Terbinafine Hcl (terbinafine HCl)

Dosage of terbinafine hydrochloride is expressed in terms of terbinafine.

Terbinafine hydrochloride tablets are used in adults; terbinafine hydrochloride oral granules are used in adults or children 4 years of age or older.

Terbinafine hydrochloride is administered orally.

Terbinafine hydrochloride oral granules should be taken with food. The contents of the single-dose packet should be sprinkled on a spoonful of pudding or other soft, nonacidic food (e.g., mashed potatoes); applesauce or fruit-based food should not be used. The entire spoonful should be swallowed (without chewing). If the indicated dosage requires 2 packets for each dose, the contents of both packets may be sprinkled on a single spoonful of nonacidic food or the contents of the packets may be sprinkled on 2 spoonfuls of nonacidic food.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cyp3a4 Inducers/Lumateperone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)

Cyp3a4 Inducers/Zuranolone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Selected Strong Cyp2d6 Inhibitors/Thioridazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of thioridazine.(1-4)

CLINICAL EFFECTS: The concurrent administration of strong CYP2D6 inhibitors with thioridazine may result in elevated levels of thioridazine.(1-4) Elevated levels of thioridazine may augment thioridazine-induced prolongation of the QTc interval, increasing the risk of serious, potentially fatal, cardiac arrhythmias such as torsades de pointes.(1)

PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: The concurrent use of thioridazine with CYP2D6 inhibitors is contraindicated.(1) Use an alternative agent, or change to another antipsychotic agent. If alternative treatments are not possible for either agent and concurrent therapy is deemed medically necessary, strongly consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Thioridazine should not be initiated in patients with a QTc interval greater than 450 msec and should be discontinued in patients found to have a corrected QTc greater than 500 msec.(3)

DISCUSSION: A study in six slow and 13 rapid metabolizers of debrisoquin, a marker of CYP2D6 activity, showed that slow metabolizers of debrisoquin had 2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and area-under-curve (AUC), respectively, than rapid metabolizers.(4) A study in 9 healthy male subjects showed a thioridazine dose-related prolongation of the QTc interval. One subtherapeutic thioridazine 10 mg dose increased QTc 9 msec (range -1 to 19 msec), and a single low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11 to 33 msec).(7) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib and terbinafine.(3)

Strong Cyp2d6 Inhibitors/Pimozide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of pimozide at CYP2D6.(1-6)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors that prolong QT may increase the levels and effects of pimozide including additive QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes. Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(8)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(7) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(7) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: The concurrent use of pimozide with strong inhibitors of CYP2D6 is contraindicated.(1) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a controlled study in healthy subjects, steady-state paroxetine (60 mg daily, a strong inhibitor of CYP2D6) increased the AUC and Cmax of a single dose of pimozide (2 mg) by 151% and 62%, respectively.(2-4) Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, paroxetine, and terbinafine.(1,9) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Strong Cyp2d6 Inhibitors/Sofpironium

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of sofpironium.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels and adverse effects of sofpironium, including increased risk of anticholinergic side effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of sofpironium and strong CYP2D6 inhibitors should be avoided.(1) If concurrent therapy is warranted with a strong CYP2D6 inhibitor, monitor patients closely for anticholinergic side effects.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with sofpironium increased the maximum concentration (Cmax) and area-under-the-curve (AUC) by approximately 2-fold compared to sofpironium administration alone.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)

Strong Cyp2d6 Inhibitors/Valbenazine (> 40 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Valbenazine's active metabolite (alpha-HTBZ) is metabolized by CYP2D6 and CYP3A4.(1) Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors of CYP2D6.(2,3)

CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine or terbinafine may result in elevated levels and adverse effects of valbenazine such as somnolence and QT prolongation.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its own metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(2) Concurrent use of strong CYP3A4 inhibitors may further increase levels of valbenazine.(1)

PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP2D6 inhibitor.(1) During concomitant therapy with a strong CYP2D6 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine did not affect valbenazine maximum concentration (Cmax) or area-under-the-curve (AUC). However, Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold, respectively. Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Cyp3a4 Inducers/Erlotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)

DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Selected Strong Cyp2d6 Inhibitors/Nasal Metoclopramide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.

CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.

PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.

