clozapine (Rx)

Brand and Other Names:Clozaril, Versacloz
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 25mg
  • 50mg
  • 100mg
  • 200mg

oral suspension (Versacloz)

  • 50mg/mL

Schizophrenia

Indicated for reducing risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder in patients who are judged to be at chronic risk to re-experience suicidal behavior

Also indicated for treatment-resistant schizophrenia in patients who fail to respond adequately to standard antipsychotic treatment

12.5 mg PO once daily or q12hr initially; increase in increments of 25-50 mg/day, if well tolerated, to achieve target dosage of 300-450 mg/day (administered in divided doses) by end of 2 weeks

Subsequently, may increase dose once or twice weekly in increments of up to 100 mg; not to exceed 900 mg/day

Maintenance: Generally, patients who respond should continue maintenance treatment on their effective dose beyond the acute episode

Reinitiation of therapy

  • If therapy interrupted for ≥48 hr, must reinitiate dose at 12.5 mg qDay or BID to minimize risk of hypotension, bradycardia, and syncope; if dose well tolerated, may increase more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration, then titrate with extreme caution

Discontinuation of therapy

  • Method of treatment discontinuation depends on patient’s last ANC
  • Reduce dose gradually over a period of 1-2 weeks if termination not related to neutropenia; taper gradually to avoid withdrawal symptoms and minimize risk of relapse; for schizophrenia, guidelines recommend gradual taper over 6-24 months (American Psychiatric Association guidelines recommend reducing dose 10% each month)
  • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continue existing ANC monitoring until ANC is ≥1500/mm3
  • If benign patient has benign ethnic neutropenia (BEN); monitor until ANC is ≥1000/mm3 or above baseline
  • Additional ANC monitoring required for onset of fever during the 2 weeks after discontinuation
  • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound (eg, profuse sweating, headache, nausea, vomiting, diarrhea)

Dosage Modifications

Coadministration with CYP inhibitors

  • Strong CYP1A2 inhibitors: Use one-third clozapine dose
  • Moderate or weak CYP1A2 inhibitors: Monitor for adverse reactions; consider reducing clozapine dose if needed
  • CYP2D6 or CYP3A4 inhibitors: Monitor for adverse reactions; consider reducing clozapine dose if needed
  • CYP2D6 poor metabolizers: Clozapine dose reduction may be needed

Coadministration with CYP inducers

  • Strong CYP3A4 inducers: Coadministration not recommended; if the inducer is necessary, clozapine dose may need to be increased
  • Moderate or weak CYP1A2 or CYP3A4 inducers: Monitor for decreased effectiveness; consider increasing clozapine dose if necessary

Renal or hepatic impairment

  • Dose reduction may be necessary with significant renal or hepatic impairment

Dosing Considerations

Required laboratory monitoring

  • Before initiating, obtain CBC count with differential for baseline ANC; to continue treatment, ANC must be monitored regularly
  • In order to initiate treatment, ANC must be ≥1500/mm3 for the general population and ≥1000/mm3 for patients with documented benign ethnic neutropenia

Safety and efficacy not established

Lower initial dosage of 12.5-25 mg/day indicated; may be titrated more slowly than in younger adults

Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to orthostatic hypotension and tachycardia; anticholinergic effects are also common (constipation, confusion, urinary retention)

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Interactions

Interaction Checker

and clozapine

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            Contraindicated (9)

            • dronedarone

              clozapine and dronedarone both increase QTc interval. Contraindicated.

            • eliglustat

              clozapine increases levels of eliglustat by affecting hepatic enzyme CYP2D6 metabolism. Contraindicated. If coadministered with strong or moderate CYP2D6 inhibitors, reduce eliglustat dose from 84 mg BID to 84 mg once daily in extensive and intermediate metabolizers; eliglustat is contraindiated if strong or moderate CYP2D6 inhibitors are given concomitantly with strong or moderate CYP3A inhibitors.

            • flibanserin

              clozapine will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of flibanserin with moderate or strong CYP3A4 inhibitors is contraindicated. Severe hypotension or syncope can occur.

            • irinotecan

              clozapine, irinotecan. Either increases toxicity of the other by Other (see comment). Contraindicated. Comment: Concomitant administraiton increases risk of agranulocytosis.

              irinotecan, clozapine. Either increases toxicity of the other by Other (see comment). Contraindicated. Comment: Concomitant administration increases risk of agranulocytosis.

            • irinotecan liposomal

              irinotecan liposomal, clozapine. Either increases toxicity of the other by Other (see comment). Contraindicated. Comment: Concomitant administration increases risk of agranulocytosis.

              clozapine, irinotecan liposomal. Either increases toxicity of the other by Other (see comment). Contraindicated. Comment: Concomitant administraiton increases risk of agranulocytosis.

            • lomitapide

              clozapine increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Increases lomitapide levels several folds.

            • lonafarnib

              clozapine will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lonafarnib is a sensitive CYP3A4 substrate. Coadministration with strong or moderate CYP3A4 inhibitors is contraindicated.

            • saquinavir

              clozapine and saquinavir both increase QTc interval. Contraindicated.

            • thioridazine

              clozapine and thioridazine both increase QTc interval. Contraindicated.

            Serious - Use Alternative (141)

            • abametapir

              abametapir will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP1A2 substrates. If not feasible, avoid use of abametapir.

            • amiodarone

              clozapine and amiodarone both increase QTc interval. Avoid or Use Alternate Drug.

            • apomorphine

              clozapine decreases effects of apomorphine by pharmacodynamic antagonism. Avoid or Use Alternate Drug.

            • aripiprazole

              aripiprazole and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • arsenic trioxide

              clozapine and arsenic trioxide both increase QTc interval. Avoid or Use Alternate Drug.

            • artemether

              artemether and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • artemether/lumefantrine

              clozapine and artemether/lumefantrine both increase QTc interval. Avoid or Use Alternate Drug.

            • asenapine

              clozapine and asenapine both increase QTc interval. Avoid or Use Alternate Drug.

            • avapritinib

              clozapine will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of avapritinib with moderate CYP3A4 inhibitors. If unable to avoid, reduce avapritinib starting dose. See drug monograph Dosage Modifications.

            • axitinib

              clozapine increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid coadministration with moderate CYP3A4 inhibitors, monitor closely and reduce dose if necessary .

            • azithromycin

              clozapine and azithromycin both increase QTc interval. Avoid or Use Alternate Drug.

            • benzhydrocodone/acetaminophen

              benzhydrocodone/acetaminophen, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • bosutinib

              clozapine increases levels of bosutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • bromocriptine

              clozapine decreases effects of bromocriptine by pharmacodynamic antagonism. Avoid or Use Alternate Drug.

            • buprenorphine

              clozapine and buprenorphine both increase QTc interval. Avoid or Use Alternate Drug.

            • bupropion

              clozapine increases toxicity of bupropion by unspecified interaction mechanism. Avoid or Use Alternate Drug. May lower seizure threshold; keep bupropion dose as low as possible.

            • cabergoline

              clozapine decreases effects of cabergoline by pharmacodynamic antagonism. Contraindicated.

            • calcium/magnesium/potassium/sodium oxybates

              clozapine, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • carbamazepine

              carbamazepine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              carbamazepine, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of agranulocytosis.

            • ceritinib

              ceritinib and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • chlorpromazine

              clozapine and chlorpromazine both increase QTc interval. Avoid or Use Alternate Drug.

            • cimetidine

              cimetidine will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ciprofloxacin

              ciprofloxacin will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Use caution when administering ciprofloxacin in patients receiving drugs that prolong the QT interval. At elevated serum concentrations, clozapine may produce clinically significant prolongation of the QTc interval.

              clozapine and ciprofloxacin both increase QTc interval. Avoid or Use Alternate Drug.

            • cisapride

              clozapine and cisapride both increase QTc interval. Avoid or Use Alternate Drug.

            • citalopram

              citalopram and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • clarithromycin

              clarithromycin will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              clarithromycin and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • cobimetinib

              clozapine will increase the level or effect of cobimetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking cobimetinib 60 mg, reduce the cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume cobimetinib 60 mg. Use an alternative to a moderate CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib (40 or 20 mg daily).

            • crizotinib

              clozapine and crizotinib both increase QTc interval. Avoid or Use Alternate Drug.

            • dasatinib

              clozapine and dasatinib both increase QTc interval. Avoid or Use Alternate Drug.

            • deferiprone

              deferiprone, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; if an alternative is not possible, monitor absolute neutrophil count more frequently.

            • deutetrabenazine

              clozapine and deutetrabenazine both increase QTc interval. Avoid or Use Alternate Drug.

            • disopyramide

              clozapine and disopyramide both increase QTc interval. Avoid or Use Alternate Drug.

            • dofetilide

              dofetilide increases toxicity of clozapine by QTc interval. Avoid or Use Alternate Drug.

            • dopamine

              clozapine decreases effects of dopamine by pharmacodynamic antagonism. Contraindicated.

            • droperidol

              clozapine and droperidol both increase QTc interval. Avoid or Use Alternate Drug.

            • eliglustat

              clozapine increases levels of eliglustat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Moderate CYP3A4 inhibitors are not recommended with eliglustat poor or intermediate metabolizers; reduce eliglustat dose from 84 mg BID to 84 mg once daily in extensive metabolizers .

              clozapine and eliglustat both increase QTc interval. Avoid or Use Alternate Drug.

            • encorafenib

              clozapine and encorafenib both increase QTc interval. Avoid or Use Alternate Drug.

            • entrectinib

              clozapine and entrectinib both increase QTc interval. Avoid or Use Alternate Drug.

              clozapine will increase the level or effect of entrectinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of moderate CYP3A4 inhibitors with entrectinib, a CYP3A4 substrate. If coadministration unavoidable, reduce dose to 200 mg/day for patients aged 12 y or older with BSA >1.50m2. Resume previous entrectinib dose after discontinuing moderate CYP3A inhibitor for 3-5 elimination half-lives.

            • eribulin

              clozapine and eribulin both increase QTc interval. Avoid or Use Alternate Drug.

            • erythromycin base

              erythromycin base will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              clozapine and erythromycin base both increase QTc interval. Avoid or Use Alternate Drug.

            • erythromycin ethylsuccinate

              erythromycin ethylsuccinate will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              clozapine and erythromycin ethylsuccinate both increase QTc interval. Avoid or Use Alternate Drug.

            • erythromycin lactobionate

              erythromycin lactobionate will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              clozapine and erythromycin lactobionate both increase QTc interval. Avoid or Use Alternate Drug.

            • erythromycin stearate

              erythromycin stearate will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              clozapine and erythromycin stearate both increase QTc interval. Avoid or Use Alternate Drug.

            • fedratinib

              clozapine will increase the level or effect of fedratinib by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of fedratinib (a CYP3A4 and CYP2C19 substrate) with dual CYP3A4 and CYP2C19 inhibitor. Effect of coadministration of a dual CYP3A4 and CYP2C19 inhibitor with fedratinib has not been studied.

            • fentanyl

              clozapine will increase the level or effect of fentanyl by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fentanyl intranasal

              clozapine will increase the level or effect of fentanyl intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fentanyl transdermal

              clozapine will increase the level or effect of fentanyl transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fentanyl transmucosal

              clozapine will increase the level or effect of fentanyl transmucosal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fexinidazole

              fexinidazole and clozapine both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of fexinidazole with drugs known to block potassium channels or prolong QT interval.

