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Nefazodone: Drug information

Nefazodone: Drug information
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For additional information see "Nefazodone: Patient drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Suicidality and antidepressants:

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Anyone considering the use of nefazodone or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared with placebo in adults aged ≥65 years. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nefazodone is not approved for use in pediatric patients.

Hepatotoxicity:

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone treatment. The total patient-years is a summation of each patient's duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc.

Ordinarily, treatment with nefazodone should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that preexisting liver disease increases the likelihood of developing liver failure; however, baseline abnormalities can complicate patient monitoring.

Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, jaundice, anorexia, GI complaints, malaise) and to report them to their doctor immediately if they occur.

Nefazodone tablets should be discontinued if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥3 times the ULN, while on nefazodone tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone is reintroduced. Accordingly, such patients should not be considered for re-treatment.

Pharmacologic Category
  • Antidepressant, Serotonin Reuptake Inhibitor/Antagonist;
  • Serotonin Modulator
Dosing: Adult
Depression

Depression: Oral: Initial: 100 mg twice daily; alternatively, depression treatment guidelines suggest starting doses of 50 to 100 mg/day (Ref). Based on response and tolerability, gradually increase dose in increments of 100 to 200 mg/day (in 2 divided doses) and intervals ≥1 week to a usual dose of 150 to 600 mg/day in 2 divided doses.

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, gradually taper the dose (eg, over 2 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks), may taper over 1 to 2 weeks; <2 weeks treatment generally does not warrant tapering (Ref). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Ref).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of nefazodone.

Allow at least 7 days to elapse between discontinuing nefazodone and initiation of an MAOI.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; however, adjustment unlikely since renal impairment does not alter steady state nefazodone plasma concentrations.

Dosing: Liver Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; however, use with caution because the AUC of nefazodone and its metabolites are ~25% greater in patients with cirrhosis. Use is contraindicated in patients with liver injury due to previous nefazodone treatment, and ordinarily should not be initiated in patients with active liver disease or elevated baseline serum transaminases.

Dosing: Older Adult

Depression: Oral: Initial: 50 mg twice daily; gradually increase dose based on response and tolerability

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Central nervous system: Headache (36%), drowsiness (16% to 28%), dizziness (10% to 22%), insomnia (11%), agitation

Gastrointestinal: Xerostomia (25%), nausea (22%), constipation (14%)

Neuromuscular & skeletal: Weakness (11%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (4%), vasodilation (4%), peripheral edema (3%), hypotension (2%), bradycardia

Central nervous system: Confusion (2% to 8%), memory impairment (4%), paresthesia (4%), abnormal dreams (3%), lack of concentration (3%), ataxia (2%), chills (2%), psychomotor retardation (2%), hypertonia (1%)

Dermatologic: Pruritus (2%), skin rash (2%)

Endocrine & metabolic: Decreased libido (1%), increased thirst (1%)

Gastrointestinal: Dyspepsia (9%), diarrhea (8%), increased appetite (5%), dysgeusia (2%), vomiting (2%), gastroenteritis

Genitourinary: Urinary frequency (2%), urinary retention (2%), mastalgia (1%), impotence

Hematologic & oncologic: Decreased hematocrit (3%)

Infection: Infection (8%)

Neuromuscular & skeletal: Tremor (2%), arthralgia (1%), neck stiffness (1%)

Ophthalmic: Visual disturbance (7% to 10%), blurred vision (3% to 9%), visual field defect (2%), eye pain

Otic: Tinnitus (2% to 3%)

Respiratory: pharyngitis (6%), cough (3%), flu-like symptoms (3%), bronchitis, dyspnea

Miscellaneous: Fever (2%)

<1%, postmarketing, and/or case reports: Abnormal gait, abnormal hepatic function tests, abnormality in thinking, accommodation disturbance, acne vulgaris, ageusia, alopecia, amenorrhea, anemia, angina pectoris, angioedema, angle-closure glaucoma, anorgasmia, apathy, arthritis, asthma, atrioventricular block, attempted suicide, breast hypertrophy, bruise, bursitis, cardiac failure, cellulitis, cerebrovascular accident, colitis, conjunctivitis, convulsions, cystitis, deafness, dehydration, depersonalization, derealization, diplopia, disturbance in attention, dry eye syndrome, dysarthria, eczema, ejaculatory disorder, enlargement of abdomen, epistaxis, eructation, esophagitis, euphoria, facial edema, galactorrhea, gastritis, gingivitis, gout, gynecomastia, halitosis, hallucination, hangover effect, heavy eyelids, hematuria, hemorrhage, hepatic failure, hepatic necrosis, hepatitis, hernia, hiccups, hostility, hyperacusis, hypercholesterolemia, hyperesthesia, hyperkinesia, hypermenorrhea, hypersensitivity reaction, hypertension, hyperventilation, hypoglycemia, hyponatremia, hypotonia, increased lactate dehydrogenase, increased libido, increased serum alt, increased serum ast, increased serum prolactin, keratoconjunctivitis, laryngitis, leukopenia, lymphadenopathy, maculopapular rash, malaise, muscle rigidity, mydriasis, myoclonus, nephrolithiasis, neuralgia, neuroleptic malignant syndrome, nocturia, nocturnal amblyopia, oliguria, oral candidiasis, oral mucosa ulcer, otalgia, pallor, paranoia, pelvic pain, peptic ulcer, periodontal abscess, photophobia, pneumonia, polyuria, priapism, rectal hemorrhage, rhabdomyolysis, seizure, serotonin syndrome (with lovastatin/simvastatin), sialorrhea, skin photosensitivity, stevens-johnson syndrome, stomatitis, suicidal ideation, syncope, tachycardia, tendinopathy, tendinous contracture, tenosynovitis, thrombocytopenia, tonic-clonic seizures, twitching, ulcerative colitis, urinary incontinence, urinary urgency, urticaria, uterine fibroid enlargement, uterine hemorrhage, vaginal hemorrhage, varicose veins, ventricular premature contractions, vertigo, vesicobullous dermatitis, voice disorder, weight loss, xeroderma, yawning

Contraindications

Hypersensitivity to nefazodone, related compounds (phenylpiperazines), or any component of the formulation; liver injury due to previous nefazodone treatment; concurrent use with carbamazepine, cisapride, terfenadine, astemizole, or pimozide; concurrent therapy with triazolam is generally contraindicated (dosage must be reduced by 75% for triazolam; such reductions may not be possible with available dosage forms).

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Nefazodone is not FDA approved for use in children.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression occurs.

Concerns related to adverse effects:

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is very low relative to other antidepressants (APA 2010).

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). The degree of sedation is moderate relative to other antidepressants (Bauer 2013).

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

• Hepatic failure: Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone treatment, which is 3 to 4 times the estimated background rate of liver failure. There is no evidence that preexisting liver disease increases the likelihood of developing liver failure; however, baseline abnormalities can complicate patient monitoring. The time to liver injury in reported, severe cases ranged from 2 weeks to 6 months; not all cases had a clear prodromal onset of symptoms. Treatment should not ordinarily be initiated in patients with active liver disease or elevated baseline serum transaminases. There is no evidence that periodic monitoring of serum transaminases will prevent serious hepatic injury, but it can be used for early detection in symptomatic patients. Nefazodone tablets should be discontinued if clinical signs or symptoms (such as jaundice, anorexia, GI complaints, malaise, or increased serum AST or ALT levels ≥3 times the ULN) suggest liver failure. Patients who develop symptoms while on nefazodone should not be considered for re-treatment. Doses as low as 100 mg/day have been associated with hepatotoxicity (Stewart 2002).

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Orthostatic hypotension: May cause orthostatic hypotension (risk is low relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, dehydration, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

• Sexual dysfunction: Rare reports of priapism have occurred. The incidence of sexual dysfunction with nefazodone is generally lower than with SSRIs (APA 2010; Bauer 2013).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk conduction abnormalities with this agent is very low relative to other antidepressants (APA 2010; Bauer 2013).