PATIENT MANAGEMENT: The manufacturer of metoclopramide nasal spray states concurrent use with strong CYP2D6 inhibitors is not recommended. If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Selected Strong Cyp2d6 Inhibitors/Tamoxifen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of strong CYP2D6 inhibitors in patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The Canadian and UK manufacturers of fluoxetine state that whenever possible co-administration with tamoxifen should be avoided.(14-15) The National Comprehensive Cancer Network's (NCCN) breast cancer guidelines advise caution when coadministering strong CYP2D6 inhibitors with tamoxifen. NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(16) Cancer Care Ontario breast cancer guidelines state concurrent use of strong CYP2D6 inhibitors should be avoided.(17) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(18) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(19) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(20-21) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(22-24) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(25-29) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Strong inhibitors of CYP2D6 include bupropion, dacomitinib, fluoxetine, paroxetine, peruvian bark extract, and terbinafine.(30-31)

Strong & Moderate Cyp2d6 Inhibitors/Eliglustat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient has hepatic impairment, is also taking an inhibitor of CYP3A4 and/or is an extensive or intermediate metabolizer of CYP2D6, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be continued at 84 mg once daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(5)

DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(1,3,4) Moderate inhibitors of CYP2D6 include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, escitalopram, levomepromazine, levomethadone, mirabegron, moclobemide, and rolapitant.(1,3,4)

Strong 2D6 Inhibitors/Atomoxetine; Vortioxetine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: FDA designates atomoxetine as a 'sensitive substrate' at CYP2D6. Sensitive substrates are drugs whose area-under-curve (AUC) increases 5-fold or higher when given a strong inhibitor of a particular enzyme.(1) Although metabolized via several CYP P-450 pathways, vortioxetine appears primarily metabolized via CYP2D6.(2-3) Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of CYP2D6.(1,4)

CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, or terbinafine may result in elevated levels and adverse effects of atomoxetine or vortioxetine. Atomoxetine adverse effects may include elevated blood pressure, tachycardia, insomnia, irritability, nausea/vomiting, or appetite suppression.(5,7) Vortioxetine adverse effects may include headache, nausea, vomiting, dizziness, or abnormal dreams.(2,3)

PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: When a strong CYP2D6 inhibitor is added to existing atomoxetine therapy, exposure to atomoxetine may increase greater than 5-fold, depending upon the dosage and specific CYP2D6 inhibitor involved. The manufacturer of atomoxetine recommends downward dosage adjustments when patients receive concomitant treatment with strong CYP2D6 inhibitors.(5) When initiating atomoxetine in children and adolescents weighing up to 70 Kg who are already receiving strong CYP2D6 inhibitors, the atomoxetine dose 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.(5) When initiating atomoxetine in children and adolescents weighing over 70 Kg and adults who are receiving strong CYP2D6 inhibitors, 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.(5) The manufacturer of vortioxetine recommends reducing vortioxetine dose by half when a strong CYP2D6 inhibitor is coadministered.(2)

DISCUSSION: In a single-blind study in 22 healthy subjects, the concurrent administration of paroxetine (20 mg twice daily in one arm, 20 mg one daily in another arm) with atomoxetine (20 mg twice daily) resulted in increases in the maximum concentration (Cmax), area-under-curve (AUC), and half-life of atomoxetine by 3.5-fold, 6.5-fold, and 2.5-fold, respectively. There were no changes in paroxetine pharmacokinetics.(4) In extensive metabolizers administered paroxetine(2,3) or fluoxetine(2) with atomoxetine, the AUC of atomoxetine is approximately 6-fold to 8-fold and the Cmax is about 3-fold to 4-fold greater than with atomoxetine alone. In vitro studies suggest that administration of CYP P-450 inhibitors to poor metabolizers would not increase plasma atomoxetine concentrations.(2) A drug interaction study conducted over 28 days evaluated the effect of bupropion 150 mg twice daily on the tolerance and steady-state kinetics of vortioxetine 10 mg daily in 28 healthy subjects. Vortioxetine AUC and Cmax increased by 2.3 and 2.1 fold respectively.(3) Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of CYP2D6.(1,4)

Terbinafine/Rifampin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifampin may induce the metabolism of terbinafine.(1)

CLINICAL EFFECTS: Concurrent use of rifampin may result in decreased levels of and clinical effects from terbinafine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of alternative agents if possible. If concurrent therapy is warranted, monitor for decreased levels and effectiveness of terbinafine. The dosage of terbinafine may need to be adjusted or rifampin may need to be discontinued.