            • flecainide

              clozapine and flecainide both increase QTc interval. Avoid or Use Alternate Drug.

            • fluconazole

              clozapine and fluconazole both increase QTc interval. Contraindicated.

            • fluvoxamine

              fluvoxamine will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug.

            • foscarnet

              clozapine and foscarnet both increase QTc interval. Avoid or Use Alternate Drug.

            • givosiran

              givosiran will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP1A2 substrates with givosiran. If unavoidable, decrease the CYP1A2 substrate dosage in accordance with approved product labeling.

            • glasdegib

              clozapine and glasdegib both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, monitor for increased risk of QTc interval prolongation.

            • hydrocodone

              hydrocodone, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • hydroxychloroquine sulfate

              hydroxychloroquine sulfate and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • hydroxyzine

              hydroxyzine increases toxicity of clozapine by QTc interval. Avoid or Use Alternate Drug. Increases risk of torsades de pointes.

            • ibutilide

              clozapine and ibutilide both increase QTc interval. Avoid or Use Alternate Drug.

            • iloperidone

              clozapine and iloperidone both increase QTc interval. Avoid or Use Alternate Drug.

            • infigratinib

              clozapine will increase the level or effect of infigratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • inotuzumab

              inotuzumab and clozapine both increase QTc interval. Avoid or Use Alternate Drug. If unable to avoid concomitant use, obtain ECGs and electrolytes before and after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment.

            • isoflurane

              clozapine and isoflurane both increase QTc interval. Avoid or Use Alternate Drug.

            • itraconazole

              itraconazole will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              clozapine and itraconazole both increase QTc interval. Avoid or Use Alternate Drug.

            • ivabradine

              clozapine will increase the level or effect of ivabradine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ivabradine with moderate CYP3A4 inhibitors.

            • ivosidenib

              ivosidenib and clozapine both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of QTc prolonging drugs with ivosidenib or replace with alternate therapies. If coadministration of a QTc prolonging drug is unavoidable, monitor for increased risk of QTc interval prolongation.

            • ketoconazole

              ketoconazole will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • lefamulin

              lefamulin and clozapine both increase QTc interval. Avoid or Use Alternate Drug.

            • lemborexant

              clozapine will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of lemborexant with moderate or strong CYP3A inhibitors.

            • levodopa

              clozapine decreases effects of levodopa by pharmacodynamic antagonism. Avoid or Use Alternate Drug.

            • levodopa inhaled

              clozapine decreases effects of levodopa inhaled by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Atypical (2nd generation) antipsychotics inhibit dopamine D2 receptors in varying degrees (clozapine and quetiapine are lower risk). .

            • lisuride

              clozapine decreases effects of lisuride by pharmacodynamic antagonism. Contraindicated.

            • lithium

              clozapine and lithium both increase QTc interval. Avoid or Use Alternate Drug.

            • lofexidine

              clozapine and lofexidine both increase QTc interval. Avoid or Use Alternate Drug.

            • loperamide

              clozapine and loperamide both increase QTc interval. Avoid or Use Alternate Drug.

            • lopinavir

              clozapine and lopinavir both increase QTc interval. Avoid or Use Alternate Drug.

            • lurbinectedin

              clozapine will increase the level or effect of lurbinectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • macimorelin

              macimorelin and clozapine both increase QTc interval. Avoid or Use Alternate Drug. Macimorelin causes an increase of ~11 msec in the corrected QT interval. Avoid coadministration with drugs that prolong QT interval, which could increase risk for developing torsade de pointes-type ventricular tachycardia. Allow sufficient washout time of drugs that are known to prolong the QT interval before administering macimorelin.

            • maprotiline

              clozapine and maprotiline both increase QTc interval. Avoid or Use Alternate Drug.

            • methadone

              clozapine and methadone both increase QTc interval. Avoid or Use Alternate Drug.

            • methimazole

              methimazole, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of agranulocytosis.

            • methyldopa

              clozapine decreases effects of methyldopa by pharmacodynamic antagonism. Contraindicated.

            • metoclopramide intranasal

              clozapine, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

              clozapine increases toxicity of metoclopramide intranasal by pharmacodynamic synergism. Avoid or Use Alternate Drug. Potential for additive effects, including increased frequency and severity of tardive dyskinesia, other extrapyramidal symptoms, and neuroleptic malignant syndrome.

            • midazolam intranasal

              clozapine will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of moderate CYP3A4 inhibitors with midazolam intranasal causes higher midazolam systemic exposure, which may prolong sedation.

            • midostaurin

              clozapine and midostaurin both increase QTc interval. Avoid or Use Alternate Drug.

            • mobocertinib

              clozapine will increase the level or effect of mobocertinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If use of moderate CYP3A4 inhibitor unavoidable, reduce mobocertinib dose by ~50% (eg, 160 to 80 mg); closely monitor QTc interval.

              mobocertinib and clozapine both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, reduce mobocertinib dose and monitor QTc interval more frequently.

            • moxifloxacin

              clozapine and moxifloxacin both increase QTc interval. Avoid or Use Alternate Drug.

            • naloxegol

              clozapine will increase the level or effect of naloxegol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministation of naloxegol with moderate CYP3A4 inhibitors is unavoidable, reduce naloxegol dose to 12.5 mg qDay

            • neratinib

              clozapine will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

            • olanzapine

              clozapine and olanzapine both increase QTc interval. Avoid or Use Alternate Drug. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances

            • olaparib

              clozapine will increase the level or effect of olaparib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with moderate CYP3A inhibitors cannot be avoided, reduce olaparib dose to 200 mg (capsule) or 150 mg (tablet) PO BID. Do not substitute tablets with capsules.

            • ondansetron

              clozapine and ondansetron both increase QTc interval. Avoid or Use Alternate Drug. Avoid with congenital long QT syndrome; ECG monitoring recommended with concomitant medications that prolong QT interval, electrolyte abnormalities, CHF, or bradyarrhythmias.

            • oxaliplatin

              clozapine and oxaliplatin both increase QTc interval. Avoid or Use Alternate Drug.

            • paliperidone

              clozapine and paliperidone both increase QTc interval. Avoid or Use Alternate Drug.

            • panobinostat

              clozapine and panobinostat both increase QTc interval. Avoid or Use Alternate Drug. Panobinostat is known to significantly prolong QT interval. Panobinostat prescribing information states use with drugs known to prolong QTc is not recommended.

            • pazopanib

              clozapine and pazopanib both increase QTc interval. Avoid or Use Alternate Drug.

            • pefloxacin

              pefloxacin will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug.

            • pemigatinib

              clozapine will increase the level or effect of pemigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors is unavoidable, reduce pemigatinib dose (refer to drug monograph dosage modifications). After discontinuing the CYP3A4 inhibitor for 3 elimination half-lives, may resume previous pemigatinib dose.

            • pentamidine

              clozapine and pentamidine both increase QTc interval. Avoid or Use Alternate Drug.

            • pexidartinib

              clozapine will increase the level or effect of pexidartinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors is unavoidable, reduce pexidartinib dose (refer to drug monograph dosage modifications). After discontinuing the CYP3A4 inhibitor for 3 elimination half-lives, may resume previous pexidartinib dose.

            • pimavanserin

              clozapine and pimavanserin both increase QTc interval. Avoid or Use Alternate Drug.

            • pimozide

              clozapine and pimozide both increase QTc interval. Contraindicated.

            • pitolisant

              clozapine and pitolisant both increase QTc interval. Avoid or Use Alternate Drug.

            • ponesimod

              clozapine and ponesimod both increase QTc interval. Avoid or Use Alternate Drug.

            • posaconazole

              clozapine and posaconazole both increase QTc interval. Contraindicated.

            • pramipexole

              clozapine decreases effects of pramipexole by pharmacodynamic antagonism. Contraindicated.

            • procainamide

              clozapine and procainamide both increase QTc interval. Avoid or Use Alternate Drug.

            • propafenone

              clozapine and propafenone both increase QTc interval. Avoid or Use Alternate Drug.

            • propylthiouracil

              propylthiouracil, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of agranulocytosis.

            • quetiapine

              clozapine and quetiapine both increase QTc interval. Avoid or Use Alternate Drug.

            • quinidine

              clozapine and quinidine both increase QTc interval. Contraindicated.

            • ranolazine

              clozapine and ranolazine both increase QTc interval. Avoid or Use Alternate Drug.

            • ribociclib

              ribociclib will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              ribociclib increases toxicity of clozapine by QTc interval. Avoid or Use Alternate Drug.

            • rifabutin

              rifabutin will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • rifampin

              rifampin will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • romidepsin

              clozapine and romidepsin both increase QTc interval. Avoid or Use Alternate Drug.

            • ropinirole

              clozapine decreases effects of ropinirole by pharmacodynamic antagonism. Contraindicated.

            • safinamide

              clozapine decreases effects of safinamide by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Dopamine antagonists may decrease safinamide effects and exacerbate Parkinson disease symptoms.

            • saquinavir

              saquinavir increases levels of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Potential for increased toxicity. Increased risk of QT prolongation and cardiac arrhythmias.

            • selinexor

              selinexor, clozapine. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

            • selumetinib

              clozapine will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

            • sevoflurane

              clozapine and sevoflurane both increase QTc interval. Avoid or Use Alternate Drug.

            • siponimod

              clozapine will increase the level or effect of siponimod by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of siponimod with a moderate or strong CYP3A4 inhibitor PLUS a moderate or strong CYP2C9 inhibitor is not recommended.

              clozapine and siponimod both increase QTc interval. Avoid or Use Alternate Drug.

            • sodium oxybate

              clozapine, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • sotalol

              clozapine and sotalol both increase QTc interval. Avoid or Use Alternate Drug.

            • St John's Wort

              St John's Wort will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • sufentanil SL

              sufentanil SL, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • tazemetostat

              clozapine will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of tazemetostat with moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce tazemetostat current dose (see drug monograph Dosage Modifications).

            • tetrabenazine

              clozapine and tetrabenazine both increase QTc interval. Avoid or Use Alternate Drug.

            • thiothixene

              clozapine and thiothixene both increase QTc interval. Avoid or Use Alternate Drug.

            • toremifene

              clozapine and toremifene both increase QTc interval. Avoid or Use Alternate Drug.

            • trazodone

              clozapine and trazodone both increase QTc interval. Avoid or Use Alternate Drug.

            • umeclidinium bromide/vilanterol inhaled

              clozapine increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

            • vandetanib

              clozapine and vandetanib both increase QTc interval. Avoid or Use Alternate Drug.

            • vemurafenib

              clozapine and vemurafenib both increase QTc interval. Avoid or Use Alternate Drug.

            • venetoclax

              clozapine will increase the level or effect of venetoclax by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If a moderate CYP3A inhibitor must be used, reduce the venetoclax dose by at least 50%. Monitor more closely for signs of venetoclax toxicities.

            • vilanterol/fluticasone furoate inhaled

              clozapine increases toxicity of vilanterol/fluticasone furoate inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.