• Hepatic impairment: [US Boxed Warning]: Ordinarily, treatment with nefazodone should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. Use with caution in patients with hepatic impairment.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Nefazodone is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications that may lower seizure threshold.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant, but commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

Generic: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablets (Nefazodone HCl Oral)

50 mg (per each): $4.69

100 mg (per each): $4.80

150 mg (per each): $4.89

200 mg (per each): $4.98

250 mg (per each): $5.07

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Administer with or without food. Dosing after meals may decrease lightheadedness and postural hypotension, but may also decrease absorption and therefore effectiveness.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm100211.pdf, must be dispensed with this medication.

Use: Labeled Indications

Depression: Treatment of depression

Medication Safety Issues
Sound-alike/look-alike issues:

Serzone may be confused with selegiline, Seroquel, sertraline

Metabolism/Transport Effects

Substrate of CYP2D6 (Minor), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (Strong);

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily. Risk D: Consider Therapy Modification

Acalabrutinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Acalabrutinib. Risk X: Avoid

Acrivastine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Acrivastine. Risk C: Monitor

Adagrasib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Adagrasib. Management: Avoid use of adagrasib and strong CYP3A4 inhibitors until adagrasib concentrations have reached steady state (ie, after approximately 8 days of therapy). Risk D: Consider Therapy Modification

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Management: Avoid concomitant use of ado-trastuzumab emtansine and strong CYP3A4 inhibitors when possible. Consider alternatives that do not inhibit CYP3A4 or consider administering after CYP3A4 inhibitor discontinuation. Monitor for toxicities if combined. Risk D: Consider Therapy Modification

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Alfuzosin. Risk X: Avoid

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Almotriptan: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Almotriptan. Management: Limit the initial almotriptan dose to 6.25 mg when combined with nefazodone, and do not exceed 12.5 mg in any 24-hour period. Avoid concomitant use in patients with impaired hepatic or renal function. Monitor for serotonin syndrome. Risk D: Consider Therapy Modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase serum concentration of Alosetron. Risk C: Monitor

Alosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

ALPRAZolam: Nefazodone may increase serum concentration of ALPRAZolam. Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider Therapy Modification

Amiodarone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Amiodarone. Management: Consider alternatives to use of amiodarone and strong CYP3A4 inhibitors. If combined, monitor for increased amiodarone concentrations and toxicities. Risk D: Consider Therapy Modification

AmLODIPine: CYP3A4 Inhibitors (Strong) may increase serum concentration of AmLODIPine. Risk C: Monitor

Amphetamines: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor

Antiemetics (5HT3 Antagonists): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Antipsychotic Agents: Serotonergic Agents (High Risk) may increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Apalutamide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Apalutamide. Risk C: Monitor

Apixaban: CYP3A4 Inhibitors (Strong) may increase serum concentration of Apixaban. Risk C: Monitor

Aprepitant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Aprepitant. Risk X: Avoid

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP3A4 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg). Max dose is 441 mg in CYP2D6 PMs or if also taking strong CYP2D6 inhibitors. Risk D: Consider Therapy Modification

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, CYP2D6 genotype, and use of CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider Therapy Modification

Artemether and Lumefantrine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Artemether and Lumefantrine. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be increased. Risk C: Monitor

Asciminib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Asciminib. Risk C: Monitor

Atazanavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Atazanavir. Risk C: Monitor

Atogepant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended atogepant dose is 10 mg once daily with a concurrent strong CYP3A4 inhibitor. If used for treatment of chronic migraine, concurrent use of atogepant with strong CYP3A4 inhibitors should be avoided. Risk D: Consider Therapy Modification

Atorvastatin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Atorvastatin. Risk C: Monitor

Avacopan: CYP3A4 Inhibitors (Strong) may increase serum concentration of Avacopan. Management: Decrease the avacopan dose to 30 mg once daily during coadministration with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Avanafil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Avanafil. Risk X: Avoid

Avapritinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Avapritinib. Risk X: Avoid

Axitinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Risk D: Consider Therapy Modification

Barnidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Barnidipine. Risk X: Avoid

Beclomethasone (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Beclomethasone (Systemic). Risk C: Monitor

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase serum concentration of Bedaquiline. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Bedaquiline. Risk C: Monitor

Benidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Benidipine. Risk C: Monitor

Benperidol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Benperidol. Risk C: Monitor

Betamethasone (Nasal): CYP3A4 Inhibitors (Strong) may increase serum concentration of Betamethasone (Nasal). Risk C: Monitor

Betamethasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Betamethasone (Ophthalmic). Risk C: Monitor

Betamethasone (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Betamethasone (Systemic). Risk C: Monitor

Betamethasone (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Betamethasone (Topical). Risk C: Monitor

Blonanserin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Blonanserin. Risk X: Avoid

Bortezomib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Bortezomib. Risk C: Monitor

Bosentan: CYP3A4 Inhibitors (Strong) may increase serum concentration of Bosentan. Risk C: Monitor

Bosutinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Bosutinib. Risk X: Avoid

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor

Brexanolone: Serotonin Reuptake Inhibitor/Antagonists may increase CNS depressant effects of Brexanolone. Risk C: Monitor

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a strong CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. Risk D: Consider Therapy Modification

Brigatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider Therapy Modification

Bromocriptine: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Bromocriptine. Management: Consider alternatives to this combination. If combined, monitor for increased bromocriptine toxicities and consider bromocriptine dose reductions. Additionally, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity. Risk D: Consider Therapy Modification

Bromperidol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Bromperidol. Risk C: Monitor

Brotizolam: CYP3A4 Inhibitors (Strong) may increase serum concentration of Brotizolam. Risk C: Monitor

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase serum concentration of Budesonide (Nasal). Risk C: Monitor

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase serum concentration of Budesonide (Oral Inhalation). Management: Consider alternatives to this combination when possible. If combined, monitor for increased corticosteroid adverse effects during coadministration of inhaled budesonide and strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Budesonide (Systemic). Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and a strong CYP3A4 inhibitor, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider Therapy Modification

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Budesonide (Topical). Risk X: Avoid

BusPIRone: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of BusPIRone. Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities, including serotonin syndrome, if combined with nefazodone. Risk D: Consider Therapy Modification

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Risk D: Consider Therapy Modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, decrease cabozantinib capsules (Cometriq) by 40 mg from previous dose or decrease cabozantinib tablets (Cabometyx) by 20 mg from previous dose. Risk D: Consider Therapy Modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Calcifediol. Risk C: Monitor

Calcitriol (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Calcitriol (Systemic). Risk C: Monitor

Cannabidiol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cannabidiol. Risk C: Monitor

Cannabis: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Risk C: Monitor

Capivasertib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Capivasertib. Management: Avoid concomitant use of capivasertib with strong CYP3A4 inhibitors when possible. If combined, reduce the capivasertib dose to 320 mg twice daily for 4 days, followed by 3 days off. Monitor patients closely for adverse reactions. Risk D: Consider Therapy Modification

Capmatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Capmatinib. Risk C: Monitor

CarBAMazepine: Nefazodone may increase serum concentration of CarBAMazepine. Also, concentrations of the active CarBAMazepine epoxide metabolite may be reduced. CarBAMazepine may decrease serum concentration of Nefazodone. Concentrations of active Nefazodone metabolites may also be reduced. Risk X: Avoid

Cariprazine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cariprazine. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. Management: Cariprazine dose adjustments are recommended and depend upon whether a patient is initiating a strong CYP3A4 inhibitor or cariprazine, as well as cariprazine indication. See full mono for details. Some non-US labels contraindicate this combination. Risk D: Consider Therapy Modification

Ceritinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ceritinib. Management: Avoid this combination whenever possible. If combined, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

ChlordiazePOXIDE: CYP3A4 Inhibitors (Strong) may increase serum concentration of ChlordiazePOXIDE. Risk C: Monitor

Ciclesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Ciclesonide (Oral Inhalation). Risk C: Monitor

Cilnidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cilnidipine. Risk C: Monitor

Cilostazol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cilostazol. Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Cinacalcet: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cinacalcet. Risk C: Monitor

Cisapride: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cisapride. Risk X: Avoid

Clarithromycin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Clarithromycin. CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Clarithromycin. Risk C: Monitor

Clindamycin (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Clindamycin (Systemic). Risk C: Monitor

ClonazePAM: CYP3A4 Inhibitors (Strong) may increase serum concentration of ClonazePAM. Risk C: Monitor

CloZAPine: CYP3A4 Inhibitors (Strong) may increase serum concentration of CloZAPine. Risk C: Monitor

Cobicistat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cobicistat. Risk C: Monitor

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cobimetinib. Risk X: Avoid

Colchicine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Colchicine. Management: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of P-gp inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: Consider Therapy Modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase serum concentration of Conivaptan. Risk X: Avoid

Copanlisib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities. Risk D: Consider Therapy Modification

Cortisone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cortisone. Risk C: Monitor

Crizotinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors whenever possible. If combined use cannot be avoided, crizotinib dose reductions are required, which vary according to indication. See full interaction monograph for details. Risk D: Consider Therapy Modification

Cyclobenzaprine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

CycloSPORINE (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of CycloSPORINE (Systemic). Management: Monitor cyclosporine serum concentrations and clinical cyclosporine closely with concurrent use of any strong CYP3A4 inhibitor. Cyclosporine dose reductions and/or prolongation of the dosing interval will likely be required. Risk D: Consider Therapy Modification

Cyproterone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Cyproterone. Risk C: Monitor

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dabrafenib. Management: Consider alternatives to any strong CYP3A4 inhibitor for patients being treated with dabrafenib. If such a combination cannot be avoided, monitor closely for evidence of dabrafenib-related adverse effects. Risk D: Consider Therapy Modification

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Dapoxetine: Nefazodone may increase serotonergic effects of Dapoxetine. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Dapoxetine. Management: Do not use nefazodone with dapoxetine or within 7 days of dapoxetine discontinuation. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid

Daridorexant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Daridorexant. Risk X: Avoid

Darifenacin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Darifenacin. Management: Limit the darifenacin dose to no more than 7.5 mg daily if combined with strong CYP3A4 inhibitors. Monitor patients for increased darifenacin toxicities (eg, dry mouth, constipation, headache, CNS effects) when these agents are combined. Risk D: Consider Therapy Modification

Darunavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Darunavir. Risk C: Monitor

Dasatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dasatinib. Management: This combination should be avoided if possible. If combined, decrease dasatinib dose from 140 mg to 40 mg, 100 mg to 20 mg, or 70 mg to 20 mg. For patients taking 60 mg or 40 mg daily, stop dasatinib until the CYP3A4 inhibitor is discontinued. Risk D: Consider Therapy Modification

Deflazacort: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Delamanid: CYP3A4 Inhibitors (Strong) may increase serum concentration of Delamanid. Management: Increase ECG monitoring frequency if delamanid is combined with strong CYP3A4 inhibitors due to the risk for QTc interval prolongation. Continue frequent ECG assessments throughout full delamanid treatment period. Risk D: Consider Therapy Modification

DexAMETHasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase serum concentration of DexAMETHasone (Ophthalmic). Risk C: Monitor

DexAMETHasone (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of DexAMETHasone (Systemic). Risk C: Monitor

Dexmethylphenidate-Methylphenidate: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Dextromethorphan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

DiazePAM: CYP3A4 Inhibitors (Strong) may increase serum concentration of DiazePAM. Risk C: Monitor

Diazoxide Choline: CYP3A4 Inhibitors (Strong) may increase serum concentration of Diazoxide Choline. Risk C: Monitor

Dienogest: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dienogest. Risk C: Monitor

Digitoxin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Digitoxin. Risk C: Monitor

Digoxin: Nefazodone may increase serum concentration of Digoxin. Risk C: Monitor

DilTIAZem: CYP3A4 Inhibitors (Strong) may increase serum concentration of DilTIAZem. Risk C: Monitor

Disopyramide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Disopyramide. Risk C: Monitor

DOCEtaxel: CYP3A4 Inhibitors (Strong) may increase serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities. Risk D: Consider Therapy Modification

Dofetilide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dofetilide. Risk C: Monitor

Domperidone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Domperidone. Risk X: Avoid

Doxazosin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Doxazosin. Risk C: Monitor

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Doxercalciferol. Risk C: Monitor

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase serum concentration of DOXOrubicin (Conventional). Risk X: Avoid

DOXOrubicin (Liposomal): CYP3A4 Inhibitors (Strong) may increase serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor

DroNABinol: CYP3A4 Inhibitors (Strong) may increase serum concentration of DroNABinol. Risk C: Monitor

Dronedarone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dronedarone. Risk X: Avoid

Dutasteride: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dutasteride. Risk C: Monitor

Duvelisib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor. Monitor closely for evidence of altered response to treatment. Risk D: Consider Therapy Modification

Dydrogesterone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Dydrogesterone. Risk C: Monitor

Ebastine: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Ebastine. CYP3A4 Inhibitors (Strong) may increase serum concentration of Ebastine. Risk C: Monitor

Efonidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Efonidipine. Risk C: Monitor

Elacestrant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Elacestrant. Risk X: Avoid

Elagolix, Estradiol, and Norethindrone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Elagolix, Estradiol, and Norethindrone. Elagolix, Estradiol, and Norethindrone may decrease serum concentration of CYP3A4 Inhibitors (Strong). Specifically, concentrations of strong CYP3A4 inhibitors that are also CYP3A4 substrates may be decreased. Risk X: Avoid

Elagolix: CYP3A4 Inhibitors (Strong) may increase serum concentration of Elagolix. Management: Use of the elagolix 200 mg twice daily dose with a strong CYP3A4 inhibitor for longer than 1 month is not recommended. Limit combined use of the elagolix 150 mg once daily dose with a strong CYP3A4 inhibitor to a maximum of 6 months. Risk D: Consider Therapy Modification

Elbasvir and Grazoprevir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Elbasvir and Grazoprevir. Management: Consider alternatives to this combination when possible. If combined, monitor for increased elbasvir/grazoprevir toxicities, including ALT elevations. Risk D: Consider Therapy Modification

Eletriptan: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Eletriptan. Risk X: Avoid

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Management: Administer elexacaftor/tezacaftor/ivacaftor in the morning, twice a week, 3 to 4 days apart, with no evening doses of ivacaftor alone. Specific dosing varies by age and weight. See full monograph for details. Risk D: Consider Therapy Modification

Eliglustat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Eliglustat. Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with strong CYP3A4 inhibitors. Use of strong CYP3A4 inhibitors is contraindicated in CYP2D6 IMs, PMs, or in CYP2D6 EMs who are also taking strong or moderate CYP2D6 inhibitors. Risk D: Consider Therapy Modification

Encorafenib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Encorafenib. Management: Avoid use of encorafenib and strong CYP3A4 inhibitors when possible. If combined, decrease encorafenib from 450 mg to 150 mg; or from 300 mg, 225 mg, or 150 mg to 75 mg. Once the CYP3A4 inhibitor is discontinued for 3 to 5 half-lives, resume prior dose. Risk D: Consider Therapy Modification

Ensartinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ensartinib. Risk X: Avoid

Entrectinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors if possible. If needed, reduce entrectinib dose to 50 mg on alternating days if starting dose 200 mg; to 50 mg/day if starting dose 300 mg or 400 mg; to 100 mg/day if starting dose 600 mg. Risk D: Consider Therapy Modification

Enzalutamide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Enzalutamide. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Enzalutamide. Risk C: Monitor

Epinephrine (Racemic): Serotonin Reuptake Inhibitor/Antagonists may increase adverse/toxic effects of Epinephrine (Racemic). Risk X: Avoid