DISCUSSION: Rifampin has been shown to increase the clearance of terbinafine by 100%.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Moderate And Weak Cyp3a4 Inducers/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)

DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)

Moderate And Weak Cyp3a4 Inducers/Ubrogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Select Strong Cyp2d6 Inhibitors/Aripiprazole Lauroxil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor. Poor metabolizers of CYP2D6 are not expected to be affected by this interaction.(1)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole lauroxil extended-release injection (Aristada) recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - Reduce the dose of aripiprazole lauroxil to the next lower strength. No dosage adjustment is necessary in patient taking the 441 mg dose, if tolerated. - For patients taking both a strong CYP2D6 and CYP3A4 inhibitor, avoid 662 mg, 882 mg, and 1,064 mg doses. No dose adjustment is necessary in patients taking the 441 mg dose, if tolerated. If the patient is a poor metabolizer of CYP2D6, no dose adjusment is required.(1)

DISCUSSION: The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. (1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)

Selected Cyp2d6 Inhibitors/Perhexiline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the metabolism of perhexiline by CYP2D6.

CLINICAL EFFECTS: Concurrent use of perhexiline and a CYP2D6 inhibitor may result in elevated levels of perhexiline and toxicity, including risk of QT prolongation or torsade de pointes.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Patients maintained on perhexiline should be carefully monitored if a CYP2D6 inhibitor is initiated or discontinued. The dosage of perhexiline may need to be adjusted. If concurrent therapy is warranted, monitor ECG more frequently and consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The Adverse Drug Reactions Advisory Committee has received five reports of an interaction between perhexiline and SSRIs.(1) In one report, an 82 year-old male developed symptoms of perhexiline toxicity ten days after the addition of citalopram to his regimen. Citalopram was discontinued on Day 10. The patient's perhexiline level, previously stable between 0.29 mg/L and 0.34 mg/l, was found to be 0.82 mg/L on day 15. Perhexiline dosage was reduced.(1) In another report, a 62 year-old male developed perhexiline toxicity following the addition of paroxetine to his regimen. After paroxetine was discontinued, perhexiline levels returned to baseline.(3) In another report, an 84 year-old female developed perhexiline toxicity following the addition of fluoxetine to her regimen. Despite the discontinuation of fluoxetine, perhexiline levels were slow to return to baseline.(3) Selected CYP2D6 inhibitors linked to this monograph include: bupropion, citalopram, dacomitinib, escitalopram, fluoxetine, hydroquinidine, levomepromazine, paroxetine, quinidine, and terbinafine.(4)

Selected Moderate To Strong Cyp2d6 Inhibitors/Tramadol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Abiraterone, asunaprevir, berotralstat, bupropion, cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, fluoxetine, hydroquinidine, levomepromazine, levomethadone, lorcaserin, mirabegron, paroxetine, quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its more active O-demethylated metabolite (M1).(1-6) M1 is up to 6 times more potent than tramadol in producing analgesia.(1)

CLINICAL EFFECTS: Tramadol analgesic efficacy may be decreased due to lower mu-opioid receptor mediated analgesia.(1,9,10) Higher concentrations of tramadol may be associated with increased inhibition of norepinephrine and serotonin reuptake, increasing risk for seizures and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)

PREDISPOSING FACTORS: Risk for seizure may be increased with tramadol doses above the recommended range, in patients with metabolic disorders, alcohol or drug withdrawal, infection of the central nervous system, or with a history of seizures or head trauma.(1) Treatment with multiple medications which increase serotonin levels, or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(1,7) Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer.(14) Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.(14)

PATIENT MANAGEMENT: If a CYP2D6 inhibitor is started in a patient stabilized on long term tramadol therapy, monitor for loss of analgesic efficacy. When initiating tramadol in a patient stabilized on a moderate or strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized patients may need added doses of rescue analgesics to achieve adequate pain control.(9,10) To decrease risk for serotonin syndrome, consider change to an alternative analgesic for patients taking other serotonin increasing drugs in addition to concomitant tramadol and a CYP2D6 inhibitor. If a CYP2D6 inhibitor is discontinued, consider lowering the dose of tramadol until patient achieves stable drug effects. The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(12)