            • voriconazole

              clozapine and voriconazole both increase QTc interval. Avoid or Use Alternate Drug.

            • vorinostat

              clozapine and vorinostat both increase QTc interval. Avoid or Use Alternate Drug.

            • zidovudine

              clozapine, zidovudine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of myelosuppression.

            • ziprasidone

              clozapine and ziprasidone both increase QTc interval. Avoid or Use Alternate Drug.

            Monitor Closely (431)

            • abobotulinumtoxinA

              abobotulinumtoxinA increases effects of clozapine by pharmacodynamic synergism. Use Caution/Monitor. Use of anticholinergic drugs after administration of botulinum toxin-containing products may potentiate systemic anticholinergic effects.

            • acalabrutinib

              clozapine will increase the level or effect of acalabrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Decrease acalabrutinib dose to 100 mg once daily if coadministered with a moderate CYP3A inhibitor.

              acalabrutinib, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may increase risk of myelosuppressive effects.

            • acarbose

              acarbose, clozapine. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • aclidinium

              aclidinium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of aclidinium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • albiglutide

              clozapine, albiglutide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • albuterol

              clozapine increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              albuterol and clozapine both increase QTc interval. Use Caution/Monitor.

            • alfentanil

              alfentanil and clozapine both increase sedation. Use Caution/Monitor.

            • alfuzosin

              clozapine and alfuzosin both increase QTc interval. Use Caution/Monitor.

              alfuzosin and clozapine both increase QTc interval. Use Caution/Monitor.

            • almotriptan

              almotriptan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • alprazolam

              alprazolam and clozapine both increase sedation. Use Caution/Monitor.

            • amifampridine

              clozapine increases toxicity of amifampridine by Other (see comment). Modify Therapy/Monitor Closely. Comment: Amifampridine can cause seizures. Coadministration with drugs that lower seizure threshold may increase this risk.

            • amifostine

              amifostine, clozapine. Either increases effects of the other by anti-hypertensive channel blocking. Use Caution/Monitor. Due to its alpha adrenergic antagonism, atypical antipsychotic agents has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly.

            • amitriptyline

              clozapine and amitriptyline both increase sedation. Use Caution/Monitor.

              clozapine and amitriptyline both increase QTc interval. Use Caution/Monitor.

            • amobarbital

              amobarbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              amobarbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              amobarbital and clozapine both increase sedation. Use Caution/Monitor.

            • amoxapine

              clozapine and amoxapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and amoxapine both increase sedation. Use Caution/Monitor.

              clozapine and amoxapine both increase QTc interval. Use Caution/Monitor.

            • anagrelide

              clozapine and anagrelide both increase QTc interval. Use Caution/Monitor.

            • anticholinergic/sedative combos

              anticholinergic/sedative combos decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              anticholinergic/sedative combos decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of anticholinergic/sedative combos by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • apomorphine

              clozapine and apomorphine both increase sedation. Use Caution/Monitor.

              apomorphine and clozapine both increase QTc interval. Use Caution/Monitor.

            • aprepitant

              aprepitant will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • arformoterol

              clozapine increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              arformoterol and clozapine both increase QTc interval. Use Caution/Monitor.

            • aripiprazole

              aripiprazole and clozapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              aripiprazole and clozapine both increase sedation. Use Caution/Monitor.

            • armodafinil

              armodafinil will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              armodafinil will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              clozapine increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • artemether/lumefantrine

              artemether/lumefantrine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • atazanavir

              atazanavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • atogepant

              clozapine will increase the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • atomoxetine

              atomoxetine and clozapine both increase QTc interval. Use Caution/Monitor.

            • atracurium

              atracurium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              atracurium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of atracurium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • atropine

              atropine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              atropine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of atropine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • atropine IV/IM

              clozapine increases effects of atropine IV/IM by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

              atropine IV/IM decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              atropine IV/IM decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

            • azelastine

              azelastine and clozapine both increase sedation. Use Caution/Monitor.

            • baclofen

              baclofen and clozapine both increase sedation. Use Caution/Monitor.

            • bedaquiline

              clozapine and bedaquiline both increase QTc interval. Modify Therapy/Monitor Closely. ECG should be monitored closely

            • belladonna alkaloids

              belladonna alkaloids decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              belladonna alkaloids decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of belladonna alkaloids by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • belladonna and opium

              belladonna and opium and clozapine both increase sedation. Use Caution/Monitor.

              belladonna and opium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              belladonna and opium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of belladonna and opium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • benazepril

              clozapine increases toxicity of benazepril by pharmacodynamic synergism. Use Caution/Monitor. Increases risk of hypotension.

              benazepril increases toxicity of clozapine by pharmacodynamic synergism. Use Caution/Monitor. Increases risk of hypotension.

            • benperidol

              benperidol and clozapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              benperidol and clozapine both increase sedation. Use Caution/Monitor.

            • benzphetamine

              clozapine increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • benztropine

              clozapine increases effects of benztropine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic adverse effects may be seen with concurrent use. .

            • bosentan

              bosentan will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • brexanolone

              brexanolone, clozapine. Either increases toxicity of the other by sedation. Use Caution/Monitor.

            • brexpiprazole

              clozapine will increase the level or effect of brexpiprazole by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Administer a quarter of brexpiprazole dose if coadministered with a moderate CYP2D6 inhibitor PLUS a strong/moderate CYP3A4 inhibitor.

              clozapine will increase the level or effect of brexpiprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Administer a quarter of brexpiprazole dose if coadministered with a moderate CYP3A4 inhibitor PLUS a strong/moderate CYP2D6 inhibitor.

            • brompheniramine

              brompheniramine and clozapine both increase sedation. Use Caution/Monitor.

            • budesonide

              budesonide will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • buprenorphine

              buprenorphine and clozapine both increase sedation. Use Caution/Monitor.

            • buprenorphine buccal

              buprenorphine buccal and clozapine both increase sedation. Use Caution/Monitor.

            • buprenorphine subdermal implant

              clozapine will increase the level or effect of buprenorphine subdermal implant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor patients already on buprenorphine subdermal implant who require newly-initiated treatment with CYP3A4 inhibitors for signs and symptoms of overmedication. If the dose of the concomitant CYP3A4 inhibitor cannot be reduced or discontinued, implant removal may be necessary and the patient should then be treated with a buprenorphine dosage form that permits dose adjustments. If a CYP3A4 inhibitor is discontinued in a patient who has been stabilized on buprenorphine, monitor the patient for withdrawal.

            • buprenorphine, long-acting injection

              clozapine will increase the level or effect of buprenorphine, long-acting injection by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Patients who transfer to buprenorphine long-acting injection from transmucosal buprenorphine coadministered with CYP3A4 inhibitors should be monitored to ensure buprenorphine plasma levels are adequate. Within 2 weeks, if signs and symptoms of buprenorphine toxicity or overdose occur and the concomitant CYP3A4 inhibitor cannot be reduced or discontinued, transition the patient back to a buprenorphine formulation that permits dose adjustments.

              clozapine increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

            • butabarbital

              butabarbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              butabarbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butabarbital and clozapine both increase sedation. Use Caution/Monitor.

            • butalbital

              butalbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butalbital and clozapine both increase sedation. Use Caution/Monitor.

            • butorphanol

              butorphanol and clozapine both increase sedation. Use Caution/Monitor.

            • cabozantinib

              clozapine will increase the level or effect of cabozantinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • caffeine

              clozapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • cannabidiol

              clozapine will increase the level or effect of cannabidiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider reducing the cannabidiol dose when coadministered with a moderate CYP3A4 inhibitor.

            • captopril

              clozapine increases toxicity of captopril by pharmacodynamic synergism. Use Caution/Monitor. Both drugs lower blood pressure. Monitor blood pressure.

            • carbamazepine

              carbamazepine will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • carbinoxamine

              carbinoxamine and clozapine both increase sedation. Use Caution/Monitor.

            • carisoprodol

              carisoprodol and clozapine both increase sedation. Use Caution/Monitor.

            • cenobamate

              cenobamate, clozapine. Either increases effects of the other by sedation. Use Caution/Monitor.

            • chloral hydrate

              chloral hydrate and clozapine both increase sedation. Use Caution/Monitor.

            • chlordiazepoxide

              chlordiazepoxide and clozapine both increase sedation. Use Caution/Monitor.

            • chloroquine

              chloroquine increases toxicity of clozapine by QTc interval. Use Caution/Monitor.

            • chlorpheniramine

              chlorpheniramine and clozapine both increase sedation. Use Caution/Monitor.

            • chlorpromazine

              chlorpromazine and clozapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              chlorpromazine and clozapine both increase sedation. Use Caution/Monitor.

            • chlorpropamide

              clozapine, chlorpropamide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • chlorzoxazone

              chlorzoxazone and clozapine both increase sedation. Use Caution/Monitor.

            • cigarette smoking

              cigarette smoking will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • cimetidine

              cimetidine will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • cinnarizine

              cinnarizine and clozapine both increase sedation. Use Caution/Monitor.

            • cisatracurium

              cisatracurium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              cisatracurium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of cisatracurium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • citalopram

              citalopram increases effects of clozapine by pharmacodynamic synergism. Use Caution/Monitor. Increased risk for serotonin syndrome.

            • clemastine

              clemastine and clozapine both increase sedation. Use Caution/Monitor.

            • clobazam

              clozapine, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

            • clomipramine

              clozapine and clomipramine both increase sedation. Use Caution/Monitor.

            • clonazepam

              clonazepam and clozapine both increase sedation. Use Caution/Monitor.

            • clonidine

              clonidine, clozapine. Mechanism: pharmacodynamic synergism. Use Caution/Monitor. Additive hypotensive effects; potential delirium.

            • clorazepate

              clorazepate and clozapine both increase sedation. Use Caution/Monitor.

            • codeine

              codeine and clozapine both increase sedation. Use Caution/Monitor.

              clozapine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • conivaptan

              conivaptan will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cortisone

              cortisone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cyclizine

              cyclizine and clozapine both increase sedation. Use Caution/Monitor.

              cyclizine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              cyclizine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of cyclizine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • cyclobenzaprine

              cyclobenzaprine and clozapine both increase sedation. Use Caution/Monitor.

              cyclobenzaprine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              cyclobenzaprine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of cyclobenzaprine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • cyclosporine

              cyclosporine will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cyproheptadine

              cyproheptadine and clozapine both increase sedation. Use Caution/Monitor.

            • dantrolene

              dantrolene and clozapine both increase sedation. Use Caution/Monitor.

            • darifenacin

              darifenacin will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              darifenacin decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              darifenacin decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of darifenacin by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • darunavir

              darunavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dasatinib

              dasatinib will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • deferasirox

              deferasirox increases levels of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • deflazacort

              clozapine will increase the level or effect of deflazacort by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Decrease deflazacort dose to one-third of the recommended dose if coadministered with moderate or strong CYP3A4 inhibitors.

            • degarelix

              clozapine and degarelix both increase QTc interval. Use Caution/Monitor.

            • desflurane

              desflurane and clozapine both increase sedation. Use Caution/Monitor.

            • desipramine

              clozapine and desipramine both increase sedation. Use Caution/Monitor.

              clozapine and desipramine both increase QTc interval. Use Caution/Monitor.