Eplerenone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Eplerenone. Risk X: Avoid

Erdafitinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly. Risk D: Consider Therapy Modification

Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): Nefazodone may increase serotonergic effects of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates). This could result in serotonin syndrome. Nefazodone may increase serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates). Risk X: Avoid

Ergot Derivatives: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Erlotinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of erlotinib-associated adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Risk D: Consider Therapy Modification

Erythromycin (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Erythromycin (Systemic). Management: Consider alternatives to this combination when possible. If combined, monitor for increased erythromycin effects and toxicities, including QTc interval prolongation. Risk D: Consider Therapy Modification

Esketamine (Injection): CYP3A4 Inhibitors (Strong) may increase serum concentration of Esketamine (Injection). Risk C: Monitor

Estrogen Derivatives: CYP3A4 Inhibitors (Strong) may increase serum concentration of Estrogen Derivatives. Risk C: Monitor

Eszopiclone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Risk D: Consider Therapy Modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase serum concentration of Etizolam. Risk C: Monitor

Etravirine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Etravirine. Risk C: Monitor

Everolimus: CYP3A4 Inhibitors (Strong) may increase serum concentration of Everolimus. Management: Consider avoiding use of strong CYP3A4 inhibitors with everolimus. If combined, closely monitor for increased everolimus serum concentrations and toxicities. Everolimus dose reductions will likely be required. Risk D: Consider Therapy Modification

Evogliptin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Evogliptin. Risk C: Monitor

Fedratinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated. Risk D: Consider Therapy Modification

Felodipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Felodipine. Management: Consider using lower felodipine doses when combined with strong CYP3A4 inhibitors. Monitor patients for increased felodipine effects and toxicities (eg, hypotension, edema) when combined. Risk D: Consider Therapy Modification

Fenfluramine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

FentaNYL: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of FentaNYL. Management: Consider reducing fentanyl dose. Monitor for signs and symptoms of respiratory depression, sedation, and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia) when these agents are combined. Risk D: Consider Therapy Modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Fesoterodine. Management: Limit fesoterodine doses to 4 mg daily in patients who are also receiving strong CYP3A4 inhibitors. This combination is not recommended in pediatric patients weighing 25 kg up to 35 kg. Risk D: Consider Therapy Modification

Fexinidazole: CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Fexinidazole. Management: Avoid use of fexinidazole and strong CYP3A4 inhibitors when possible. If combined, monitor for reduced fexinidazole efficacy. Risk D: Consider Therapy Modification

Finerenone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Finerenone. Risk X: Avoid

Flibanserin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Flibanserin. Management: Use of flibanserin with strong CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid

Flunitrazepam: CYP3A4 Inhibitors (Strong) may increase serum concentration of Flunitrazepam. Risk C: Monitor

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase serum concentration of Fluticasone (Nasal). Risk X: Avoid

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase serum concentration of Fluticasone (Oral Inhalation). Management: Consider alternatives to this combination if possible. Coadministration of fluticasone propionate and strong CYP3A4 inhibitors is not recommended. If combined, monitor patients for systemic corticosteroid adverse effects (eg, adrenal suppression). Risk D: Consider Therapy Modification

Fluticasone (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Fluticasone (Topical). Risk C: Monitor

Fosamprenavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Fosamprenavir. Risk C: Monitor

Fosaprepitant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Fosaprepitant. Risk X: Avoid

Fostamatinib: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Fostamatinib. Risk C: Monitor

Gefitinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Gefitinib. Risk C: Monitor

Gepirone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Gepirone. Risk X: Avoid

Gepotidacin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Gepotidacin. Management: Avoid coadministration of gepotidacin and strong CYP3A4 inhibitors if possible. If coadministration cannot be avoided, conduct a baseline ECG, monitor closely for altered electrolytes, and correct electrolyte abnormalities as needed. Risk D: Consider Therapy Modification

Gilteritinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Gilteritinib. Management: Consider alternatives to the use of a strong CYP3A4 inhibitor with gilteritinib. If the combination cannot be avoided, monitor more closely for evidence of gilteritinib toxicities. Risk D: Consider Therapy Modification

Glasdegib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib. Risk D: Consider Therapy Modification

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase serum concentration of GuanFACINE. Management: Reduce the extended-release guanfacine dose 50% when combined with a strong CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider Therapy Modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Halofantrine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for halofantrine toxicities, including QTc interval prolongation. Risk D: Consider Therapy Modification

Haloperidol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Haloperidol. Risk C: Monitor

Hormonal Contraceptives: CYP3A4 Inhibitors (Strong) may increase serum concentration of Hormonal Contraceptives. Risk C: Monitor

Hydrocortisone (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Hydrocortisone (Systemic). Risk C: Monitor

Ibrexafungerp: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ibrexafungerp. Management: Decrease the ibrexafungerp dose to 150 mg every 12 hours for 2 doses in patients receiving strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued. Risk X: Avoid

Idelalisib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Idelalisib. Management: Use alternative therapies that are not strong CYP3A4 inhibitors whenever possible. If unable to use alternative drugs, monitor patients more frequently for idelalisib toxicities. Risk D: Consider Therapy Modification

Ifosfamide: CYP3A4 Inhibitors (Strong) may increase adverse/toxic effects of Ifosfamide. CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Ifosfamide. Risk C: Monitor

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Iloperidone. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Imatinib. Risk C: Monitor

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Imidafenacin. Risk C: Monitor

Indinavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Indinavir. Risk C: Monitor

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. Management: Avoid administration of strong CYP3A4 inhibitors during and within 1 week prior to irinotecan administration, unless no therapeutic alternatives to these agents exist. If combined, monitor closely for increased irinotecan toxicities. Risk D: Consider Therapy Modification

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Risk X: Avoid

Isradipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Isradipine. Risk C: Monitor

Istradefylline: CYP3A4 Inhibitors (Strong) may increase serum concentration of Istradefylline. Management: Limit the maximum istradefylline dose to 20 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased istradefylline effects/toxicities. Risk D: Consider Therapy Modification

Itraconazole: CYP3A4 Inhibitors (Strong) may increase serum concentration of Itraconazole. Risk C: Monitor

Ivabradine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ivabradine. Risk X: Avoid

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full drug interaction monograph content for age- and weight-specific recommendations. Risk D: Consider Therapy Modification

Ivosidenib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ivosidenib. Management: Avoid use of a strong CYP3A4 inhibitor with ivosidenib whenever possible. When combined use is required, reduce the ivosidenib dose to 250 mg once daily and monitor for increased ivosidenib toxicities, including QTc interval prolongation. Risk D: Consider Therapy Modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ixabepilone. Management: Avoid use of ixabepilone and strong CYP3A4 inhibitors when possible. If combined, reduce the ixabepilone dose to 20 mg/m2. The previous ixabepilone dose can be resumed 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Ketamine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ketamine. Risk C: Monitor

Ketoconazole (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Ketoconazole (Systemic). Risk C: Monitor

Lacidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lacidipine. Risk C: Monitor

Lapatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lapatinib. Management: Avoid use of lapatinib and strong CYP3A4 inhibitors when possible. If combined, a reduced lapatinib dose of 500 mg daily should be considered. The previous lapatinib dose can be resumed 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Larotrectinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor's half-life. Risk D: Consider Therapy Modification

Lasmiditan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Lefamulin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4. Risk X: Avoid

Lemborexant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lemborexant. Risk X: Avoid

Leniolisib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Leniolisib. Risk X: Avoid

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lercanidipine. Risk X: Avoid

Leuprolide and Norethindrone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Leuprolide and Norethindrone. Specifically, concentrations of norethindrone may increase. Risk C: Monitor

Levamlodipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Levamlodipine. Risk C: Monitor

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Levobupivacaine. Risk C: Monitor