DISCUSSION: Tramadol and its M1 metabolite both contribute to analgesic efficacy. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP2D6 converts tramadol to M1.(1,8) A prospective study evaluated the impact of 2D6 genotype on tramadol analgesia after abdominal surgery. Rescue doses of opioids were required in 47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of 2D6.(9) A follow-up study included 2D6 EM patients who received concomitant treatment with 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. The authors noted some EM patients were converted to the PM phenotype.(10) In both studies, higher M1 levels were associated with greater analgesic efficacy and decreased need for rescue opioid treatment.(9,10) A study in 12 healthy volunteers found that a single dose of tramadol (50 mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively, than tramadol given alone. The AUC and Cmax of M1 were decreased by 64 % and 78 %, respectively.(13) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(12)

Selected Moderate-Weak Cyp3a4 Inducers/Exemestane

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.

DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Selected Strong Cyp2d6 Inhibitors/Aripiprazole Im Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM monthly injection (Abilify Maintena) recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 400 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 300 mg per month. - if the aripiprazole dose is 400 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 160 mg per month.(1)

DISCUSSION: There have been no drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(3,4)

Selected Strong Cyp2d6 Inhibitors/Dextromethorphan

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of dextromethorphan.(1-4)

CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Elevated levels of dextromethorphan or concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(5) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(5) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(5) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(5)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(5)

PATIENT MANAGEMENT: Monitor patients for elevated dextromethorphan levels or on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Results: overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(1) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(4) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(6,7) and paroxetine.(8) Selected strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(8)

Selected Strong Cyp2d6 Inhibitors/Dextromethorphan-Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of dextromethorphan.(1-5)

CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Elevated levels of dextromethorphan or concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(6) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(6) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(6) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(6)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(6)

PATIENT MANAGEMENT: The manufacturer of dextromethorphan-bupropion recommends a dose reduction when coadministered with strong CYP2D6 inhibitors as follows: - For major depressive disorder, the maximum dosage is 45 mg/105 mg daily. - For agitation associated with Alzheimer's dementia, start with 30 mg/105 mg daily then increase to a maximum dosage of 45 mg/105 mg daily on day 8.(1) Monitor patients for elevated dextromethorphan levels or symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a clinical trial, paroxetine 20 mg (a strong CYP2D6 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of dextromethorphan by 2.69- and 2.38-fold, respectively.(1) An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(2) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(7,8) and paroxetine.(9) Selected strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(10)

Selected Strong Cyp2d6 Inhibitors/Iloperidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors(1) such as dacomitinib, fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of iloperidone.(2)

CLINICAL EFFECTS: Concurrent administration of iloperidone with dacomitinib, fluoxetine, paroxetine, or terbinafine may result in elevated iloperidone levels and toxicities, including the risk for QTc prolongation.(2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP3A4, which metabolizes iloperidone.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of iloperidone states that the dose of iloperidone should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as dacomitinib, fluoxetine or paroxetine are coadministered.(2) Due to its long half-life it may take 2 or more weeks to see the full effects of fluoxetine CYP2D6 inhibition on iloperidone exposure and tolerance. Maximal CYP2D6 inhibitory effects due to paroxetine coadministration are generally expected within one week after initiation or increase in the paroxetine dosage. When the inhibitor is discontinued iloperidone exposure will wane and the dose of iloperidone should be increased.(2) Concurrent administration of iloperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor does not have additive inhibitory effects compared to either inhibitor alone. The dose of iloperidone should be reduced to one-half of its normal dose, and further dose reduction is not required.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 23 healthy subjects, fluoxetine (20 mg twice daily for 21 days) increased the AUC of iloperidone (3 mg single dose) and its P88 metabolite by 2-3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(2) In a study in patients with schizophrenia, paroxetine (20 mg daily for 5-8 days) increased the maximum concentration (Cmax) of iloperidone and its P88 metabolite by about 1.6-fold. The Cmax of iloperidone's P95 metabolite decreased by 50%.(2) Coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(2) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(2)

Selected Strong Cyp2d6 Inhibitors/Metoclopramide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.

CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.

PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.

