clozapine (Rx)

Brand and Other Names:Clozaril, FazaClo ODT, more...Versacloz
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 25mg
  • 50mg
  • 100mg
  • 200mg

tablet, orally disintegrating (FazaClo ODT)

  • 12.5mg
  • 25mg
  • 100mg
  • 150mg
  • 200mg

oral suspension (Versacloz)

  • 50mg/mL
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Schizophrenia or Suicidal Behavior in Schizophrenia or Schizoaffective Disorder

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; increased daily in increments of 25-50 mg/day, if well tolerated, to achieve target dosage of 300-450 mg/day by end of 2 weeks

On occasion, may have to be increased to 600-900 mg/day to obtain acceptable response

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

Dosage Modifications

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

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; consider reducing dose if CYP1A2 or CYP3A4 inducers are discontinued

CYP2D6 poor metabolizers: Clozapine dose reduction may be needed

Significant renal or hepatic impairment: Clozapine dose reduction may be needed

Dosing Considerations

Reinitiation of therapy

  • If therapy interrupted for ≥48 hr, must reinitiate dose at 12.5 mg qDay or BID to minimize risk of hypotensioin, 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

  • 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)

Required laboratory monitoring

  • Prior to initiating, obtain CBC with differential, 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
  • See prescribing information for detailed monitoring requirements, including those for patients with 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

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            Frequency Not Defined

            Common

            • Hypotension, tachycardia
            • Fever, sedation, seizures (with high doses)
            • Appetite increase
            • Constipation
            • Heartburn
            • Nausea
            • Polyphagia
            • Sialorrhea
            • Vomiting
            • Weight gain

            Less common

            • Extrapyramidal symptoms (EPS), such as tremor, restlessness, rigidity, akathisia
            • Dizziness
            • Headache
            • Insomnia
            • Delirium
            • Depression
            • Fatigue
            • Weakness
            • Slurred speech
            • Seizures (with low doses)
            • Hyperglycemia, potential for new-onset diabetes
            • Leukopenia, neutropenia, thrombocytosis
            • Shortness of breath, wheezing
            • Polyuria, enuresis, impotence, dysmenorrhea

            Rare

            • Myocarditis
            • Amnesia, hallucinations
            • Parkinsonian syndrome
            • Periodic cataplexy
            • Neuroleptic malignant syndrome (NMS)
            • Anemia
            • Leukocytosis
            • Increased platelet count
            • Agranulocytosis
            • Change in libido

            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

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

            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

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

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

            Vision disorders: Narrow-angle glaucoma

            Falls

            Miscellaneous: CPK elevation, hyperuricemia, hyponatremia, weight loss

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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
            • Prior to initiating treatment, a 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
            • Do not rechallenge patients with history of clozapine-associated myocarditis or cardiomyopathy

            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

            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)

            Increased risk of seizures

            Risk of potentially fatal myocarditis

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

            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

            FDA warning regarding off-label use for dementia in elderly

            May cause anticholinergic effects (eg, xerostomia, urinary retention, constipation)

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

            Possible increased serum levels and toxicity in patients with reduced activity of CYP isoenzymes 1A2, 2D6, or 3A4

            Coadministration with other drugs that prolong QT interval or drugs that inhibit metabolism of clozapine (eg, inhibitors of CYP isoenzymes 1A2, 2D6, and 3A4)

            Postmarketing analysis has suggested an increased incidence of myocarditis that is particularly prevalent within first month of treatment; accordingly, do not stop medication abruptly, and perform WBC testing every 2 weeks for duration of therapy

            Esophageal dysmotility may occur; use caution in patients with esophageal dysmotility at risk for aspiration pneumonia (eg, >75 years)

            Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis) if eosinophilia occurs

            Monitor glucose regularly in patients with diabetes or at risk for diabetes

            Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics

            Significant weight gain has occurred; monitor weight gain

            Immediately discontinue and monitor closely if neuroleptic malignant syndrome occurs; assess for co-morbid conditions

            Evaluate for infections, agranulocytosis, and neuroleptic malignant syndrome if fever occurs

            Consider pulmonary embolism if respiratory distress, chest pain, or deep vein thrombosis occur

            Use with caution in history of narrow glaucoma or concomitant use with other anticholinergic drugs

            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

            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

            May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, tardive dyskenesia, akathisia; patients at risk of tardive dyskenesia include older in age, female gender, combined with postmenopausal status, affective disorders, previous brain damage, alcoholism; consider discontinuing therapy when tardive dyskenesia symptoms occur

            Sialorrhea and drooling may occur, which may be profound during sleep and may be dose related; patients may experience chocking sensations from excessive production of saliva; titrate dose to minimize chances of inducing sialorrhea; consider dose reduction with or without therapeutic augmentation or therapeutic substitution is symptoms develop; use caution with drugs that have anticholinergic effects to avoid additive adverse effects with drug, including constipation or cognitive impairment

            Use caution in patients at high risk for suicidal ideation during initiation of therapy

            Impaired core body temperature regulation may occur; caution with strenuous exercise, dehydration, heat exposure, and concomitant medication possessing anticholinergic effects

            Cases of deep vein thrombosis and pulmonary embolism reported; avoid risk factors, including sedentary lifestyle, weight gain to minimize risk; evaluate benefits of continuing therapy if thromboembolism occurs

            Hepatic impairment may occur; monitor hepatic function regularly

            Dose reduction may be necessary in patients with renal impairment

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            Pregnancy & Lactation

            Pregnancy category: B

            Neonates exposed to antipsychotic drugs during 3rd trimester of pregnancy are at risk for EPS or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization

            Lactation: Drug enters breast milk; not recommended (American Academy of Pediatrics Committee states that this is "of concern")

            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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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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