            • deutetrabenazine

              clozapine and deutetrabenazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Modify Therapy/Monitor Closely. The risk for parkinsonism, neuroleptic malignant syndrome, and akathisia may be increased by concomitant use of deutetrabenazine and dopamine antagonists or antipsychotics.

              clozapine and deutetrabenazine both increase sedation. Use Caution/Monitor.

            • dexamethasone

              dexamethasone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dexchlorpheniramine

              dexchlorpheniramine and clozapine both increase sedation. Use Caution/Monitor.

            • dexfenfluramine

              clozapine increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dexmedetomidine

              dexmedetomidine and clozapine both increase sedation. Use Caution/Monitor.

            • dexmethylphenidate

              clozapine increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dextroamphetamine

              clozapine increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dextromethorphan

              dextromethorphan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • dextromoramide

              dextromoramide and clozapine both increase sedation. Use Caution/Monitor.

            • DHEA, herbal

              DHEA, herbal will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • diamorphine

              diamorphine and clozapine both increase sedation. Use Caution/Monitor.

            • diazepam

              diazepam and clozapine both increase sedation. Use Caution/Monitor.

              diazepam, clozapine. Mechanism: pharmacodynamic synergism. Use Caution/Monitor. Possible risk of cardiorespiratory collapse.

            • diazepam intranasal

              clozapine will increase the level or effect of diazepam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Strong or moderate CYP3A4 inhibitors may decrease rate of diazepam elimination, thereby increasing adverse reactions to diazepam.

            • dicyclomine

              dicyclomine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              dicyclomine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of dicyclomine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • diethylpropion

              clozapine increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • difenoxin hcl

              difenoxin hcl and clozapine both increase sedation. Use Caution/Monitor.

            • dihydroergotamine

              dihydroergotamine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • diltiazem

              diltiazem will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors can increase clozapine levels and lead to adverse reactions. Use caution and monitor patients closely when using such inhibitors. Consider reducing clozapine dose.

            • dimenhydrinate

              dimenhydrinate and clozapine both increase sedation. Use Caution/Monitor.

            • diphenhydramine

              diphenhydramine and clozapine both increase sedation. Use Caution/Monitor.

              diphenhydramine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              diphenhydramine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of diphenhydramine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • diphenoxylate hcl

              diphenoxylate hcl and clozapine both increase sedation. Use Caution/Monitor.

            • dipipanone

              dipipanone and clozapine both increase sedation. Use Caution/Monitor.

            • dobutamine

              clozapine increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dolasetron

              clozapine and dolasetron both increase QTc interval. Use Caution/Monitor.

            • dopamine

              clozapine increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dopexamine

              clozapine increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dosulepin

              clozapine and dosulepin both increase sedation. Use Caution/Monitor.

            • doxepin

              clozapine and doxepin both increase sedation. Use Caution/Monitor.

            • doxylamine

              doxylamine and clozapine both increase sedation. Use Caution/Monitor.

            • dronedarone

              dronedarone will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • droperidol

              clozapine and droperidol both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and droperidol both increase sedation. Use Caution/Monitor.

            • efavirenz

              efavirenz will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • eletriptan

              eletriptan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • ephedrine

              clozapine increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • epinephrine

              clozapine increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clozapine decreases effects of epinephrine by pharmacodynamic antagonism. Use Caution/Monitor. Block pressor response to epinephrine, which may result in severe hypotension and tachycardia.

            • epinephrine racemic

              clozapine increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clozapine decreases effects of epinephrine racemic by pharmacodynamic antagonism. Use Caution/Monitor. Block pressor response to epinephrine, which may result in severe hypotension and tachycardia.

            • ergoloid mesylates

              ergoloid mesylates, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • ergotamine

              ergotamine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • erythromycin base

              erythromycin base will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • erythromycin ethylsuccinate

              erythromycin ethylsuccinate will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • erythromycin lactobionate

              erythromycin lactobionate will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • erythromycin stearate

              erythromycin stearate will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • escitalopram

              escitalopram increases levels of clozapine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Plasma levels of clozapine may be increased, resulting in increased pharmacologic and toxic effects. Adjust clozapine dose as needed when initiating or discontinuing certain SSRIs. .

              escitalopram increases toxicity of clozapine by QTc interval. Use Caution/Monitor.

            • esketamine intranasal

              esketamine intranasal, clozapine. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

            • esomeprazole

              esomeprazole will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • estazolam

              estazolam and clozapine both increase sedation. Use Caution/Monitor.

            • ethanol

              clozapine and ethanol both increase sedation. Use Caution/Monitor.

            • etomidate

              etomidate and clozapine both increase sedation. Use Caution/Monitor.

            • etravirine

              etravirine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • exenatide injectable solution

              clozapine, exenatide injectable solution. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • exenatide injectable suspension

              clozapine, exenatide injectable suspension. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • fenfluramine

              clozapine increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clozapine decreases effects of fenfluramine by pharmacodynamic antagonism. Use Caution/Monitor. Potent serotonin receptor antagonists may decrease fenfluramine efficacy. If coadministered, monitor appropriately.

            • fentanyl

              fentanyl, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • fesoterodine

              fesoterodine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              fesoterodine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of fesoterodine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • fexinidazole

              fexinidazole will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • finerenone

              clozapine will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or moderate CYP3A4 inhibitors. Adjust finererone dosage as needed.

            • flavoxate

              flavoxate decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              flavoxate decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of flavoxate by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • flibanserin

              flibanserin, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • fluconazole

              fluconazole will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fludrocortisone

              fludrocortisone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fluoxetine

              fluoxetine increases levels of clozapine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Plasma levels of clozapine may be increased, resulting in increased pharmacologic and toxic effects. Adjust clozapine dose as needed when initiating or discontinuing certain SSRIs. .

              clozapine and fluoxetine both increase QTc interval. Modify Therapy/Monitor Closely.

            • fluphenazine

              clozapine and fluphenazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and fluphenazine both increase sedation. Use Caution/Monitor.

              clozapine and fluphenazine both increase QTc interval. Use Caution/Monitor.

            • flurazepam

              flurazepam and clozapine both increase sedation. Use Caution/Monitor.

            • fluvoxamine

              fluvoxamine will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

            • formoterol

              clozapine increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • fosamprenavir

              fosamprenavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fosphenytoin

              fosphenytoin will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fostemsavir

              clozapine and fostemsavir both increase QTc interval. Use Caution/Monitor. QTc prolongation reported with higher than recommended doses of fostemsavir.

            • frovatriptan

              frovatriptan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • gadobenate

              clozapine and gadobenate both increase QTc interval. Use Caution/Monitor.

            • gemifloxacin

              clozapine and gemifloxacin both increase QTc interval. Use Caution/Monitor.

            • gemtuzumab

              clozapine and gemtuzumab both increase QTc interval. Use Caution/Monitor.

            • gilteritinib

              clozapine and gilteritinib both increase QTc interval. Use Caution/Monitor.

            • glimepiride

              clozapine, glimepiride. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • glipizide

              clozapine, glipizide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • glyburide

              clozapine, glyburide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • glycopyrrolate

              clozapine increases effects of glycopyrrolate by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • glycopyrrolate inhaled

              glycopyrrolate inhaled decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              glycopyrrolate inhaled decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of glycopyrrolate inhaled by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • goserelin

              goserelin increases toxicity of clozapine by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

            • granisetron

              clozapine and granisetron both increase QTc interval. Use Caution/Monitor.

            • grapefruit

              grapefruit will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • green tea

              green tea decreases effects of clozapine by Other (see comment). Use Caution/Monitor. Comment: (Theoretical, due to caffeine content) High caffeine doses (400 1000mg/day) may increase levels/toxicity of clozapine. Clozapine clearance may decrease during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. .

            • griseofulvin

              griseofulvin will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • guanfacine

              guanfacine, clozapine. Mechanism: pharmacodynamic synergism. Use Caution/Monitor. Additive hypotensive effects; potential delirium.

              clozapine will increase the level or effect of guanfacine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Strong or moderate CYP3A4 inhibitors significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if coadministered, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available.

            • haloperidol

              clozapine and haloperidol both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and haloperidol both increase sedation. Use Caution/Monitor.

              haloperidol and clozapine both increase QTc interval. Use Caution/Monitor.

            • henbane

              henbane decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              henbane decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of henbane by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • histrelin

              histrelin increases toxicity of clozapine by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

            • homatropine

              homatropine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              homatropine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of homatropine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • hydrocortisone

              hydrocortisone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • hydromorphone

              hydromorphone and clozapine both increase sedation. Use Caution/Monitor.

            • hydroxyurea

              clozapine, hydroxyurea. Other (see comment). Use Caution/Monitor. Comment: Avoid combination. Combination may increase risk of myelosuppression.

            • hydroxyzine

              hydroxyzine and clozapine both increase sedation. Use Caution/Monitor.

            • hyoscyamine

              hyoscyamine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              hyoscyamine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of hyoscyamine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • hyoscyamine spray

              clozapine increases effects of hyoscyamine spray by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

              hyoscyamine spray decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              hyoscyamine spray decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

            • ibrutinib

              clozapine increases levels of ibrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with moderate CYP3A4 inhibitors, reduce ibrutinib dose to 280 mg qDay (B-cell malignancies) or 420 mg qDay (graft versus host disease). After CYP3A inhibitor discontinuation, resume previous dose of ibrutinib.

            • ifosfamide

              ifosfamide, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Ifosfamide may enhance the toxicities of myelosuppressive agents. Monitor for increased risk of myelosuppression.

            • iloperidone

              clozapine and iloperidone both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and iloperidone both increase sedation. Use Caution/Monitor.

            • imipramine

              clozapine and imipramine both increase sedation. Use Caution/Monitor.

            • incobotulinumtoxinA

              clozapine, incobotulinumtoxinA. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Use of anticholinergic drugs after administration of botulinum toxin-containing products may potentiate systemic anticholinergic effects.

            • indacaterol, inhaled

              clozapine and indacaterol, inhaled both increase QTc interval. Use Caution/Monitor.

            • indinavir

              indinavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • insulin aspart

              clozapine, insulin aspart. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • insulin degludec

              clozapine decreases effects of insulin degludec by Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; dose of antidiabetic agents may need adjustment and increased frequency of glucose monitoring may be required.

            • insulin degludec/insulin aspart

              clozapine decreases effects of insulin degludec/insulin aspart by Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; dose of antidiabetic agents may need adjustment and increased frequency of glucose monitoring may be required.

            • insulin detemir

              clozapine, insulin detemir. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • insulin glargine

              clozapine, insulin glargine. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • insulin glulisine

              clozapine, insulin glulisine. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • insulin inhaled

              clozapine decreases effects of insulin inhaled by Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; dose of antidiabetic agents may need adjustment and increased frequency of glucose monitoring may be required.

            • insulin lispro

              clozapine, insulin lispro. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • insulin NPH

              clozapine, insulin NPH. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • insulin regular human

              clozapine, insulin regular human. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • ipratropium

              ipratropium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              ipratropium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of ipratropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • isavuconazonium sulfate

              clozapine will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • isoniazid

              isoniazid will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              isoniazid will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • isoproterenol

              clozapine increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • isradipine

              clozapine and isradipine both increase QTc interval. Use Caution/Monitor.

