; Medroxyprogesterone: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Levonorgestrel: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norethindrone: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norgestimate: As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estropipate: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Eszopiclone: Patients should be advised of the potential for next-day psychomotor and/or memory impairment during co-administration of eszopiclone and CYP3A4 inhibitors, such as fluoxetine or fluvoxamine. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethacrynic Acid: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Ethotoin: Cytochrome CYP2C19 is one of two pathways by which phenytoin and fosphenytoin is metabolized, and fluoxetine inhibits this pathway. Phenytoin toxicity has been described in several patients after the addition of fluoxetine. Also, use caution if ethotoin is prescribed with fluoxetine.
Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with fluoxetine. Fluoxetine is a weak inhibitor of CYP3A4 and etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations. This also applies to combination products containing fluoxetine, such as fluoxetine; olanzapine.
Everolimus: Everolimus is a substrate of CYP3A4. Coadministration with weak inhibitors of CYP3A4, such as fluoxetine, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, everolimus is a mixed inhibitor of CYP2D6. The effect of everolimus on a CYP2D6 substrate, such as fluoxetine, has not been established.
Exenatide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Ezogabine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ezogabine.
Felodipine: Fluoxetine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism.
Fenofibric Acid: As fenofibric acid is a mild-to-moderate inhibitor of CYP2C9 and CYP2C19; while fluoxetine is a substrate of both. Although not formally studied, co-administration may lead to increased fluoxetine plasma concentrations and toxicity. Monitor the therapeutic effect of fluoxetine during coadministration with fenofibric acid.
Fentanyl: Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fentanyl is metabolized by CYP3A4 and concurrent use of inhibitors of this isoenzyme, such as fluoxetine and fluvoxamine, may increase the bioavailability of fentanyl leading to increased or prolonged effects such as respiratory depression. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
Fesoterodine: Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. Although not studied, the weak CYP3A4 inhibitory effects of fluoxetine, in theory, may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. Of note, the manufacturer does not recommend dosage adjustments of fesoterodine during concurrent use of moderate CYP3A4 inhibitors.
Fingolimod: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include fingolimod.
Flecainide: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Flecainide is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine is a potent CYP2D6 inhibitor, and increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including flecainide, can occur. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias.
Flibanserin: The concomitant use of flibanserin and a strong CYP2C19 inhibitor or multiple weak CYP3A4 inhibitors, including fluoxetine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fluconazole: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include fluconazole.
Flumazenil: The use of flumazenil to treat overdosage of mixtures of drugs should be undertaken with caution. Treatment with flumazenil can result in convulsions and cardiac dysrhythmias induced by these drugs.
Fluoxetine; Olanzapine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Olanzapine has a possible risk of QT prolongation and TdP; however, fluoxetine and olanzapine are commonly used together in a commercially available combination product for treating certain mood disorders. Fluoxetine, a CYP2D6 inhibitor, minimally increases the systemic exposure to olanzapine, a CYP2D6 substrate (mean increase in maximum olanzapine concentration of 16% and mean decrease in olanzapine clearance of 16%). Dose modifications are not required based upon this kinetic interaction.
Fluphenazine: Because fluphenazine and some SSRIs including fluoxetine are associated with a possible risk of QT prolongation and torsade de pointes (TdP), combination therapy should be used cautiously and with close monitoring. In addition, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum phenothiazine concentrations, leading to side effects. The effects of fluoxetine on hepatic metabolism of interacting drugs may persist for a time after discontinuation of fluoxetine because of its long elimination half-life.
Flurazepam: Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including flurazepam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Fluticasone; Salmeterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Fluticasone; Vilanterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Fluvastatin: In theory, concurrent use CYP2C9 inhibitors, such as fluoxetine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
Fluvoxamine: Due to the similarity in pharmacology of fluoxetine and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both fluoxetine and fluvoxamine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Folic Acid, Vitamin B9: Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Fondaparinux: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like fondaparinux. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
Food: The incidence of marijuana associated adverse effects may change following coadministration with fluoxetine. Fluoxetine is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with fluoxetine the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
Formoterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Formoterol; Mometasone: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Foscarnet: When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as fluoxetine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have also been reported in patients treated with fluoxetine. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Fosphenytoin: Cytochrome CYP2C19 is one of two pathways by which hydantoins are metabolized, and fluoxetine inhibits this pathway. Hydantoin toxicity has been described in several patients after the addition of fluoxetine.