PATIENT MANAGEMENT: Concurrent use of a strong 2D6 inhibitor requires a dosage adjustment of metoclopramide. For gastroesophageal reflux, reduce the dosage of metoclopramide to 5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg taken three times daily for a maximum daily dosage of 30 mg in patients taking strong CYP2D6 inhibitors.(1) For acute and recurrent diabetic gastroparesis, reduce the dosage of metoclopramide to 5 mg four times daily (30 minutes before each meal and at bedtime) for a maximum daily dosage of 20 mg in patients taking strong CYP2D6 inhibitors.(1) If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Selected Strong Cyp2d6 Inhibitors/Risperidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The US manufacturer of risperidone (Risperdal) recommends that when CYP2D6 inhibitors are co-administered with risperidone that the dose should be reduced. The risperidone dose should not exceed 8 mg per day when co-administered with CYP2D6 inhibitors. When initiating therapy with risperidone, the dose of risperidone should be titrated slowly. It may be necessary to increase the risperidone dose, when CYP2D6 inhibitors are discontinued.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)

DISCUSSION: In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(3) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(4) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(5) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(5) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(6) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(7)

Slt Strong 2D6 Inhibitors/Risperidone Im Every 2 Weeks

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The dosage of risperidone should be re-evaluated.(1) The US manufacturer of extended release risperidone microspheres for injection (Risperdal Consta) recommends that patients maintained on the 25 mg dose of this product continue to receive the 25 mg dose when either fluoxetine or paroxetine (strong CYP2D6 inhibitors) is initiated, unless clinical judgment necessitates lowering the dose or interrupting therapy. If a decision is made to lower the dose, the dose may be lowered 2 to 4 weeks before the initiation of fluoxetine or paroxetine.(1) When initiating the product in patients maintained on fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of this dose has not been confirmed in clinical trials.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)

DISCUSSION: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(3) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(3) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(4) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)

Slt Strong Cyp2d6 Inhibitors/Aripiprazole Im Every 2 Months

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP2D6 inhibitor AND a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.

DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)

Slt Strong Cyp2d6 Inhibitors/Aripiprazole Immediate Release

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: The US manufacturer of oral aripiprazole states that the dose of aripiprazole should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine and quinidine are coadministered, unless aripiprazole is being used as adjunctive therapy for Major Depressive Disorder. If the patient is also receiving a strong CYP3A4 inhibitor, the dose of aripiprazole should be reduced to one-fourth its normal dose. When the inhibitor(s) is(are) discontinued, the dose of aripiprazole should be increased.(1)

DISCUSSION: The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)

Slt Strong Cyp2d6 Inhibitors/Risperidone Sq Every 1-2 Months

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms.(2) The manufacturer of extended release risperidone injectable suspension (Uzedy) recommends patients be placed on the lowest dose (50 mg monthly or 100 mg once every 2 months) of Uzedy before the planned start of strong CYP2D6 inhibitor therapy to adjust for the expected increase in risperidone plasma concentrations. When strong CYP2D6 inhibitors are initiated in patients receiving Uzedy 50 mg monthly or 100 mg once every 2 months, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of risperidone treatment.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(3)

DISCUSSION: In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(4) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(5) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(6) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(6) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(7) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(3) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(3) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)

Strong Cyp2d6 Inhibitors/Brexpiprazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of brexpiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are receiving concomitant treatment with a strong or moderate CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor. Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in extensive metabolizers of CYP2D6.(1)

PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a strong CYP2D6 inhibitor: - in patients with major depressive disorder who are taking a strong CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, no dosage adjustment is required. - in patients with major depressive disorder who are taking a strong CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, administer half the usual dosage of brexpiprazole. - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. The dose of brexpiprazole should be adjusted to its original level if the CYP2D6 inhibitor is discontinued.(1)

DISCUSSION: Coadministration of quinidine, a strong inhibitor of CYP2D6, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(2,3)

Strong Cyp2d6 Inhibitors/Codeine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of codeine to its active form, morphine.

CLINICAL EFFECTS: The concurrent administration of codeine and a strong inhibitor of CYP2D6 may result in decreased efficacy of codeine. If a strong CYP2D6 inhibitor is discontinued, the effects of codeine may be increased, including respiratory depression.