            • ivacaftor

              clozapine will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with moderate CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification.

            • ketamine

              ketamine and clozapine both increase sedation. Use Caution/Monitor.

            • ketotifen, ophthalmic

              clozapine and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

            • lapatinib

              clozapine and lapatinib both increase QTc interval. Use Caution/Monitor.

            • lasmiditan

              lasmiditan, clozapine. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

            • lefamulin

              clozapine will increase the level or effect of lefamulin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for adverse effects if lefamulin is coadministered with moderate CYP3A inhibitors.

            • lemborexant

              lemborexant, clozapine. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

            • lenvatinib

              clozapine and lenvatinib both increase QTc interval. Use Caution/Monitor. Lenvatinib prescribing information recommends monitoring ECG closely when coadministered with QT prolonging drugs.

            • letermovir

              letermovir increases levels of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • leuprolide

              leuprolide increases toxicity of clozapine by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

            • levalbuterol

              clozapine increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clozapine and levalbuterol both increase QTc interval. Use Caution/Monitor.

            • levamlodipine

              clozapine will increase the level or effect of levamlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with moderate and strong CYP3A inhibitors results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors to determine the need for dose adjustment.

            • levofloxacin

              clozapine and levofloxacin both increase QTc interval. Use Caution/Monitor.

            • levomilnacipran

              levomilnacipran, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • levorphanol

              levorphanol and clozapine both increase sedation. Use Caution/Monitor.

            • linezolid

              linezolid, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • liraglutide

              clozapine, liraglutide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • lisdexamfetamine

              clozapine increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • lithium

              lithium, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • lofepramine

              clozapine and lofepramine both increase sedation. Use Caution/Monitor.

            • lofexidine

              clozapine and lofexidine both increase sedation. Use Caution/Monitor.

            • lomustine

              lomustine, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Monitor for neutropenia when taking clozapine and another myelosuppressive agent.

            • loprazolam

              loprazolam and clozapine both increase sedation. Use Caution/Monitor.

            • lorazepam

              lorazepam and clozapine both increase sedation. Use Caution/Monitor.

              lorazepam, clozapine. Mechanism: pharmacodynamic synergism. Use Caution/Monitor. Possible risk of cardiorespiratory collapse.

            • lorcaserin

              lorcaserin, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • lormetazepam

              lormetazepam and clozapine both increase sedation. Use Caution/Monitor.

            • loxapine

              clozapine and loxapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and loxapine both increase sedation. Use Caution/Monitor.

            • loxapine inhaled

              clozapine and loxapine inhaled both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and loxapine inhaled both increase sedation. Use Caution/Monitor.

            • lumefantrine

              lumefantrine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lurasidone

              lurasidone, clozapine. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

            • maprotiline

              clozapine and maprotiline both increase sedation. Use Caution/Monitor.

            • marijuana

              marijuana will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              clozapine and marijuana both increase sedation. Use Caution/Monitor.

            • mechlorethamine

              mechlorethamine, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Mechlorethamine may enhance the toxicities of myelosuppressive agents. Monitor for increased risk of myelosuppression.

            • meclizine

              meclizine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              meclizine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of meclizine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • mefloquine

              clozapine will increase the level or effect of mefloquine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              clozapine and mefloquine both increase QTc interval. Use Caution/Monitor.

            • melatonin

              clozapine and melatonin both increase sedation. Use Caution/Monitor.

            • meperidine

              meperidine and clozapine both increase sedation. Use Caution/Monitor.

              meperidine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • meprobamate

              clozapine and meprobamate both increase sedation. Use Caution/Monitor.

            • metaproterenol

              clozapine increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • metaxalone

              metaxalone and clozapine both increase sedation. Use Caution/Monitor.

            • metformin

              clozapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • methadone

              methadone and clozapine both increase sedation. Use Caution/Monitor.

              methadone, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • methamphetamine

              clozapine increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • methocarbamol

              methocarbamol and clozapine both increase sedation. Use Caution/Monitor.

            • methscopolamine

              methscopolamine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              methscopolamine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of methscopolamine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • methylenedioxymethamphetamine

              clozapine increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • methylergonovine

              methylergonovine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • methylphenidate

              clozapine increases toxicity of methylphenidate by pharmacodynamic antagonism. Use Caution/Monitor. Closely monitor for signs of altered clinical response to either methylphenidate or an antipsychotic when using these drugs in combination.

            • methylprednisolone

              methylprednisolone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • metoclopramide

              clozapine and metoclopramide both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

            • metronidazole

              metronidazole will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • mexiletine

              mexiletine will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • miconazole vaginal

              miconazole vaginal will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • midazolam

              midazolam and clozapine both increase sedation. Use Caution/Monitor.

            • midazolam intranasal

              midazolam intranasal, clozapine. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

            • midodrine

              clozapine increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • mifepristone

              mifepristone, clozapine. QTc interval. Modify Therapy/Monitor Closely. Use alternatives if available.

            • miglitol

              clozapine, miglitol. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • milnacipran

              milnacipran, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • mirtazapine

              clozapine and mirtazapine both increase sedation. Use Caution/Monitor.

              clozapine and mirtazapine both increase QTc interval. Use Caution/Monitor.

            • modafinil

              modafinil will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              modafinil will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              clozapine increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • morphine

              morphine and clozapine both increase sedation. Use Caution/Monitor.

            • motherwort

              clozapine and motherwort both increase sedation. Use Caution/Monitor.

            • moxonidine

              clozapine and moxonidine both increase sedation. Use Caution/Monitor.

            • nabilone

              clozapine and nabilone both increase sedation. Use Caution/Monitor.

            • nalbuphine

              nalbuphine and clozapine both increase sedation. Use Caution/Monitor.

            • naldemedine

              clozapine increases levels of naldemedine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor naldemedine for potential adverse effects if coadministered with strong or moderate CYP3A4 inhibitors.

            • naratriptan

              naratriptan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • nateglinide

              clozapine, nateglinide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • nefazodone

              nefazodone will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nelfinavir

              nelfinavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nevirapine

              nevirapine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nifedipine

              nifedipine will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nilotinib

              nilotinib will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              clozapine and nilotinib both increase QTc interval. Use Caution/Monitor.

            • norepinephrine

              clozapine increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • nortriptyline

              clozapine and nortriptyline both increase sedation. Use Caution/Monitor.

              clozapine and nortriptyline both increase QTc interval. Use Caution/Monitor.

            • octreotide

              clozapine and octreotide both increase QTc interval. Use Caution/Monitor.

            • ofloxacin

              clozapine and ofloxacin both increase QTc interval. Use Caution/Monitor.

            • olanzapine

              clozapine and olanzapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and olanzapine both increase sedation. Use Caution/Monitor.

            • oliceridine

              clozapine will increase the level or effect of oliceridine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. If concomitant use is necessary, may require less frequent oliceridine dosing. Closely monitor for respiratory depression and sedation and titrate subsequent doses accordingly. If inhibitor is discontinued, consider increase oliceridine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

              clozapine will increase the level or effect of oliceridine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If concomitant use is necessary, may require less frequent oliceridine dosing. Closely monitor for respiratory depression and sedation and titrate subsequent doses accordingly. If inhibitor is discontinued, consider increase oliceridine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

              oliceridine, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • olodaterol inhaled

              clozapine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor.

            • omeprazole

              omeprazole will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • onabotulinumtoxinA

              onabotulinumtoxinA decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              onabotulinumtoxinA decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of onabotulinumtoxinA by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • opium tincture

              opium tincture and clozapine both increase sedation. Use Caution/Monitor.

            • orphenadrine

              orphenadrine and clozapine both increase sedation. Use Caution/Monitor.

            • osilodrostat

              osilodrostat and clozapine both increase QTc interval. Use Caution/Monitor.

            • osimertinib

              osimertinib and clozapine both increase QTc interval. Use Caution/Monitor. Conduct periodic monitoring with ECGs and electrolytes in patients taking drugs known to prolong the QTc interval.

            • oxaliplatin

              oxaliplatin and clozapine both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Use of oxaliplatin with concomitant immunosuppressants or with impaired immune systems may increased risk for serious infections.

              oxaliplatin will increase the level or effect of clozapine by Other (see comment). Use Caution/Monitor. Monitor for ECG changes if therapy is initiated in patients with drugs known to prolong QT interval.

            • oxazepam

              oxazepam and clozapine both increase sedation. Use Caution/Monitor.

            • oxcarbazepine

              oxcarbazepine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • oxybutynin

              oxybutynin decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              oxybutynin decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of oxybutynin by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • oxybutynin topical

              oxybutynin topical decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              oxybutynin topical decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of oxybutynin topical by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • oxybutynin transdermal

              oxybutynin transdermal decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              oxybutynin transdermal decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of oxybutynin transdermal by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • oxycodone

              oxycodone and clozapine both increase sedation. Use Caution/Monitor.

            • oxymorphone

              oxymorphone and clozapine both increase sedation. Use Caution/Monitor.

            • ozanimod

              ozanimod and clozapine both increase QTc interval. Modify Therapy/Monitor Closely. The potential additive effects on heart rate, treatment with ozanimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties.

            • palbociclib

              clozapine will increase the level or effect of palbociclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • paliperidone

              clozapine and paliperidone both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and paliperidone both increase sedation. Use Caution/Monitor.

            • pancuronium

              pancuronium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              pancuronium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of pancuronium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • papaveretum

              papaveretum and clozapine both increase sedation. Use Caution/Monitor.

            • papaverine

              clozapine and papaverine both increase sedation. Use Caution/Monitor.

            • paroxetine

              paroxetine increases levels of clozapine by decreasing metabolism. Use Caution/Monitor. Plasma levels of clozapine may be increased, resulting in increased pharmacologic and toxic effects. Adjust clozapine dose as needed when initiating or discontinuing certain SSRIs. .

              paroxetine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • pasireotide

              clozapine and pasireotide both increase QTc interval. Modify Therapy/Monitor Closely.

            • peginterferon alfa 2a

              peginterferon alfa 2a will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • pentazocine

              pentazocine and clozapine both increase sedation. Use Caution/Monitor.

            • pentobarbital

              pentobarbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              pentobarbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              pentobarbital and clozapine both increase sedation. Use Caution/Monitor.

            • perphenazine

              clozapine and perphenazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and perphenazine both increase sedation. Use Caution/Monitor.

              clozapine and perphenazine both increase QTc interval. Use Caution/Monitor.

            • phendimetrazine

              clozapine increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenelzine

              phenelzine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • phenobarbital

              phenobarbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              phenobarbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenobarbital and clozapine both increase sedation. Use Caution/Monitor.

            • phentermine

              clozapine increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenylephrine

              clozapine increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenylephrine PO

              clozapine increases and phenylephrine PO decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. .

            • phenytoin

              phenytoin will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. When adding phenytoin therapy to patients stabilized on clozapine, monitor patient closely for worsening of psychotic symptoms. If needed, increase the clozapine dose cautiously on basis of psychotic symptoms. Conversely, when phenytoin is discontinued, levels of clozapine may significantly increase.