Levoketoconazole: CYP3A4 Inhibitors (Strong) may increase serum concentration of Levoketoconazole. Risk X: Avoid

Levomilnacipran: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Levomilnacipran. Management: Limit the levomilnacipran dose to 80 mg daily and monitor patients for increased levomilnacipran effects/toxicities, including serotonin syndrome, if combined with nefazodone. Risk D: Consider Therapy Modification

Lidocaine (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Lidocaine (Systemic). Risk C: Monitor

Linezolid: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Risk X: Avoid

Lomitapide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lomitapide. Risk X: Avoid

Lonafarnib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lonafarnib. Risk X: Avoid

Lopinavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lopinavir. Risk C: Monitor

Lorlatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily. Risk D: Consider Therapy Modification

Lovastatin: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Lovastatin. CYP3A4 Inhibitors (Strong) may increase serum concentration of Lovastatin. Risk X: Avoid

Lumacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lumacaftor and Ivacaftor. Management: When initiating or resuming lumacaftor/ivacaftor after a therapy interruption of 7 days or more, reduce the lumacaftor/ivacaftor dose to 1 tablet daily or 1 packet of oral granules every other day for the first week, and then resume the standard dose. Risk D: Consider Therapy Modification

Lumateperone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lumateperone. Management: Limit the lumateperone dose to 10.5 mg once daily when used with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Lurasidone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lurasidone. Risk X: Avoid

Lurbinectedin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Lurbinectedin. Management: Avoid concomitant use of lurbinectedin and strong CYP3A4 inhibitors. If coadministration with a strong CYP3A4 inhibitor cannot be avoided, reduce the lurbinectedin dose by 50%. Risk D: Consider Therapy Modification

Macitentan: CYP3A4 Inhibitors (Strong) may increase serum concentration of Macitentan. Risk X: Avoid

Manidipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required. Risk D: Consider Therapy Modification

Maraviroc: CYP3A4 Inhibitors (Strong) may increase serum concentration of Maraviroc. Management: Reduce maraviroc to 150mg twice/day in adult and pediatrics weighing 40kg or more. See full interaction monograph for dose adjustments in pediatrics weighing 10 to less than 40kg. Do not use if CrCl less than 30mL/min or in those weighing less than 10 kg. Risk D: Consider Therapy Modification

Mavacamten: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mavacamten. Management: For patients on stable therapy with a strong CYP3A4 inhibitor initiate mavacamten at 2.5 mg daily. For patients initiating a strong CYP3A4 inhibitor during mavacamten therapy, dose reductions are recommended. See full mono for details. Risk D: Consider Therapy Modification

Mavorixafor: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mavorixafor. Management: Decrease the mavorixafor dose to 200 mg daily if combined with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Mefloquine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mefloquine. Risk C: Monitor

Meperidine: Nefazodone may increase serotonergic effects of Meperidine. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Meperidine. Management: Consider reducing meperidine dose. Monitor for signs and symptoms of respiratory depression, sedation, and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia) when these agents are combined. Risk D: Consider Therapy Modification

Metaxalone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Methylene Blue: Nefazodone may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase serum concentration of MethylPREDNISolone. Risk C: Monitor

Metoclopramide: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Midazolam: CYP3A4 Inhibitors (Strong) may increase serum concentration of Midazolam. Management: Avoid use of nasal midazolam and strong CYP3A4 inhibitors whenever possible, and consider alternatives to use with other routes of midazolam (oral, IV, IM). If combined, consider lower midazolam doses and monitor for increased midazolam toxicities. Risk D: Consider Therapy Modification

Midostaurin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Risk D: Consider Therapy Modification

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase serum concentration of MiFEPRIStone. Management: For treatment of hyperglycemia in Cushing's syndrome, start mifepristone at 300 mg/day, may titrate to a maximum of 900 mg/day. If starting a strong CYP3A4 inhibitor and taking > 300 mg/day mifepristone, decrease the mifepristone dose by 300 mg/day. Risk D: Consider Therapy Modification

Mirodenafil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Risk D: Consider Therapy Modification

Mirtazapine: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Mirtazapine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and for increased mirtazapine toxicities when these agents are combined. Risk C: Monitor

Mirvetuximab Soravtansine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mirvetuximab Soravtansine. Risk C: Monitor

Mitapivat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mitapivat. Risk X: Avoid

Mobocertinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Mobocertinib. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Mobocertinib. Risk X: Avoid

Mometasone (Nasal): CYP3A4 Inhibitors (Strong) may increase serum concentration of Mometasone (Nasal). Risk C: Monitor

Mometasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase serum concentration of Mometasone (Oral Inhalation). Risk C: Monitor

Mometasone (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Mometasone (Topical). Risk C: Monitor

Monoamine Oxidase Inhibitors (Antidepressant): May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Risk X: Avoid

Naldemedine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Naldemedine. Risk C: Monitor

Nalfurafine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nalfurafine. Risk C: Monitor

Naloxegol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Naloxegol. Risk X: Avoid

Nelfinavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nelfinavir. Risk C: Monitor

Neratinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Neratinib. Risk X: Avoid

NiCARdipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of NiCARdipine. Risk C: Monitor

NIFEdipine (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of NIFEdipine (Topical). Risk X: Avoid

NIFEdipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of NIFEdipine. Management: Consider alternatives to this combination when possible. If combined, initiate nifedipine at the lowest dose available and monitor patients closely for increased nifedipine effects and toxicities (eg, hypotension, edema). Risk D: Consider Therapy Modification

Nilotinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nilotinib. Management: Avoid if possible. If coadministration cannot be avoided, nilotinib dose adjustments are recommended and depend on the dosage form of nilotinib used and indication treated. See full monograph for details. Risk D: Consider Therapy Modification

Nilvadipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nilvadipine. Risk C: Monitor

NiMODipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of NiMODipine. Risk X: Avoid

Nirmatrelvir and Ritonavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nirmatrelvir and Ritonavir. Risk C: Monitor

Nirogacestat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nirogacestat. Risk X: Avoid

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nisoldipine. Risk X: Avoid

Nitrendipine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Nitrendipine. Risk C: Monitor

Olaparib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 100 mg twice daily and the dose of olaparib capsules should be reduced to 150 mg twice daily. Risk D: Consider Therapy Modification

Olmutinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Olmutinib. Risk C: Monitor

Omaveloxolone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Omaveloxolone. Management: Avoid this combination if possible. If coadministration is required, decrease the omaveloxolone dose to 50 mg daily and monitor closely for adverse reactions. Discontinue coadministration if adverse reactions occur. Risk D: Consider Therapy Modification

Ondansetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Risk C: Monitor

Opioid Agonists (metabolized by CYP3A4): May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Opioid Agonists (metabolized by CYP3A4). Management: If concomitant use of opioid agonists that are metabolized by CYP3A4 and nefazodone is necessary, consider dose reduction of the opioid until stable drug effects are achieved. Monitor for increased opioid effects and serotonin syndrome/serotonin toxicity. Risk D: Consider Therapy Modification

Opioid Agonists: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Opipramol: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Osilodrostat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Osilodrostat. Management: Reduce osilodrostat dose by 50% during coadministration with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Ospemifene: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ospemifene. Risk C: Monitor

Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

OxyBUTYnin: CYP3A4 Inhibitors (Strong) may increase serum concentration of OxyBUTYnin. Risk C: Monitor

PACLitaxel (Conventional): CYP3A4 Inhibitors (Strong) may increase serum concentration of PACLitaxel (Conventional). Risk C: Monitor

PACLitaxel (Protein Bound): CYP3A4 Inhibitors (Strong) may increase serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor

Pacritinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pacritinib. Risk X: Avoid

Palbociclib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Palbociclib. Management: Avoid concurrent use of strong CYP3A4 inhibitors with palbociclib when possible. If the use of a strong CYP3A4 inhibitor cannot be avoided, decrease the palbociclib dose to 75 mg/day. Risk D: Consider Therapy Modification