PREDISPOSING FACTORS: Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with codeine and a strong CYP2D6 inhibitor should be observed for decreased effectiveness of codeine. Dose increase of codeine may be required, or an alternative analgesic, such as morphine, may need to be considered. After discontinuation of a CYP2D6 inhibitor, consider reducing the dosage of codeine and monitor the patient for signs and symptoms of respiratory depression or sedation.

DISCUSSION: Strong inhibitors of CYP2D6 have been shown to decrease the metabolism of codeine to morphine at CYP2D6. Quinidine has also been shown to decrease cerebrospinal fluid levels of morphine after codeine administration. Concurrent administration resulted in decreased effects of codeine. Strong CYP2D6 inhibitors linked to this monograph are: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.

Strong Cyp2d6 Inhibitors/Deutetrabenazine;Tetrabenazine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: After ingestion, tetrabenazine is rapidly to converted the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and beta-HTBZ). Both alpha and beta-HTBZ are metabolized by CYP2D6. Strong inhibitors of CYP2D6 may inhibit the metabolism of tetrabenazine active metabolites.(1) Deutetrabenazine is a deuterated form of tetrabenazine.(2)

CLINICAL EFFECTS: Concurrent use of a strong CYP2D6 inhibitor may result in increased levels of and adverse effects from deutetrabenazine(2) or tetrabenazine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of deutetrabenazine when administered with a strong inhibitor of CYP2D6 is 36 mg daily (tablets: given as 18 mg twice daily; or extended-release tablets: given as 36 mg daily).(2,3) The maximum recommended dose of tetrabenazine when administered with a strong inhibitor of CYP2D6 is 50 mg daily (given as 25 mg twice daily).(1) Monitor patients receiving concurrent deutetrabenazine or tetrabenazine and a strong CYP2D6 inhibitor for adverse effects, including depression, suicidal thoughts, stiff muscles, trouble swallowing, irritability or agitation, shaking, and restlessness. If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or tetrabenazine may need adjustment.

DISCUSSION: In a study in 24 healthy subjects, following the administration of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively. The area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and 6.5-fold, respectively.(2) In a study in 25 healthy subjects, following the administration of a single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold, respectively. The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and 9-fold, respectively.(1) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(1-4)

Strong Cyp2d6 Inhibitors/Milsaperidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of milsaperidone.(1)

CLINICAL EFFECTS: Concurrent administration of milsaperidone with strong CYP2D6 inhibitors may result in elevated milsaperidone levels and toxicities, including the risk for QTc prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP3A4, which metabolizes milsaperidone.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of milsaperidone states that the maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor, follow the recommended titration schedule in the labeling.(1) Further dose reduction is not required for concurrent administration of milsaperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor. The maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor, follow the recommended titration schedule in the labeling.(1) Due to its long half-life it may take 2 or more weeks to see the full effects of fluoxetine CYP2D6 inhibition on milsaperidone exposure and tolerance. Maximal CYP2D6 inhibitory effects due to paroxetine coadministration are generally expected within one week after initiation or increase in the paroxetine dosage. When the inhibitor is discontinued milsaperidone exposure will wane and the dose of milsaperidone should be titrated to the recommended dose in the labeling.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, fluoxetine (20 mg twice daily for 21 days) increased the area-under-curve (AUC) of iloperidone (3 mg single dose) and milsaperidone by 2-3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(1) In a study in patients with schizophrenia, paroxetine (20 mg daily for 5-8 days) increased the maximum concentration (Cmax) of iloperidone and milsaperidone by about 1.6-fold. The Cmax of iloperidone's P95 metabolite decreased by 50%.(1) Coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(2) Coadministration of ketoconazole (200 mg twice daily, an inhibitor of CYP3A4) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, paroxetine, and terbinafine.(3)

Strong Cyp2d6 Inhibitors/Oliceridine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1)

PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(4)