            • pholcodine

              clozapine and pholcodine both increase sedation. Use Caution/Monitor.

            • pimozide

              clozapine and pimozide both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and pimozide both increase sedation. Use Caution/Monitor.

            • pioglitazone

              clozapine, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • pipemidic acid

              pipemidic acid will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • pirbuterol

              clozapine increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • posaconazole

              posaconazole will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • pralidoxime

              pralidoxime decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              pralidoxime decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of pralidoxime by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • prednisone

              prednisone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • primaquine

              clozapine and primaquine both increase QTc interval. Use Caution/Monitor.

            • primidone

              primidone will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              primidone will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              primidone and clozapine both increase sedation. Use Caution/Monitor.

            • procarbazine

              procarbazine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • prochlorperazine

              clozapine and prochlorperazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and prochlorperazine both increase sedation. Use Caution/Monitor.

            • promethazine

              clozapine and promethazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              promethazine and clozapine both increase sedation. Use Caution/Monitor.

              promethazine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • propantheline

              propantheline decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              propantheline decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of propantheline by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • propofol

              propofol and clozapine both increase sedation. Use Caution/Monitor.

            • propylhexedrine

              clozapine increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • protriptyline

              clozapine and protriptyline both increase sedation. Use Caution/Monitor.

              clozapine and protriptyline both increase QTc interval. Use Caution/Monitor.

            • quazepam

              quazepam and clozapine both increase sedation. Use Caution/Monitor.

            • quetiapine

              clozapine and quetiapine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and quetiapine both increase sedation. Use Caution/Monitor.

            • quinine

              clozapine and quinine both increase QTc interval. Use Caution/Monitor.

            • quinupristin/dalfopristin

              quinupristin/dalfopristin will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ramelteon

              clozapine and ramelteon both increase sedation. Use Caution/Monitor.

            • rapacuronium

              rapacuronium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              rapacuronium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of rapacuronium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • remimazolam

              remimazolam, clozapine. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

            • repaglinide

              clozapine, repaglinide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • rifampin

              rifampin will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • rifapentine

              rifapentine will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rilpivirine

              clozapine and rilpivirine both increase QTc interval. Use Caution/Monitor.

            • rimabotulinumtoxinB

              clozapine increases effects of rimabotulinumtoxinB by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • rimegepant

              clozapine will increase the level or effect of rimegepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid repeating rimegepant dose within 48 hr if coadministered with a moderate CYP3A4 inhibitor.

            • risperidone

              clozapine and risperidone both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and risperidone both increase sedation. Use Caution/Monitor.

              clozapine and risperidone both increase QTc interval. Use Caution/Monitor.

            • ritonavir

              ritonavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rocuronium

              rocuronium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              rocuronium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of rocuronium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • rucaparib

              rucaparib will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP1A2 substrates, if clinically indicated.

            • rufinamide

              rufinamide will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ruxolitinib

              clozapine will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • salmeterol

              clozapine increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clozapine and salmeterol both increase QTc interval. Use Caution/Monitor.

            • saxagliptin

              clozapine, saxagliptin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • scopolamine

              scopolamine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              scopolamine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of scopolamine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • scullcap

              clozapine and scullcap both increase sedation. Use Caution/Monitor.

            • secobarbital

              secobarbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              secobarbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              secobarbital and clozapine both increase sedation. Use Caution/Monitor.

            • selegiline

              selegiline, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • selpercatinib

              selpercatinib increases toxicity of clozapine by QTc interval. Use Caution/Monitor.

            • sertraline

              sertraline increases levels of clozapine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Plasma levels of clozapine may be increased, resulting in increased pharmacologic and toxic effects. Adjust clozapine dose as needed when initiating or discontinuing certain SSRIs. .

              clozapine and sertraline both increase QTc interval. Use Caution/Monitor.

            • sevoflurane

              sevoflurane and clozapine both increase sedation. Use Caution/Monitor.

            • shepherd's purse

              clozapine and shepherd's purse both increase sedation. Use Caution/Monitor.

            • sitagliptin

              clozapine, sitagliptin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • smoking

              smoking will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • sodium sulfate/?magnesium sulfate/potassium chloride

              sodium sulfate/?magnesium sulfate/potassium chloride increases effects of clozapine by unknown mechanism. Use Caution/Monitor. Closely monitor for evidence of enhanced CNS depression when using higher dose of magnesium sulfate together with a CNS depressant.

            • sodium sulfate/potassium sulfate/magnesium sulfate

              sodium sulfate/potassium sulfate/magnesium sulfate increases effects of clozapine by unknown mechanism. Use Caution/Monitor. Closely monitor for evidence of enhanced CNS depression when using higher dose of magnesium sulfate together with a CNS depressant.

            • solifenacin

              solifenacin decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              solifenacin decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of solifenacin by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

              clozapine and solifenacin both increase QTc interval. Use Caution/Monitor.

            • sonidegib

              clozapine will increase the level or effect of sonidegib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of sonidegib with moderate CYP3A4 inhibitors. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for <14 days and monitor closely for adverse reactions, particularly musculoskeletal adverse reactions.

            • sorafenib

              sorafenib and clozapine both increase QTc interval. Use Caution/Monitor.

            • stiripentol

              stiripentol, clozapine. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP1A2 inhibitor and inducer. Monitor CYP1A2 substrates coadministered with stiripentol for increased or decreased effects. CYP1A2 substrates may require dosage adjustment.

            • sufentanil

              sufentanil and clozapine both increase sedation. Use Caution/Monitor.

            • sufentanil SL

              clozapine will increase the level or effect of sufentanil SL by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of sufentanil SL with any CYP3A4 inhibitor may increase sufentanil plasma concentration, and, thereby increase or prolonged adverse effects, including potentially fatal respiratory depression.

            • sulfamethoxypyridazine

              sulfamethoxypyridazine increases toxicity of clozapine by unspecified interaction mechanism. Use Caution/Monitor. Possibly increased neutropenic effects.

            • sumatriptan

              sumatriptan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • sumatriptan intranasal

              sumatriptan intranasal, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • sunitinib

              clozapine and sunitinib both increase QTc interval. Use Caution/Monitor.

            • suvorexant

              clozapine will increase the level or effect of suvorexant by affecting hepatic enzyme CYP2E1 metabolism. Modify Therapy/Monitor Closely. Decrease suvorexant starting dose to 5 mg HS if coadministered with moderate CYP3A4 inhibitors

            • tacrolimus

              clozapine and tacrolimus both increase QTc interval. Use Caution/Monitor.

            • tamsulosin

              clozapine increases levels of tamsulosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.

              clozapine increases levels of tamsulosin by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • tapentadol

              tapentadol and clozapine both increase sedation. Use Caution/Monitor.

            • telavancin

              clozapine and telavancin both increase QTc interval. Use Caution/Monitor.

            • temazepam

              temazepam and clozapine both increase sedation. Use Caution/Monitor.

            • terbutaline

              clozapine increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • teriflunomide

              teriflunomide decreases levels of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • tetrabenazine

              clozapine and tetrabenazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Modify Therapy/Monitor Closely.

            • tezacaftor

              clozapine will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a moderate CYP3A inhibitor.

            • thioridazine

              clozapine and thioridazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and thioridazine both increase sedation. Use Caution/Monitor.

            • thiothixene

              clozapine and thiothixene both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and thiothixene both increase sedation. Use Caution/Monitor.

            • tinidazole

              clozapine will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tiotropium

              tiotropium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              tiotropium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • tobacco use

              tobacco use will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • tofacitinib

              clozapine increases levels of tofacitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. No specific dose adjustment recommended when tofacitinib coadministered with moderate CYP3A4 inhibitors; decrease tofacitinib dose if coadministered with both moderate CYP3A4 and potent CYP2C19 inhibitors.

            • tolazamide

              clozapine, tolazamide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • tolbutamide

              clozapine, tolbutamide. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

            • tolterodine

              tolterodine decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              tolterodine decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of tolterodine by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • topiramate

              topiramate will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              clozapine and topiramate both increase sedation. Modify Therapy/Monitor Closely.

            • trabectedin

              clozapine will increase the level or effect of trabectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tramadol

              tramadol and clozapine both increase sedation. Use Caution/Monitor.

            • tranylcypromine

              tranylcypromine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • trazodone

              clozapine and trazodone both increase sedation. Use Caution/Monitor.

            • triazolam

              triazolam and clozapine both increase sedation. Use Caution/Monitor.

            • triclabendazole

              clozapine and triclabendazole both increase QTc interval. Use Caution/Monitor.

            • triclofos

              triclofos and clozapine both increase sedation. Use Caution/Monitor.

            • trifluoperazine

              clozapine and trifluoperazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and trifluoperazine both increase sedation. Use Caution/Monitor.

            • trihexyphenidyl

              clozapine increases effects of trihexyphenidyl by pharmacodynamic synergism. Use Caution/Monitor. Potential for additive anticholinergic effects.

            • trimipramine

              clozapine and trimipramine both increase sedation. Use Caution/Monitor.

              clozapine and trimipramine both increase QTc interval. Use Caution/Monitor.

            • triprolidine

              triprolidine and clozapine both increase sedation. Use Caution/Monitor.

            • triptorelin

              triptorelin increases toxicity of clozapine by QTc interval. Use Caution/Monitor. Increases risk of torsades de pointes.

            • trospium chloride

              trospium chloride decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              trospium chloride decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of trospium chloride by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • vardenafil

              clozapine and vardenafil both increase QTc interval. Use Caution/Monitor.

            • vecuronium

              vecuronium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              vecuronium decreases levels of clozapine by pharmacodynamic antagonism. Use Caution/Monitor.

              clozapine increases effects of vecuronium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

            • venlafaxine

              venlafaxine, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • verapamil

              verapamil will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              verapamil will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • vilazodone

              vilazodone, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • voclosporin

              clozapine will increase the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce voclosporin daily dosage to 15.8 mg PO in AM and 7.9 mg PO in PM.

              voclosporin, clozapine. Either increases effects of the other by QTc interval. Use Caution/Monitor.

            • voriconazole

              voriconazole will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • xylometazoline

              clozapine increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • yohimbine

              clozapine increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • zafirlukast

              zafirlukast will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • zanubrutinib

              clozapine will increase the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce zanubrutinib dose when coadministered with a moderate CYP3A4 inhibitor. Interrupt dose as recommended for adverse reactions. After discontinuing the CYP3A4 inhibitor, resume previous dose of zanubrutinib. See zanubrutinib Dosage Modifications for precise recommendation.

            • ziconotide

              clozapine and ziconotide both increase sedation. Use Caution/Monitor.

            • zileuton

              zileuton will increase the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • ziprasidone

              clozapine and ziprasidone both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and ziprasidone both increase sedation. Use Caution/Monitor.

            • zolmitriptan

              zolmitriptan, clozapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).

            • zotepine

              clozapine and zotepine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor.

              clozapine and zotepine both increase sedation. Use Caution/Monitor.

            Minor (10)

            • azithromycin

              azithromycin increases toxicity of clozapine by unspecified interaction mechanism. Minor/Significance Unknown. Enhanced CNS toxicity.