Palovarotene: CYP3A4 Inhibitors (Strong) may increase serum concentration of Palovarotene. Risk X: Avoid

Panobinostat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Monitor patient response to therapy closely for evidence of more severe adverse effects related to panobinostat therapy. Risk D: Consider Therapy Modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Parecoxib. Specifically, serum concentrations of the active moiety valdecoxib may be increased. Risk C: Monitor

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Paricalcitol. Risk C: Monitor

PAZOPanib: CYP3A4 Inhibitors (Strong) may increase serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib dose to 400 mg. Further dose reductions may also be required if adverse reactions occur. Risk D: Consider Therapy Modification

Pemigatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pemigatinib. Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the strong inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider Therapy Modification

Pexidartinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pexidartinib. Management: If combined use cannot be avoided, pexidartinib dose should be reduced as follows: reduce pexidartinib doses of 500 mg or 375 mg daily to 125 mg twice daily; reduce pexidartinib 250 mg daily to 125 mg once daily. Risk D: Consider Therapy Modification

Pimavanserin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease metabolism of Pimecrolimus. Risk C: Monitor

Pimozide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pimozide. Risk X: Avoid

Piperaquine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Piperaquine. Risk C: Monitor

Pirtobrutinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pirtobrutinib. Management: Avoid concomitant use when possible. If combined, reduce the pirtobrutinib dose by 50 mg. If current dose is 50 mg, interrupt pirtobrutinib treatment during strong CYP3A4 inhibitor use. Risk D: Consider Therapy Modification

Polatuzumab Vedotin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased. Risk C: Monitor

PONATinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of PONATinib. Management: Avoid concomitant use if possible. If combined, reduce ponatinib dose as follows: If taking 45 mg, reduce to 30 mg; if taking 30 mg, reduce to 15 mg; if taking 15 mg, reduce to 10 mg. If taking 10 mg, avoid concomitant use with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Pralsetinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider Therapy Modification

Prazepam: CYP3A4 Inhibitors (Strong) may increase serum concentration of Prazepam. Risk C: Monitor

Praziquantel: CYP3A4 Inhibitors (Strong) may increase serum concentration of Praziquantel. Risk C: Monitor

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of PrednisoLONE (Systemic). Risk C: Monitor

PredniSONE: CYP3A4 Inhibitors (Strong) may increase serum concentration of PredniSONE. Risk C: Monitor

Propafenone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Propafenone. Risk C: Monitor

Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor

QUEtiapine: CYP3A4 Inhibitors (Strong) may increase serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce quetiapine to one-sixth of original dose after starting a strong CYP3A4 inhibitor. In those on strong CYP3A4 inhibitors, start quetiapine at lowest dose and up-titrate as needed. Risk D: Consider Therapy Modification

Quinidine (Non-Therapeutic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Quinidine (Non-Therapeutic). Risk C: Monitor

QuiNIDine: CYP3A4 Inhibitors (Strong) may increase serum concentration of QuiNIDine. Risk C: Monitor

QuiNINE: CYP3A4 Inhibitors (Strong) may increase serum concentration of QuiNINE. Risk C: Monitor

Quizartinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Quizartinib. Management: If combination is necessary, reduce quizartinib dose as follows: from 53 mg daily to 26.5 mg daily; from 35.4 mg daily to 17.7 mg daily; from 26.5 mg daily to 17.7 mg daily. If taking 17.7 mg daily avoid quizartinib while on the strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Radotinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Radotinib. Risk X: Avoid

Ramelteon: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ramelteon. Risk C: Monitor

Ramosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Ranolazine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ranolazine. Risk X: Avoid

Rasagiline: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Risk X: Avoid

Reboxetine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Reboxetine. Risk C: Monitor

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Risk X: Avoid

Regorafenib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Regorafenib. CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Regorafenib. Risk X: Avoid

Repaglinide: CYP3A4 Inhibitors (Strong) may increase serum concentration of Repaglinide. Risk C: Monitor

Repotrectinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Repotrectinib. Risk X: Avoid

Retapamulin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Retapamulin. Management: The use of retapamulin with strong CYP3A4 inhibitors is not recommended in patients less than 2 years old. No action is required in other populations. Risk C: Monitor

Revumenib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Revumenib. Management: If combined use is required, decrease revumenib dose for patients weighing 40 kg or more to 160 mg orally twice/day; for patients weighing less than 40 kg to 95 mg/m2 twice daily. Risk D: Consider Therapy Modification

Ribociclib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ribociclib. Management: Avoid use of ribociclib with strong CYP3A4 inhibitors when possible; if combined use cannot be avoided, reduce ribociclib dose to 400 mg once daily in advanced or metastatic breast cancer; reduce ribociclib dose to 200 mg daily in early breast cancer. Risk D: Consider Therapy Modification

Rifabutin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Rifabutin. Risk C: Monitor

Rilpivirine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Rilpivirine. Risk C: Monitor

Rimegepant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Rimegepant. Risk X: Avoid

Riociguat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Riociguat. Risk C: Monitor

Ripretinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ripretinib. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Ripretinib. Risk C: Monitor

RisperiDONE: CYP3A4 Inhibitors (Strong) may increase serum concentration of RisperiDONE. Risk C: Monitor

Ritonavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ritonavir. Risk C: Monitor

Rivaroxaban: CYP3A4 Inhibitors (Strong) may increase serum concentration of Rivaroxaban. For clarithromycin, refer to more specific clarithromycin-rivaroxaban monograph recommendations. Risk C: Monitor

Roflumilast-Containing Products: CYP3A4 Inhibitors (Strong) may increase serum concentration of Roflumilast-Containing Products. Risk C: Monitor

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase serum concentration of RomiDEPsin. Risk C: Monitor

Rupatadine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Rupatadine. Risk X: Avoid

Ruxolitinib (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Ruxolitinib (Systemic). Management: This combination should be avoided under some circumstances; dose adjustments may be required in some circumstances and depend on the indication for ruxolitinib. See monograph for details. Risk D: Consider Therapy Modification

Ruxolitinib (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Ruxolitinib (Topical). Risk X: Avoid

Safinamide: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Risk X: Avoid

Salmeterol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Salmeterol. Risk X: Avoid

Saquinavir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Saquinavir. Risk C: Monitor

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase serum concentration of SAXagliptin. Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Selective Serotonin Reuptake Inhibitor: Nefazodone may increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Selegiline: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Risk X: Avoid

Selpercatinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Selpercatinib. Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120 mg twice/day to 40 mg twice/day, or from 160 mg twice/day to 80 mg twice/day. Risk D: Consider Therapy Modification

Selumetinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Selumetinib. Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider Therapy Modification

Serotonergic Agents (High Risk, Miscellaneous): Nefazodone may increase serotonergic effects of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Serotonin 5-HT1D Receptor Agonists (Triptans): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Serotonin/Norepinephrine Reuptake Inhibitor: Nefazodone may increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Sertindole: CYP3A4 Inhibitors (Strong) may increase serum concentration of Sertindole. Risk X: Avoid

Sildenafil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary arterial hypertension (PAH) should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, consider using a lower starting dose of 25 mg and monitor patients for sildenafil toxicities. Risk D: Consider Therapy Modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Silodosin. Risk X: Avoid

Simeprevir: CYP3A4 Inhibitors (Strong) may increase serum concentration of Simeprevir. Risk X: Avoid

Simvastatin: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Simvastatin. CYP3A4 Inhibitors (Strong) may increase serum concentration of Simvastatin. Risk X: Avoid

Sirolimus (Conventional): CYP3A4 Inhibitors (Strong) may increase serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with strong CYP3A4 inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Concomitant use of sirolimus and voriconazole or posaconazole is contraindicated. Risk D: Consider Therapy Modification

Sirolimus (Protein Bound): CYP3A4 Inhibitors (Strong) may increase serum concentration of Sirolimus (Protein Bound). Risk X: Avoid