Frovatriptan: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) with serotonin-receptor agonists. Of the 27 cases reviewed by the FDA, 2 were considered life-threatening and 13 required hospitalization. Some patients had used the combination previously without incident. Eight of 27 cases involved a recent dose increase or addition of another serotonergic drug to the regimen, with a median onset of 1 day (range: 10 minutes to 6 days). It is thought that the interaction between SNRIs or SSRIs and serotonin-receptor agonists is the result of increased serotonergic activity by each of the drug classes. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 6 patients taking an SSRI antidepressant are known to have received sumatriptan for migraine where no apparent adverse effects were seen. In another case report, the addition of fluoxetine lead to loss of migraine control with sumatriptan. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required.
Furosemide: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Galantamine: Galantamine is metabolized, at least in part, through the hepatic CYP450 system. The bioavailability of galantamine may be increased by co-administration with the CYP2D6 inhibitors, including fluoxetine. An increase in cholinergic side effects may occur, particularly nausea and vomiting.
Gemifloxacin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include gemifloxacin.
Glipizide; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Glyburide; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Glycopyrrolate; Formoterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Goserelin: Fluoxetine should be used cautiously and with close monitoring with goserelin. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Granisetron: Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as fluoxetine. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include granisetron.
Guaifenesin; Hydrocodone: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Guaifenesin; Hydrocodone; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Halofantrine: Drugs which significantly inhibit cytochrome CYP3A4, such as fluoxetine, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically
Halogenated Anesthetics: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
Haloperidol: Fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of antipsychotics that are CYP2D6 and CYP3A4 substrates including haloperidol. Decrease metabolism of haloperidol can result in adverse effects associated with haloperidol use including dizziness, impaired psychomotor performance, and extrapyramidal symptoms. In addition, haloperidol is associated with a risk for QT prolongation and TdP, and should be used cautiously with potent CYP2D6 inhibitors such as fluoxetine. Because symptoms consistent with elevated haloperidol levels have been observed during co-administration of SSRIs, patients receiving these combinations should be carefully monitored for adverse effects. The effects of fluoxetine on hepatic metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Halothane: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
Heparin: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
Homatropine; Hydrocodone: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydralazine; Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Irbesartan: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia. Irbesartan is a substrate of the CYP 2C9 isoenzyme. Drugs that inhibit the cytochrome CYP 2C9 isoenzyme in vitro, such as fluoxetine, should be used cautiously in patients receiving irbesartan until further data are available regarding the clinical significance of theoretical drug interactions.
Hydrochlorothiazide, HCTZ; Lisinopril: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Losartan: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia. Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
Hydrochlorothiazide, HCTZ; Methyldopa: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Metoprolol: Coadministration of metoprolol, a primary substrate of CYP2D6, and fluoxetine, a potent CYP2D6 inhibitor, may result in significantly increased metoprolol serum concentrations. Monitor for bradycardia, reduced blood pressure, and increased side effects of metoprolol if coadministered with fluoxetine. An increase in metoprolol serum concentrations would decrease the cardioselectivity of metoprolol. One report noted an interaction between fluoxetine and metoprolol in which bradycardia occurred in a patient receiving metoprolol after fluoxetine was added. The patient had not previously experienced this reaction while on either drug alone. The authors postulated that fluoxetine may have inhibited hepatic metabolism of metoprolol. Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Moexipril: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Olmesartan: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Propranolol: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia. Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could impair propranolol metabolism. Bradycardia has occurred in a patient receiving propranolol after fluoxetine was added. Monitor for decreased blood pressure, reduced heart rate, or for other propranolol-induced side effects if these drugs are coadministered.
Hydrochlorothiazide, HCTZ; Quinapril: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Spironolactone: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Telmisartan: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Triamterene: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Valsartan: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Hydrocodone: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydrocodone; Ibuprofen: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydrocodone; Phenylephrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydrocodone; Potassium Guaiacolsulfonate: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydrocodone; Pseudoephedrine: The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
Hydromorphone: Fluoxetine may inhibit the metabolism of hydromorphone. Clinicians should be alert for an exaggerated opiate response if hydromorphone is given with fluoxetine.
Hydroxychloroquine: Avoid coadministration of hydroxychloroquine and fluoxetine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. QT prolongation and TdP have been reported in patients treated with fluoxetine.
Hydroxyzine: Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include fluoxetine.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Ibuprofen; Oxycodone: Fluoxetine is a relatively potent inhibitor of CYP2D6 resulting in increased concentrations of opiate agonists metabolized via this same pathway including oxycodone. Clinicians should be alert for an exaggerated opiate response if fluoxetine is given with oxycodone.
Ibutilide: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ibutilide.