            • brimonidine

              brimonidine increases effects of clozapine by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

            • chasteberry

              chasteberry decreases effects of clozapine by pharmacodynamic antagonism. Minor/Significance Unknown. (Theoretical interaction).

            • cilostazol

              clozapine increases levels of cilostazol by decreasing metabolism. Minor/Significance Unknown.

            • eslicarbazepine acetate

              eslicarbazepine acetate will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • estradiol vaginal

              clozapine will increase the level or effect of estradiol vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ethanol

              ethanol, clozapine. Either increases toxicity of the other by pharmacodynamic synergism. Minor/Significance Unknown. Additive CNS depression.

            • eucalyptus

              clozapine and eucalyptus both increase sedation. Minor/Significance Unknown.

            • sage

              clozapine and sage both increase sedation. Minor/Significance Unknown.

            • valproic acid

              valproic acid decreases levels of clozapine by plasma protein binding competition. Minor/Significance Unknown.

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            Adverse Effects

            >10%

            Hypersalivation (13-48%)

            Sedation/somnolence (21-46%)

            Weight gain (4-31%)

            Dizziness (14-27%)

            Tachycardia (17-25%)

            Constipation (14-25%)

            Insomnia (2-20%)

            Dizziness/vertigo (19%)

            Nausea (17%)

            Vomiting (17%)

            Dyspepsia (14%)

            Hypotension (9-13%)

            Fever (5-13%)

            1-10%

            Headache (7-10%)

            Tremor (6%)

            Syncope (6%)

            Sweating (6%)

            Dry mouth (5-6%)

            Visual disturbances (5%)

            Disturbed sleep/nightmares (4%)

            Restlessness (4%)

            Hypokinesia/akinesia (4%)

            Agitation (4%)

            Hypertension (4%)

            Abdominal discomfort/heartburn (4%)

            Seizures (3%)

            Rigidity (3%)

            Akathisia (3%)

            Confusion (3%)

            Leukopenia/neutropenia (3%)

            Fatigue (2%)

            Diarrhea (2%)

            Urinary abnormalities (2%)

            Rash (2%)

            Postmarketing Reports

            Skin: Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome, skin pigmentation disorder

            Musculoskeletal system: Myasthenic syndrome, rhabdomyolysis, systemic lupus erythematosus

            Respiratory system: Aspiration, pleural effusion, pneumonia and lower respiratory tract infection (LRTI), which may be fatal, sleep apnea

            Central nervous system: Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions, tardive dyskinesia, neuroleptic malignant syndrome, restless leg syndrome

            Cardiovascular: Atrial or ventricular tachycardia or fibrillation, periorbital edema, myocardial infarction, cardiac arrest, QT prolongation, Torsades de pointes, hypertension, mitral valve incompetence, bradycardia, cardiomyopathy, myocarditis

            Endocrine system: Pseudopheochromocytoma

            Gastrointestinal system: Acute pancreatitis, dysphagia, salivary gland swelling, colitis, hypersalivation, dry mouth

            Hepatobiliary: Hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure

            Immune system disorders: Angioedema, leukocytoclastic vasculitis

            Urogenital: Renal failure, nocturnal enuresis, acute interstitial nephritis, priapism, retrograde ejaculation

            Hemic and lymphatic system: DVT; elevated hemoglobin/hematocrit, ESR; sepsis, pulmonary embolism, thrombocytosis, thrombocytopenia, angioedema, leukocytoclastic vasculitis, eosinophilia

            Vision disorders: Narrow-angle glaucoma

            Miscellaneous: CPK elevation, hyperuricemia, hyponatremia, weight loss, polyserositis

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            Warnings

            Black Box Warnings

            Agranulocytosis

            • Available only through a restricted program called the Clozapine REMS
            • Severe neutropenia, defined as an absolute neutrophil count (ANC) <500/mm3, has been reported
            • Severe neutropenia can lead to serious infection and death
            • Before initiating, baseline ANC must be ≥1500/mm3 for the general population and ≥1000/mm3 for patients with documented benign ethnic neutropenia
            • Regularly monitor ANC during treatment
            • Advise patients to immediately report symptoms consistent with severe neutropenia or infection (eg, fever, weakness, lethargy, sore throat)

            Seizures

            • Caution with history of seizure or other factors predisposing to seizure
            • Risk is dose-related

            Myocarditis, cardiomyopathy, and mitral valve incompetence

            • Fatal myocarditis and cardiomyopathy reported; discontinue and obtain cardiac evaluation if suspected
            • Measuring brain NP levels may offer a means of monitoring to detect early, asymptomatic myocarditis
            • Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged; however, if benefit of treatment is judged to outweigh potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenging in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring

            Orthostatic hypotension, bradycardia, syncope

            • Orthostatic hypotension, bradycardia, syncope, and cardiac arrest may occur
            • Risk is highest during initial titration period, particularly with rapid dose escalation
            • May occur with the first dose, and with doses as low as 12.5 mg/day
            • Caution with history of cardiovascular or cerebrovascular disease or conditions predisposing to hypotension

            Increased mortality in elderly with dementia-related psychosis

            • Not approved for dementia-related psychosis; patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; deaths in these trials appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature

            Contraindications

            Hypersensitivity (eg, photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome)

            Cautions

            Increased risk of dose-related seizures

            Eosinophilia (blood eosinophil count >700/mm3) reported; associated in some patients with myocarditis, pancreatitis, hepatitis, colitis, and nephritis; organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS)

            Increased risk of cerebrovascular adverse events reported with some atypical antipsychotics (mechanism unknown)

            FDA warning regarding off-label use for dementia-related psychosis in elderly patients; increased risk of death

            Antipsychotic drugs can cause the potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS); if NMS occurs, immediately discontinue antipsychotic drug, and other drugs not essential to therapy; implement intensive symptomatic treatment and medical monitoring

            Possible QT prolongation; use with caution in patients with history of long QT syndrome or other conditions that may increase risk (eg, hypokalemia, hypomagnesemia)

            Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis reported in post marketing studies; monitor for appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy; perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine

            Transient fever reported; peak incidence is within first 3 weeks of treatment; although this fever is generally benign and self-limited, it may necessitate discontinuing treatment since fever can be associated with an increase or decrease in WBC count; evaluate patients with fever to rule out severe neutropenia or infection; consider possibility of NMS

            Pulmonary embolism (PE) and DVT reported; unclear whether PE and DVT can be attributed to clozapine

            Myocarditis, cardiomyopathy and mitral valve incompetence

            • Myocarditis, cardiomyopathy, and mitral valve incompetence reported, including fatalities; discontinue and obtain cardiac evaluation upon suspicion of myocarditis or cardiomyopathy
            • Consider the possibility of myocarditis or cardiomyopathy in patients receiving therapy who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression)
            • Myocarditis most frequently presents within first two months of clozapine treatment; symptoms generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment
            • However, myocarditis and cardiomyopathy can occur at any period during treatment; it is common for nonspecific flu- like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure
            • Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP)
            • Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction
            • In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported; these cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography
            • In patients with suspected cardiomyopathy, consider a 2D-echo Doppler examination to identify mitral valve incompetence

            Neutropenia

            • Only available through a restricted access program because of risk for neutropenia (ie, low ANC); patients must be registered, prescriber must enroll and complete training, and pharmacies dispensing clozapine must be certified and complete training
            • Severe neutropenia (ANC <500/mm³) occurs in a small percentage of patients and is associated with increased risk of serious and potentially fatal infections; risk is greatest during the first 18 weeks of treatment and then declines; see prescribing information for detailed information regarding monitoring ANC, including patients with benign ethnic neutropenia
            • Benign transient elevation of temperature reported, peaking within first 3 weeks of treatment (rule out agranulocytosis, infection, NMS)

            Metabolic changes

            • Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with esophageal dysmotility, ketoacidosis, hyperosmolar coma, or death; monitor blood glucose of high-risk patients
            • Dyslipidemia and weight gain reported with atypical antipsychotics

            Anticholinergic effects

            • Potent anticholinergic effects can occur that can result in CNS and peripheral anticholinergic toxicity
            • Caution with narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions
            • Impaired core body temperature regulation may occur; caution with strenuous exercise, dehydration, heat exposure, and concomitant medication possessing anticholinergic effects
            • Gastrointestinal adverse reactions, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus reported; such reactions can be fatal
            • Constipation should be initially treated by ensuring adequate hydration and use of ancillary therapy (eg, bulk laxatives); consult with gastroenterologist in more serious cases
            • Evaluate bowel function before initiating treatment
            • Instruct patients on preventive measures and to seek medical help if constipation occurs

            Cognitive and motor abilities

            • May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long- term antipsychotic therapy
            • May cause CNS depression, which may impair physical or mental abilities; caution patients about performing tasks that require mental alertness

            Tardive dyskinesia

            • Tardive dyskinesia (TD) has occurred with antipsychotic drugs
            • Syndrome consists of potentially irreversible, involuntary, dyskinetic movements
            • Risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses; however, the syndrome can develop after relatively brief treatment periods at low doses
            • Prescribe drug in a manner that is most likely to minimize TD risk
            • Use the lowest effective dose and the shortest duration necessary to control symptoms
            • Periodically assess need for continued treatment; consider discontinuing treatment if TD occurs
            • Some patients may require treatment despite the presence of the syndrome
            • There is no known treatment for TD; however, the syndrome may remit partially or completely if treatment is discontinued

            Drug interaction overview

            • CYP inhibitors and inducers
              • Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4
              • Clozapine dosage modification may be required if coadministered with drugs that inhibit or induce metabolism of clozapine (eg, CYP 1A2, 2D6, and 3A4 inhibitors)
            • QT prolongation
              • Clozapine associated with QT prolongation
              • Caution if coadministered with other drugs that prolong QT interval
            • CYP2D6 substrates
              • Clozapine inhibits CYP2D6
              • Coadministration with CYP2D6 substrates can increase levels of these substrate; lower dose of CYP2D6 substrate may be required
            • Anticholinergic drugs
              • Caution if coadministered with other drugs that elicit anticholinergic effects
              • Monitor carefully for additive anticholinergic effects
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            Pregnancy & Lactation

            Pregnancy

            There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy; health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/

            Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery; overall, available data from published epidemiologic studies of pregnant women exposed to clozapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; there are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, during pregnancy

            Animal data

            • In animal reproduction studies, no adverse developmental effects were observed with drug administered to pregnant rats or rabbits during period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m2 body surface area
            • There is risk to mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide; schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth; it is not known if this is a direct result of the illness or other comorbid factors
            • Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder reported in neonates exposed to antipsychotic drugs during third trimester of pregnancy; these symptoms have varied in severity; monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately; some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization

            Lactation

            Clozapine is present in human milk; there are reports of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk; there is no information on effects of clozapine on milk production; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed-child from drug or from underlying maternal condition

            Infants exposed to drug should be monitored for excess sedation

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Demonstrates weak D2-receptor and D1-receptor blocking activity, but noradrenolytic, anticholinergic, antihistaminic, and arousal reaction inhibiting effects are significant; also possesses antiserotoninergic (5-HT1C, 5-HT2, 5-HT3) properties

            Affinity for mesolimbic dopamine D4 receptor accounts for striking effects in control of behavioral and psychiatric symptoms with low incidence of EPS; histamine receptor blockade accounts for increased incidence of sleep disturbances