Strong Cyp2d6 Inhibitors/Pitolisant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of pitolisant at CYP2D6.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from pitolisant including potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer states the concurrent use of pitolisant with strong CYP2D6 inhibitors requires dose adjustment. - Adult patients currently receiving a strong CYP2D6 inhibitor prior to initiation of pitolisant: start pitolisant at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg daily. - Patients 6 years and older weighing <40 kg: start pitolisant at 4.45 mg once daily and increase after 7 days to a maximum dosage of 8.9 mg once daily. - Patients 6 years and older weighing >=40 kg: start pitolisant at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily. May increase after another 7 days to a maximum dosage of 17.8 mg once daily. - All patients who are stable on pitolisant: reduce the dose of pitolisant by half upon initiating a strong CYP2D6 inhibitor.(1) The UK manufacturer states concurrent use of pitolisant with CYP2D6 inhibitors should be done with caution and dose adjustment could be considered.(2) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical study, concurrent use of pitolisant with paroxetine increased the concentration maximum (Cmax) and area-under-curve (AUC) by approximately 1.75 and 2.25, respectively.(1) In two dedicated QT prolongation studies, supra-therapeutic doses of pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen to cause mild to moderate QTc prolongation (10-13 ms). A study in patients who were CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold compared to CYP2D6 extensive metabolizers.(1) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(5,6)

Strong Cyp2d6 Inhibitors/Primaquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of primaquine to its active metabolite.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in reduced antimalarial effect of primaquine due to decreased formation of the active primaquine metabolite.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, consider alternative medications that are not strong CYP2D6 inhibitors. If concurrent therapy is warranted, monitor patients closely for possible relapse.

DISCUSSION: Published clinical reports indicate that primaquine is a CYP2D6 substrate. Reduced CYP2D6 activity may decrease the formation of the active metabolite of primaquine.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)

Strong Cyp2d6 Inhibitors/Risperidone Intramuscular Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The US manufacturer of risperidone for monthly intramuscular injection (Risvan) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor: - Initiation of a CYP2D6 inhibitor: the recommended dose of risperidone is 75 mg started at least 2 to 4 weeks prior to starting a strong CYP2D6 inhibitor to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving risperidone 75 mg, it is recommended to continue treatment with 75 mg unless clinical judgment necessitates interruption of risperidone treatment. - Discontinuation of a CYP2D6 inhibitor: the effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite) have not been studied.(1)

DISCUSSION: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(2) A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(3) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(4) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)

Strong Cyp2d6 Inhibitors/Risperidone Sq Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The manufacturer of extended release risperidone injectable suspension (Perseris) recommends patients be placed on the lowest dose (90 mg) of Perseris two to four weeks before the planned start of a strong CYP2D6 inhibitor to adjust for the expected increase in risperidone plasma concentrations. When a strong CYP2D6 inhibitor is initiated in patients receiving Perseris 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of risperidone treatment.(1)

DISCUSSION: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(2) A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(3) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(4) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)

Strong Cyp2d6 Inhibitors/Valbenazine (<=40 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valbenazine's active metabolite (alpha-HTBZ) is metabolized by CYP2D6 and CYP3A4.(1) Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors of CYP2D6.(2,3)

CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine or terbinafine may result in elevated levels and adverse effects of valbenazine such as somnolence and QT prolongation.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its own metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(2) Concurrent use of strong CYP3A4 inhibitors may further increase levels of valbenazine.(1)

PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP2D6 inhibitor.(1) During concomitant therapy with a strong CYP2D6 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine did not affect valbenazine maximum concentration (Cmax) or area-under-the-curve (AUC). However, Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold, respectively. Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.

Terbinafine/Selected Cyp2d6 Substrates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Terbinafine is a strong inhibitor of CYP2D6 and may convert patients from the extensive metabolizer to poor metabolizer phenotype for this enzyme.(1)

CLINICAL EFFECTS: Concurrent use of terbinafine may result in increased serum levels and adverse effects of drugs primarily metabolized by or sensitive to changes in the activity of the CYP2D6 metabolic pathway.(1,2)

PREDISPOSING FACTORS: With paroxetine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Terbinafine has a serum half-life of approximately 36 hours, so the maximal effect of this interaction may be delayed for one to two weeks. Extended monitoring may be necessary. Patients receiving therapy with agents primarily metabolized by CYP2D6 need increased monitoring for adverse effects and may need a dose reduction. Plasma level monitoring should be considered in patients receiving flecainide.(4) The effect of terbinafine on CYP2D6 substrates may last for up to four weeks after terbinafine discontinuation. Over time, patients previously stabilized on the combination of terbinafine and a selected CYP2D6 substrate may need an increase in the dose of the CYP2D6 metabolized drug.