Sirolimus (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Sirolimus (Topical). Risk C: Monitor

Solifenacin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Solifenacin. Management: Limit adult solifenacin doses to 5 mg daily and limit doses in pediatric patients to the recommended weight-based starting dose (and do not increase the dose) when combined with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Sonidegib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Sonidegib. Risk X: Avoid

Sparsentan: CYP3A4 Inhibitors (Strong) may increase serum concentration of Sparsentan. Risk X: Avoid

St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

SUNItinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of SUNItinib. Management: Avoid when possible. If combined, decrease sunitinib dose to a minimum of 37.5 mg daily when treating GIST or RCC. Decrease sunitinib dose to a minimum of 25 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider Therapy Modification

Suvorexant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Suvorexant. Risk X: Avoid

Suzetrigine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Suzetrigine. Risk X: Avoid

Syrian Rue: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Tacrolimus (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to one-third of the original dose if starting posaconazole or voriconazole. Coadministration with nelfinavir is not generally recommended. Tacrolimus dose reductions or prolongation of dosing interval will likely be required. Risk D: Consider Therapy Modification

Tacrolimus (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Tacrolimus (Topical). Risk C: Monitor

Tadalafil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tadalafil. Management: Avoid this combination in patients taking tadalafil for pulmonary arterial hypertension. In patients taking tadalafil for ED or BPH, max tadalafil dose is 2.5 mg if taking daily or 10 mg no more frequently than every 72 hours if used as needed. Risk D: Consider Therapy Modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tamsulosin. Risk X: Avoid

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tasimelteon. Risk C: Monitor

Tazemetostat: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tazemetostat. Risk X: Avoid

Temsirolimus: CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Temsirolimus. Specifically, concentrations of sirolimus may be increased. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors. If coadministration is unavoidable, decrease temsirolimus dose to 12.5 mg per week. Resume previous temsirolimus dose 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tetrahydrocannabinol. Risk C: Monitor

Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tezacaftor and Ivacaftor. Management: If combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph for details. Risk D: Consider Therapy Modification

Thiotepa: CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Thiotepa. CYP3A4 Inhibitors (Strong) may increase serum concentration of Thiotepa. Management: Avoid coadministration of thiotepa and strong CYP3A4 inhibitors. If concomitant use cannot be avoided, monitor for thiotepa adverse effects and decreased efficacy. Risk D: Consider Therapy Modification

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease active metabolite exposure of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase serum concentration of Ticagrelor. Risk X: Avoid

Tisotumab Vedotin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tisotumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full Lexi Interact monograph for details. Risk D: Consider Therapy Modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tolterodine. Management: The maximum recommended dose of tolterodine is 2 mg per day (1 mg twice daily for immediate-release tablets or 2 mg daily for extended-release capsules) when used together with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase serum concentration of Tolvaptan. Risk X: Avoid

Toremifene: CYP3A4 Inhibitors (Strong) may increase serum concentration of Toremifene. Management: Use of toremifene with strong CYP3A4 inhibitors should be avoided if possible. If coadministration is necessary, monitor for increased toremifene toxicities, including QTc interval prolongation. Risk D: Consider Therapy Modification

Trabectedin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Trabectedin. Risk X: Avoid

TraMADol: Nefazodone may increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Nefazodone may increase serum concentration of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and tramadol adverse effects when these agents are combined. Risk C: Monitor

TraZODone: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects such as sedation, QTc prolongation, and signs and symptoms of serotonin syndrome/serotonin toxicity when these agents are combined. Risk D: Consider Therapy Modification

Tretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Tretinoin (Systemic). Management: Avoid use of tretinoin and strong CYP3A4 inhibitors when possible. If combined, monitor for increased tretinoin concentrations and toxicities (eg, pseudotumor cerebri, hypercalcemia). Risk D: Consider Therapy Modification

Triamcinolone (Nasal): CYP3A4 Inhibitors (Strong) may increase serum concentration of Triamcinolone (Nasal). Risk C: Monitor

Triamcinolone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Triamcinolone (Ophthalmic). Risk C: Monitor

Triamcinolone (Systemic): CYP3A4 Inhibitors (Strong) may increase serum concentration of Triamcinolone (Systemic). Management: Consider alternatives to this combination when possible. If combined, monitor for increased corticosteroid adverse effects during coadministration of triamcinolone and strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Triamcinolone (Topical): CYP3A4 Inhibitors (Strong) may increase serum concentration of Triamcinolone (Topical). Risk C: Monitor

Triazolam: CYP3A4 Inhibitors (Strong) may increase serum concentration of Triazolam. Risk X: Avoid

Tricyclic Antidepressants: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor

Ubrogepant: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ubrogepant. Risk X: Avoid

Udenafil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Udenafil. Risk X: Avoid

Ulipristal: CYP3A4 Inhibitors (Strong) may increase serum concentration of Ulipristal. Risk C: Monitor

Upadacitinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Upadacitinib. Management: Upadacitinib dose adjustments are often needed when combined with strong CYP3A4 inhibitors. Specific adjustments vary based on upadacitinib indication. See full interact monograph for details. Risk D: Consider Therapy Modification

Valbenazine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Valbenazine. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Vamorolone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vamorolone. Management: Reduce the vamorolone dose to 4 mg/kg daily, with a maximum dose of 200 mg daily for patients weighing over 50 kg, when combined with strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification

Vanzacaftor, Tezacaftor, and Deutivacaftor: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Management: Age- and weight-specific dose reductions of vanzacaftor, tezacaftor, and deutivacaftor are recommended. Please see full Interact monograph or labeling for details. Risk D: Consider Therapy Modification

Vardenafil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vardenafil. Management: Limit Levitra (vardenafil) dose to a single 2.5 mg dose within a 24-hour period if combined with strong CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and strong CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider Therapy Modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. If concomitant use is unavoidable, consider a vemurafenib dose reduction if clinically indicated. Risk D: Consider Therapy Modification

Venetoclax: CYP3A4 Inhibitors (Strong) may increase serum concentration of Venetoclax. Management: Coadministration is contraindicated during venetoclax initiation and ramp-up in CLL/SLL patients. Reduced venetoclax doses are required during ramp-up for patients with AML, and all maintenance therapy. See full Lexi Interact monograph for details. Risk D: Consider Therapy Modification

Verapamil: CYP3A4 Inhibitors (Strong) may increase serum concentration of Verapamil. Risk C: Monitor

Vilanterol: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vilanterol. Risk C: Monitor

Vilazodone: Nefazodone may increase serotonergic effects of Vilazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Vilazodone. Management: Limit maximum vilazodone dose to 20 mg daily and monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider Therapy Modification

VinBLAStine: CYP3A4 Inhibitors (Strong) may increase serum concentration of VinBLAStine. Risk C: Monitor

VinCRIStine: CYP3A4 Inhibitors (Strong) may increase serum concentration of VinCRIStine. Risk X: Avoid

Vindesine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vindesine. Risk C: Monitor

Vinflunine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vinflunine. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of Vinflunine. Risk X: Avoid

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vinorelbine. Risk C: Monitor

Voclosporin: CYP3A4 Inhibitors (Strong) may increase serum concentration of Voclosporin. Risk X: Avoid

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase serum concentration of Vorapaxar. Risk X: Avoid

Voriconazole: CYP3A4 Inhibitors (Strong) may increase serum concentration of Voriconazole. Risk C: Monitor

Zanubrutinib: CYP3A4 Inhibitors (Strong) may increase serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg once daily during coadministration with a strong CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider Therapy Modification

Ziprasidone: May increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Ziprasidone. Risk C: Monitor

Zolpidem: CYP3A4 Inhibitors (Strong) may increase serum concentration of Zolpidem. Risk C: Monitor

Zopiclone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Zopiclone. Management: If coadministered with strong CYP3A4 inhibitors, initiate zopiclone at 3.75 mg in adults, with a maximum dose of 5 mg. Monitor for zopiclone toxicity (eg, drowsiness, confusion, lethargy, ataxia, respiratory depression). Risk D: Consider Therapy Modification

Zuranolone: CYP3A4 Inhibitors (Strong) may increase serum concentration of Zuranolone. Management: Reduce the zuranolone dose to 30 mg once daily when used concomitantly with a strong CYP3A4 inhibitor. Risk D: Consider Therapy Modification

Food Interactions

Nefazodone absorption may be delayed and bioavailability may be decreased if taken with food. Management: Administering after meals may decrease lightheadedness and postural hypotension, but may also decrease absorption and therefore effectiveness.