Idarubicin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Iloperidone: Fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of atypical antipsychotics that are CYP2D6 and CYP3A4 substrates including iloperidone. Decreased metabolism of iloperidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. In addition, iloperidone is associated with a risk for QT prolongation and TdP, and should be used cautiously with potent CYP2D6 inhibitors such as fluoxetine. In one study, concurrent use of fluoxetine (20 mg twice daily for 21 days) and iloperidone (3 mg single dose) in CYP2D6 extensive metabolizers increased the AUC of iloperidone and its metabolite P88 by 2- to 3-fold, and decreased the AUC of its metabolite P95 by one-half. The manufacturer of iloperidone recommends that the iloperidone dose be reduced by one-half during concurrent use of a potent CYP2D6 inhibitor such as fluoxetine. If fluoxetine is subsequently withdrawn, the iloperidone dose should be returned to the previous amount. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Imatinib, STI-571: Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
Imipramine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Incretin Mimetics: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Indacaterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Indacaterol; Glycopyrrolate: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Indapamide: Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
Insulin Degludec; Liraglutide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Insulin Glargine; Lixisenatide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Insulins: Monitor patients receiving fluoxetine concomitantly with insulin for changes in glycemic control. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents.
Irbesartan: Irbesartan is a substrate of the CYP 2C9 isoenzyme. Drugs that inhibit the cytochrome CYP 2C9 isoenzyme in vitro, such as fluoxetine, should be used cautiously in patients receiving irbesartan until further data are available regarding the clinical significance of theoretical drug interactions.
Irinotecan Liposomal: Use caution if irinotecan liposomal is coadministered with fluoxetine, a weak CYP3A4 inhibitor, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
Irinotecan: Fluoxetine is a mild inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
Isavuconazonium: Concomitant use of isavuconazonium with fluoxetine may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; fluoxetine is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Isoflurane: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
Isoniazid, INH: Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Rifampin: Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isradipine: Fluoxetine may decrease the clearance of calcium-channel blockers, including isradipine, via inhibition of CYP3A4 metabolism.
Itraconazole: Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include fluoxetine.
Ivabradine: Use caution during coadministration of ivabradine and fluoxetine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; norfluoxetine, the active metabolite of fluoxetine, inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Ixabepilone: Fluoxetine is a mild CYP3A4 inhibitor. Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with mild or moderate CYP3A4 inhibitors has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with fluoxetine; closely monitor patients for ixabepilone-related toxicities.
Kava Kava, Piper methysticum: The German Commission E and other groups warn that any substances that act on the CNS, including SSRIs, may interact with the phytomedicinal kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
Ketoconazole: Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include fluoxetine.
Lapatinib: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include lapatinib.
Lenvatinib: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
Lesinurad: Use lesinurad and fluoxetine together with caution; fluoxetine may increase the systemic exposure of lesinurad. Fluoxetine is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
Leuprolide: Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include fluoxetine.
Leuprolide; Norethindrone: Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include fluoxetine.
Levalbuterol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Levofloxacin: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include levofloxacin.
Levomefolate: Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Levomethadyl: Fluoxetine may inhibit the metabolism of levomethadyl via cytochrome P450 CYP3A4. Increased concentrations of levomethadyl may predispose patients to the development of serious arrhythmias.
Levomilnacipran: Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
Levorphanol: Fluoxetine may inhibit the metabolism of levorphanol. Clinicians should be alert for an exaggerated opiate response if levorphanol is given with fluoxetine.
Lidocaine: Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4.
Linagliptin: Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
Linagliptin; Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
Linezolid: According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with linezolid, fluoxetine should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of linezolid. Linezolid is an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with fluoxetine can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid.
Liraglutide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Lisdexamfetamine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI activity of amphetamines may also be of concern with SSRI use. The safe and effective use of SSRIs with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and SSRIs. Patients receiving an SSRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SSRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Lithium: Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has been associated with QT prolongation and should be used cautiously and with close monitoring with other drugs having the potential to prolong the QT interval such as fluoxetine. In addition, lithium has been reported to have central serotonin-enhancing effects and may interact pharmacodynamically with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine to cause serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, fluoxetine and lithium should be discontinued and symptomatic treatment should be initiated. Fluoxetine has been reported to increase or decrease lithium concentrations. One systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression found no difference in discontinuation rate due to adverse events between the lithium and placebo groups. However, there are case reports of neurotoxicity (e.g., confusion, ataxia) as well as fever and seizures when SSRIs have been used with lithium. Neurotoxicity may be more likely to occur in the elderly.
Lixisenatide: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Lomitapide: Concomitant use of lomitapide and fluoxetine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Fluoxetine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Long-acting beta-agonists: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Loperamide: Loperamide should be used cautiously and with close monitoring with fluoxetine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). In addition, the plasma concentrations of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with fluoxetine, a CYP3A4 and CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
Loperamide; Simethicone: Loperamide should be used cautiously and with close monitoring with fluoxetine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). In addition, the plasma concentrations of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with fluoxetine, a CYP3A4 and CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
Lopinavir; Ritonavir: Because both ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring for adverse effects is prudent. Because lopinavir; ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring of SSRI therapeutic and adverse effects is prudent.