DISCUSSION: In a randomized, placebo-controlled trial in 12 healthy subjects, terbinafine (150 mg daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of paroxetine (20 mg) by 2.9-fold and 1.9-fold, respectively.(6) In a placebo-controlled trial in 12 healthy males, terbinafine (250 mg for 4 days) increased the Cmax and AUC of a single dose of venlafaxine (75 mg) by 2.67-fold and 4.9-fold, respectively.(7) CYP2D6 substrates linked to this monograph are: dapoxetine, flecainide, metoprolol, nebivolol, paroxetine, perphenazine, propafenone, propranolol, venlafaxine and yohimbine.

Terbinafine/Tricyclic Compounds

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Terbinafine may inhibit the metabolism of tricyclic compounds by CYP2D6.(1-5)

CLINICAL EFFECTS: Concurrent use of terbinafine may result in elevated levels of and toxicity from the tricyclic agent.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: Monitor tricyclic levels in patients receiving concurrent therapy with terbinafine. The dose of the tricyclic agent may need to be adjusted if terbinafine is initiated or discontinued. The effect of terbinafine on tricyclics may last for up to four weeks after terbinafine discontinuation.

DISCUSSION: In a study in 12 healthy subjects, a single dose of desipramine (50 mg) was given alone, after 21 days of terbinafine (250 mg daily), and 2 and 4 weeks after discontinuation of terbinafine. Administration after 21 days of terbinafine therapy increased the area-under-curve (AUC) and maximum concentration (Cmax) of desipramine by 5-fold and 2-fold, respectively. The AUC and Cmax of desipramine were still elevated when desipramine was administered 4 weeks after the completion of terbinafine therapy.(1,2) There are case reports of toxicity during concurrent terbinafine and desipramine,(3) imipramine,(4) and nortriptyline.(5,7-8) In the UK manufacturer states that terbinafine decreased the clearance of desipramine by 82%.(9)

Weak Cyp3a4 Inducers/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

Hypersensitivity to terbinafine or any ingredient in the formulation.

• Disease of liver

• Severe neutropenic disorder

• Depression
• Systemic lupus erythematosus

The most frequent adverse effects of oral terbinafine are GI effects (diarrhea, dyspepsia, nausea, vomiting, abdominal pain, taste disturbances), headache, fever, upper respiratory tract infection or symptoms (cough, nasopharyngitis, nasal congestion, pharyngolaryngeal pain, influenza), liver test abnormalities, and dermatologic effects (rash, urticaria, pruritus).

More Frequent

• Abnormal hepatic function tests
• Skin rash

Less Frequent

• Urticaria
• Visual changes

Rare or Very Rare

• Acute eruptions of skin
• Acute generalized exanthematous pustulosis
• Acute hepatic failure
• Acute lupus erythematosus
• Agranulocytosis
• Anemia
• Angioedema
• Bullous dermatitis
• Cholestasis
• DRESS syndrome
• Drug-induced hepatitis
• Eosinophilia
• Erythema multiforme
• Hearing loss
• Hemolytic uremic syndrome
• Hypersensitivity pneumonitis
• Loss of sense of smell
• Myocarditis
• Nephritis
• Neutropenic disorder
• Pancreatitis
• Pancytopenia
• Pericarditis
• Psoriasiform eruption
• Rhabdomyolysis
• Serum sickness
• Stevens-johnson syndrome
• Systemic lupus erythematosus
• Thrombocytopenic disorder
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis
• Vasculitis

More Frequent

• Acute abdominal pain
• Diarrhea
• Dysgeusia
• Dyspepsia
• Flatulence
• Headache disorder
• Pruritus of skin

Less Frequent

• Lymphopenia
• Nausea
• Upper abdominal pain
• Vomiting

Rare or Very Rare

• Alopecia
• Arthralgia
• Depression
• Fatigue
• Fever
• Flu-like symptoms
• Loss of taste
• Malaise
• Myalgia
• Parosmia
• Skin photosensitivity
• Tinnitus
• Vertigo

No enhanced messaging available.

Safety and efficacy of terbinafine tablets not established in children younger than 18 years of age.

Safety and efficacy of terbinafine oral granules not established in children younger than 4 years of age.

Category B. (See Users Guide.)

The manufacturer recommends that use of oral terbinafine be postponed until after pregnancy is completed.

Distributed into milk. Use not recommended.

Terbinafine oral granules have not been studied in geriatric patients.