Reproductive Considerations

Evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). When treating depression, nefazodone is not a first line medication for use prior to conception in patients who are treatment naive or who do not have a history of effective treatment. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).

Pregnancy Considerations

Outcome data following maternal use of nefazodone during pregnancy are limited (Anderson 2020; Einarson 2003; Einarson 2009; Yaris 2004).

Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process (ACOG 2023). Patients effectively treated for depression prepregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status. Nefazodone is not a first line medication for pregnant patients who are treatment naive or who do not have a history of effective treatment with another medication. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Pregnant patients 45 years and younger with a history of psychiatric illness are encouraged to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).

Breastfeeding Considerations

Nefazodone and its active metabolites are present in breast milk (Dodd 1999; Dodd 2000; Yapp 2000).

Multiple case reports summarize data related to the presence of nefazodone in breast milk:

• As part of validating a method to detect nefazodone in plasma and breast milk, application of the test was done in 2 lactating patients. Both patients were taking nefazodone for at least 3 weeks; testing in 1 patient was conducted after 2 different doses. Sampling occurred prior to the morning dose (10 to 15 hours after the last dose). Following a dose of 200 mg twice daily, trough nefazodone maternal plasma and breast milk concentrations were 617 ng/mL and 57 ng/mL, respectively. Following a dose of nefazodone 50 mg twice daily, breast milk concentrations were <50 ng/mL (maternal plasma) and 687 ng/mL (breast milk). Maternal plasma concentrations were <50 ng/mL following a dose of nefazodone 50 mg in the morning and 100 mg in the evening; breast milk concentrations were 213 ng/mL. The hydroxynefazodone metabolite was also detected in 2 of the breast milk samples (Dodd 1999). Using a milk concentration of 687 ng/mL, the estimated infant dose of nefazodone via breast milk is 0.1 mg/kg/day providing a relative infant dose (RID) of 4.7% compared to weight-adjusted maternal dose of 150 mg/day. (This RID does not include metabolites).

• Data related to the presence of nefazodone and metabolites in breast milk are available from a lactating patient after delivery of an infant at 27 weeks' gestation. Nefazodone 200 mg in the morning and 100 mg in the evening was initiated at 7 weeks postpartum. Breast milk was sampled at 10.5 weeks postpartum due to adverse events in the breastfed infant. Sampling was conducted with the morning dose and at intervals over 6 hours after nefazodone administration. Maximum breast milk concentrations of nefazodone (358 ng/mL) occurred 3 hours after the dose. The following metabolites were also present in breast milk at this time: triazoledione (83 ng/mL), hydroxynefazodone (32 ng/mL), and m-chlorophenylpiperazine (18 ng/mL). Authors of the study calculated the RID of nefazodone + metabolites via breast milk to be 0.45% of the weight-adjusted maternal dose. Drowsiness, lethargy, poor feeding, and failure to maintain body temperature were reported in the premature infant; symptoms resolved over 72 hours once breastfeeding was stopped (Yapp 2000).

• A report describes the presence of nefazodone but not the metabolites in the breast milk of 2 patients. The first patient was 21 weeks postpartum. Nefazodone 50 mg/day was taken for 6 weeks prior to a dose increase to 100 mg in the morning and 50 mg at night. Sampling occurred 6 days after the dose adjustment. The second patient was 4 weeks postpartum and had been taking nefazodone 200 mg twice daily for 7 months. Breast milk was collected prior to the morning dose and at intervals for 6 hours after the dose in both patients. Authors of the study calculated the estimated infant dose of nefazodone via breast milk to be 0.54 mg/kg/day providing a RID of 2.2% based on the weight-adjusted maternal dose for the first patient, and 0.028 mg/kg/day, providing a RID of 0.4% for the second patient. Abnormal developmental outcomes were not observed in the breastfed infants (Dodd 2000).

• In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).

Infants exposed to psychotropic medication via breast milk should be monitored for adverse effects (eg, over sedation, poor feeding) (BAP [McAllister-Williams 2017]).

The manufacturer recommends that caution be exercised when administering nefazodone to patients who are breastfeeding. Patients effectively treated for depression during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum. When first initiating an antidepressant in a patient who is treatment naive and breastfeeding, an agent other than nefazodone may be preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]).

Monitoring Parameters

Liver function tests (baseline and periodic; if AST/ALT increase ≥3 times ULN, the drug should be discontinued and not reintroduced); mental status, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks, or other unusual changes in behavior

Mechanism of Action

Inhibits neuronal reuptake of serotonin and norepinephrine; also blocks 5-HT2 and alpha1 receptors; has no significant affinity for alpha2, beta-adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine receptors

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).

Absorption: Rapid; well absorbed; food delays absorption by ~20%.

Distribution: Vd: 0.22 to 0.87 L/kg.

Protein binding: >99%.

Metabolism: Hepatic by n-dealkylation and aliphatic and aromatic hydroxylation to at least three metabolites: Triazoledione, hydroxynefazodone (active), and m-chlorophenylpiperazine (mCPP; active).

Bioavailability: 20% (variable); food decreases bioavailability by ~20%; AUC increased by 25% in patients with cirrhosis of the liver.

Half-life elimination: Note: Active metabolites persist longer in all populations.

Children: 4.1 hours.

Adolescents: 3.9 hours.

Adults: Parent drug: 2 to 4 hours; Active metabolites: 1.4 to 8 hours.

Time to peak, serum: Note: Prolonged in presence of food.

Children and Adolescents: 0.5 to 1 hour.

Adults: 1 hour.

Excretion: Primarily urine (~55%; as metabolites); feces (~20% to 30%).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Older adult: Cmax and AUC for nefazodone and hydroxynefazodone were twice as high in patients >65 years of age after single doses and 10% to 20% higher after multiple doses.

Sex: Nefazodone has a higher Cmax and AUC in women after single doses, but no difference after multiple doses.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Serzone;
  • (AR) Argentina: Deprefax;
  • (AT) Austria: Dutonin;
  • (AU) Australia: Serzone;
  • (BR) Brazil: Serzone;
  • (CH) Switzerland: Nefadar;
  • (DE) Germany: Nefadar;
  • (EG) Egypt: Serzone;
  • (ES) Spain: Dutonin | Menfazona | Rulivan;
  • (FI) Finland: Nefadar;
  • (GR) Greece: Nefirel;
  • (HK) Hong Kong: Serzone;
  • (IE) Ireland: Dutonin;
  • (IL) Israel: Serzonil;
  • (IT) Italy: Reseril;
  • (JO) Jordan: Serzone;
  • (KR) Korea, Republic of: Serzone;
  • (KW) Kuwait: Serzone;
  • (LB) Lebanon: Serzone;
  • (MY) Malaysia: Serzone;
  • (NL) Netherlands: Dutonin;
  • (NO) Norway: Nefadar;
  • (NZ) New Zealand: Serzone;
  • (PR) Puerto Rico: Nefazodone | Nefazodone HCL | Serzone;
  • (SA) Saudi Arabia: Serzone;
  • (SE) Sweden: Nefadar;
  • (SG) Singapore: Serzone;
  • (TH) Thailand: Serzone;
  • (TR) Turkey: Serzone;
  • (UY) Uruguay: Nefaril | Nefazod;
  • (ZA) South Africa: Serzone
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