            Absorption

            Bioavailability: 50-60%

            Onset: 15 min

            Duration: 4-12 hr

            Peak plasma time: 1.5-2.5 hr

            Peak plasma concentration: 102-771 ng/mL

            Distribution

            Protein bound: 97%

            Vd: 4.67 L/kg

            Metabolism

            Metabolized by hepatic P450 enzyme CYP1A2, N-demethylation, N-oxidation, 3'-carbon oxidation, epoxidation of chlorine-containing aromatic ring, substitution of chlorine by hydroxyl or thiomethyl groups, and sulfur oxidation; also CYP2D6 and CYP3A4

            Metabolites: Norclozapine

            Elimination

            Half-life: 12 hr

            Blood clearance: 250 mL/min

            Total plasma clearance: 217 mL/min

            Excretion: Urine (50%), feces (30%)

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            Administration

            Oral Administration

            May take with or without food

            Minimize risk of orthostatic hypotension, bradycardia, and syncope by using low starting dose, gradual titration schedule, and divided dosages

            Storage

            Store at temperature not exceeding 30ºC (86ºF)

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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            Clozaril oral
            -
            200 mg tablet
            Clozaril oral
            -
            100 mg tablet
            Clozaril oral
            -
            50 mg tablet
            Clozaril oral
            -
            25 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
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            50 mg tablet
            clozapine oral
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            200 mg tablet
            clozapine oral
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            25 mg tablet
            clozapine oral
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            100 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            50 mg tablet
            clozapine oral
            -
            200 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            200 mg tablet
            clozapine oral
            -
            50 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            50 mg tablet
            clozapine oral
            -
            200 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            25 mg tablet
            clozapine oral
            -
            200 mg tablet
            clozapine oral
            -
            200 mg tablet
            clozapine oral
            -
            150 mg tablet
            clozapine oral
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            25 mg tablet
            clozapine oral
            -
            200 mg tablet
            clozapine oral
            -
            50 mg tablet
            clozapine oral
            -
            100 mg tablet
            clozapine oral
            -
            12.5 mg tablet
            clozapine oral
            -
            150 mg tablet
            Versacloz oral
            -
            50 mg/mL suspension

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Patient Education
            clozapine oral

            CLOZAPINE - ORAL

            (KLOE-za-peen)

            COMMON BRAND NAME(S): Clozaril, Versacloz

            WARNING: While clozapine can provide great benefits, it can rarely cause serious, possibly fatal side effects. For this reason, clozapine is used when other treatments have not worked or you cannot take them.For patients to receive this medication, all doctors, pharmacists, and patients must agree to, understand, and carefully follow the requirements of the Clozapine REMS Program. These requirements apply in the United States. If you live in Canada or any other country, consult your doctor and pharmacist for your country's regulations.This medication can cause a serious decrease of a certain type of white blood cells (neutropenia). To make sure you have enough white blood cells, your doctor will order lab tests before starting and while your are taking clozapine. Neutropenia may lower your ability to fight infections. Get medical help right away if you have any signs of severe neutropenia or infection (such as sore throat that doesn't go away, fever, swollen lymph nodes, unusual tiredness, weakness).Clozapine can also cause seizures, especially in higher doses. Let your doctor or pharmacist know if you have ever had seizures. While taking this medication, avoid driving or other activities during which a sudden loss of consciousness could be dangerous (e.g., operating heavy machinery, swimming).This medication may rarely cause an inflammation of the heart muscle (myocarditis) or heart failure. Get medical help right away if you develop chest pain, fast/irregular heartbeat, shortness of breath, swelling ankles/feet, unusual tiredness, or unusual/sudden weight gain.Clozapine can cause low blood pressure or a slow heartbeat, which can make you dizzy or cause you to faint when you stand up. The risk is higher when you first start or increase your dose of medication. Dizziness and lightheadedness can increase the risk of falling. Get up slowly when rising from a sitting or lying position.There may be a slightly increased risk of serious, possibly fatal side effects (such as stroke, heart failure, fast/irregular heartbeat, pneumonia) when this medication is used by older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor.

            USES: See also Warning section.This medication is used to treat certain mental/mood disorders (schizophrenia, schizoaffective disorders). Clozapine is a psychiatric medication (anti-psychotic type) that works by helping to restore the balance of certain natural substances (neurotransmitters) in the brain.Clozapine decreases hallucinations and helps prevent suicide in people who are likely to try to harm themselves. It helps you to think more clearly and positively about yourself, feel less nervous, and take part in everyday life.

            HOW TO USE: If you are using the liquid form of this medication, read the Patient Information Leaflet if available from your pharmacist before you start taking clozapine and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food, as directed by your doctor. If you are taking the tablets that dissolve in the mouth, carefully remove each tablet from the blister pack immediately before taking your dose. Allow the tablets to dissolve on your tongue and swallow. You do not need to take the dissolving tablets with water. Discard any dissolving tablets that have been previously exposed to air due to opened/damaged packaging. Do not save them for your next dose.If you are using the liquid form of this medication, shake the bottle well for 10 seconds before each use. Carefully measure the dose using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.It is important to begin taking this drug at a low dose, increasing your dose slowly, to lessen side effects such as dizziness, drowsiness and seizures. Follow your doctor's instructions exactly. Your dosage is based on your medical condition and response to therapy. Since clozapine can cause a decrease in white blood cells, you will need to get blood tests done regularly as directed. Be sure to keep all appointments for these laboratory tests. (See also Notes section.)If you miss your doses for longer than a day or two, consult your doctor for a new schedule to get back to the dose you were on (see Missed Dose section). Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time(s) each day.Do not stop taking clozapine without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Also, you may experience symptoms such as severe sweating, headache, nausea, vomiting, and diarrhea. To prevent these symptoms while you are stopping treatment with this drug, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details. Report any new or worsening symptoms right away.It may take several weeks before the full benefit of this drug takes effect. Inform your doctor if your condition persists or worsens.

            SIDE EFFECTS: See also Warning section.Drooling, drowsiness, dizziness, lightheadedness, headache, shaking (tremor), vision problems (e.g., blurred vision), constipation, and weight gain may occur. Many of these effects (especially drowsiness) lessen as your body gets used to the medication. If any of these effects persist or worsen, contact your doctor or pharmacist promptly.To prevent constipation, eat dietary fiber, drink enough water, and exercise. You may also need to take a laxative. Ask your pharmacist which type of laxative is right for you.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.This medication may rarely make your blood sugar rise, which can cause or worsen diabetes. Tell your doctor right away if you have symptoms of high blood sugar such as increased thirst/urination. If you already have diabetes, check your blood sugar regularly as directed and share the results with your doctor. Your doctor may need to adjust your diabetes medication, exercise program, or diet.This drug may also cause significant weight gain and a rise in your cholesterol (or triglyceride) levels. These effects, along with diabetes, may increase your risk for developing heart disease. Discuss the risks and benefits of treatment with your doctor.Tell your doctor right away if you have any serious side effects, including: facial/muscle twitching, seizures, uncontrollable movements, interrupted breathing during sleep, trouble urinating, severe constipation.Get medical help right away if you have any very serious side effects, including: severe dizziness, fainting, mental/mood changes, difficulty breathing with exercise, sudden weakness, pain/redness/swelling of the arms/legs, persistent nausea/vomiting, stomach/abdominal pain, yellowing of eyes/skin.This medication may rarely cause a very serious condition called neuroleptic malignant syndrome (NMS). Get medical help right away if you have any of the following symptoms: fever, muscle stiffness/pain/tenderness/weakness, severe tiredness, severe confusion, sweating, fast/irregular heartbeat, dark urine, signs of kidney problems (such as change in the amount of urine).A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: See also Warning and Side Effects sections.Before taking clozapine, tell your doctor or pharmacist if you are allergic to it or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: history of blood disorders (such as leukemia, low white blood cell count), bowel problems (such as paralytic ileus, irritable bowel syndrome ), breathing problems, diabetes/family history of diabetes, high cholesterol/triglyceride levels, glaucoma, heart problems, kidney problems, liver problems, obesity/family history of obesity, seizures, difficulty urinating (for example, due to enlarged prostate), breathing trouble during sleep (sleep apnea).Clozapine may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can rarely cause serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that need medical attention right away.The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may affect the heart rhythm. Before using clozapine, tell your doctor or pharmacist of all the drugs you take and if you have any of the following conditions: certain heart problems (heart failure, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/"water pills") or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using clozapine safely.This drug may make you dizzy or drowsy or blur your vision. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Tell your doctor if you are a descendent of Ashkenazi Jews because you may be at a higher risk for a drop in your white blood cells.Before having surgery, tell your doctor or dentist that you are using this medication.Liquid products or dissolving tablets may contain sugar and/or aspartame. Liquid products may also contain alcohol. Caution is advised if you have diabetes, liver disease, phenylketonuria (PKU), or any other condition that requires you to limit/avoid these substances in your diet. Ask your doctor or pharmacist about using this product safely.Older adults may be more sensitive to the side effects of this drug, especially constipation, trouble urinating, drowsiness, dizziness, lightheadedness, and QT prolongation (see above). Drowsiness, dizziness, and lightheadedness can increase the risk of falling.During pregnancy, this medication should be used only when clearly needed. Babies born to mothers who have used this drug during the last 3 months of pregnancy may rarely develop symptoms including muscle stiffness or shakiness, drowsiness, feeding/breathing difficulties, or constant crying. If you notice any of these symptoms in your newborn especially during their first month, tell the doctor right away.Since untreated mental/mood problems (such as schizophrenia, schizoaffective disorders) can be a serious condition, do not stop taking this medication unless directed by your doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately discuss with your doctor the benefits and risks of using this medication during pregnancy.This medication may pass into breast milk and have undesirable effects on a nursing infant. Breast feeding is not recommended while taking clozapine. Consult your doctor before breast-feeding.

            DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.A product that may interact with this drug is: metoclopramide.Other medications can affect the removal of clozapine from your body, which may affect how clozapine works. Examples include fluvoxamine, rifamycins (such as rifabutin, rifampin), saquinavir, St. John's wort, drugs used to treat seizures (such as carbamazepine, phenytoin), among others.Tell your doctor or pharmacist if you are taking other products that cause drowsiness such as opioid pain or cough relievers (such as codeine, hydrocodone), alcohol, marijuana (cannabis), drugs for sleep or anxiety (such as alprazolam, lorazepam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), or antihistamines (such as cetirizine, diphenhydramine).Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.Cigarette smoking decreases blood levels of this medication. Tell your doctor if you smoke or if you have recently stopped smoking.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

            NOTES: Do not share this medication with others.Lab and/or medical tests (such as complete blood count, liver function, blood sugar, weight, cholesterol/triglyceride levels) must be done before you start taking this medication and while you are taking it. Clozapine blood levels may also be checked. Keep all medical and lab appointments. Consult your doctor for more details.

            MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. If you miss doses for longer than a day or two, consult your doctor for a new schedule to get back to the dose you were taking. Do not double the dose to catch up.

            STORAGE: Store at room temperature away from light and moisture. Store the dissolving tablets in their blister packets, and do not remove each dose until just before taking. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

            Information last revised August 2021. Copyright(c) 2021 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.