Lorcaserin: Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, selective serotonin reuptake inhibitors (SSRIs). Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Losartan: Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
Low Molecular Weight Heparins: Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
Lumacaftor; Ivacaftor: Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Lumacaftor; Ivacaftor: Concomitant use of fluoxetine and lumacaftor; ivacaftor may alter fluoxetine exposure; caution and close monitoring are advised if these drugs are used together. Fluoxetine is a substrate of CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of fluoxetine through the CYP2C19 pathway could potentially lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased fluoxetine efficacy or increased or prolonged therapeutic effects and adverse events. Of note, norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A inhibitor. Although lumacaftor; ivacaftor is a primary substrate of CYP3A, lumacaftor; ivacaftor dosage adjustment is not required.
Lurasidone: The metabolite of fluoxetine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as lurasidone. Decreased metabolism of lurasidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. The manufacturer of lurasidone recommends that the lurasidone dose be reduced to half of the original dose during concurrent use of a moderate CYP3A4 inhibitor. If a moderate CYP3A4 inhibitor is being prescribed and lurasidone is added, the recommended adult starting dose of lurasidone is 20 mg/day and the maximum recommended adult daily dose of lurasidone is 80 mg/day. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Magnesium Salicylate: The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Maprotiline: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including maprotiline. In addition, clinicians should be alert for pharmacokinetic or pharmacodynamic interactions between cyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants. The SSRIs are known to inhibit CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the cyclic antidepressants. CYP2D6 is impaired most by fluoxetine and is the isozyme most responsible for metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. Patients receiving maprotiline should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7-9 days).
Maraviroc: Use caution if coadministration of maraviroc with fluoxetine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and fluoxetine is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Meclizine: Meclizine is metabolized by CYP2D6, fluoxetine is a CYP2D6 inhibitor. Concomitant use may increase meclizine plasma concentrations which may intensify its sedative and anticholinergic effects.
Mefloquine: Mefloquine is metabolized by CYP3A4. Inhibitors of this enzyme, such as fluoxetine, may decrease the clearance of mefloquine and increase mefloquine systemic exposure. Fluoxetine has also been reported to prolong the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. This interaction is also relevant to combination drugs containing fluoxetine, such as fluoxetine; olanzapine. Olanzapine may also increase the QT interval.
Meglitinides: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Melatonin: It is unknown if melatonin would interact with psychotropic medications. One limited 4-week study in depressed patients with insomnia noted no interactions when melatonin was added to fluoxetine therapy. However, one case report of excessive melatonin ingestion in combination with fluoxetine therapy resulted in a case of acute psychosis that resolved within 24 hours of melatonin ingestion. The possibility of pharmacodynamic or pharmacokinetic interaction between fluoxetine and melatonin should be considered in this case.
Meperidine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. A 42 year-old man became agitated, restless, diaphoretic, tachycardiac, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
Meperidine; Promethazine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. A 42 year-old man became agitated, restless, diaphoretic, tachycardiac, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued. Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine.
Mesoridazine: Fluoxetine is contraindicated for use with some phenothiazine antipsychotics including thioridazine and mesoridazine. Mesoridazine has an established risk of QT prolongation and torsade de pointes (TdP), and post-marketing reports suggest a possible risk of QT prolongation and TdP with fluoxetine. In addition, the phenothiazine metabolism may be decreased during use of CYP2D6 inhibitors such as fluoxetine. Due to the long half-life of fluoxetine and its active metabolite, mesoridazine should not be initiated within 5 weeks after discontinuing fluoxetine. Decreased metabolism of these CYP2D6 substrates by fluoxetine may also lead to arrhythmias or other clinically important adverse reactions such as extrapyramidal symptoms.
Metaproterenol: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
Metformin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Metformin; Pioglitazone: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Metformin; Repaglinide: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Metformin; Rosiglitazone: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Metformin; Saxagliptin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Metformin; Sitagliptin: Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Methadone: QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine; therefore, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Methadone is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine may inhibit the metabolism of methadone via CYP3A4 or CYP2D6. In patients treated with methadone and fluoxetine, the plasma concentration of methadone increased. Interestingly in patients treated with methadone, the R-enantiomer (the active moiety) was increased by the addition of fluoxetine. Patients may experience increases in CNS depressive effects or respiratory depression. Thus, methadone-treated patients receiving SSRIs should be carefully monitored and dosage adjustment should be undertaken if warranted.
Methamphetamine: Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI activity of amphetamines may also be of concern with SSRI use. The safe and effective use of SSRIs with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and SSRIs. Patients receiving an SSRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SSRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Methyclothiazide: Patien