Clozapine Orally Disintegrating Tablet

2.1 Required Laboratory Testing Prior to Initiation and During Therapy

Prior to initiating treatment with Clozapine Orally Disintegrating Tablets, a baseline ANC must be obtained. The baseline ANC must be at least 1500/μL for the general population, and at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1)].

Important Administration Instructions

Clozapine Orally Disintegrating Tablets should be immediately placed in the mouth after removing the tablet from the blister pack or bottle. The tablet disintegrates rapidly after placement in the mouth. The tablets can be allowed to disintegrate, or they may be chewed. They may be swallowed with saliva. No water is necessary for administration.

The orally disintegrating tablets in a blister pack should be left in the unopened blister until the time of use. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet. Do not push the tablets through the foil, because this could damage the tablet.

Dosing Information

The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3)].

Clozapine Orally Disintegrating Tablets can be taken with or without food [see Pharmacokinetics (12.3)].

Maintenance Treatment

Generally, patients responding to Clozapine Orally Disintegrating Tablets should continue maintenance treatment on their effective dose beyond the acute episode.

Discontinuation of Treatment

Method of treatment discontinuation will vary depending on the patient’s last ANC:

• See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. • Reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine therapy is planned and there is no evidence of moderate to severe neutropenia. • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/μL and for BEN patients until their ANC is ≥1000/μL or above their baseline. • Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1)]. • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Re-Initiation of Treatment

When restarting Clozapine Orally Disintegrating Tablets in patients who have discontinued Clozapine Orally Disintegrating Tablets (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well-tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

2.7 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].  

Table 1: Dose Adjustment in Patients Taking Concomitant Medications

Co-medications	Scenarios
	Initiating Clozapine Orally Disintegrating Tablets while taking a co-medication	Adding a co-medication while taking Clozapine Orally Disintegrating Tablets	Discontinuing a co-medication while continuing Clozapine Orally Disintegrating Tablets
Strong CYP1A2 Inhibitors	Use one third of the Clozapine Orally Disintegrating Tablets dose.		Increase Clozapine Orally Disintegrating Tablets dose based on clinical response.
Moderate or Weak CYP1A2 Inhibitors	Monitor for adverse reactions. Consider reducing the Clozapine Orally Disintegrating Tablets dose if necessary.		Monitor for lack of effectiveness. Consider increasing Clozapine Orally Disintegrating Tablets dose if necessary.
CYP2D6 or CYP3A4 Inhibitors
Strong CYP3A4 Inducers	Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the Clozapine Orally Disintegrating Tablets dose. Monitor for decreased effectiveness.		Reduce Clozapine Orally Disintegrating Tablets dose based on clinical response.
Moderate or weak CYP1A2 or CYP3A4 Inducers	Monitor for decreased effectiveness. Consider increasing the Clozapine Orally Disintegrating Tablets dose if necessary.		Monitor for adverse reactions. Consider reducing the Clozapine Orally Disintegrating Tablets dose if necessary.

2.8 Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers

It may be necessary to reduce the Clozapine Orally Disintegrating Tablets dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].

Hypersensitivity

Clozapine Orally Disintegrating Tablets are contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of Clozapine Orally Disintegrating Tablets [see Adverse Reactions (6.2)].

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Severe Neutropenia [see Warnings and Precautions (5.1)]. • Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.3)]. • Falls [see Warnings and Precautions (5.4)]. • Seizures [see Warnings and Precautions (5.5)]. • Myocarditis and Cardiomyopathy [see Warnings and Precautions (5.6)]. • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.7)]. • Eosinophilia [see Warnings and Precautions (5.8)]. • QT Interval Prolongation [see Warnings and Precautions (5.9)]. • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.10)]   • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.11)]. • Hepatotoxicity [see Warnings and Precautions (5.12)]. • Fever [see Warnings and Precautions (5.13)]. • Pulmonary Embolism [see Warnings and Precautions (5.14)]. • Anticholinergic Toxicity [see Warnings and Precautions (5.15)]. • Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.16)]. • Tardive Dyskinesia [see Warnings and Precautions (5.17)]. • Patients with Phenylketonuria [see Warnings and Precautions (5.18)]. • Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.19)]. • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.20)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most commonly reported adverse reactions (≥5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia.

Table 9: Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-Controlled Trial in Treatment-Resistant Schizophrenia

	Clozapine	Chlorpromazine
Adverse Reaction	(N=126)	(N=142)
	(%)	(%)
Sedation	21	13
Tachycardia	17	11
Constipation	16	12
Dizziness	14	16
Hypotension	13	38
Fever (hyperthermia)	13	4
Hypersalivation	13	1
Hypertension	12	5
Headache	10	10
Nausea/vomiting	10	12
Dry mouth	5	20

Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2 year InterSePT™ Study). These rates are not adjusted for duration of exposure.

Table 10: Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) Across all Clozapine Studies (excluding the 2 year InterSePT™ Study)

* Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.
Body System	Clozapine
Adverse Reaction	N=842
	Percentage of Patients
Central Nervous System
Drowsiness/Sedation	39
Dizziness/Vertigo	19
Headache	7
Tremor	6
Syncope	6
Disturbed Sleep/Nightmares	4
Restlessness	4
Hypokinesia/Akinesia	4
Agitation	4
Seizures (convulsions)	3*
Rigidity	3
Akathisia	3
Confusion	3
Fatigue	2
Insomnia	2
Cardiovascular
Tachycardia	25*
Hypotension	9
Hypertension	4
Gastrointestinal
Constipation	14
Nausea	5
Abdominal Discomfort/Heartburn	4
Nausea/Vomiting	3
Vomiting	3
Diarrhea	2
Urogenital
Urinary abnormalities	2
Autonomic Nervous System
Salivation	31
Sweating	6
Dry mouth	6
Visual disturbances	5
Skin
Rash	2
Hemic/Lymphatic
Leukopenia/Decreased WBC/Neutropenia	3
Miscellaneous
Fever	5
Weight Gain	4

Table 11 summarizes the most commonly reported adverse reactions (≥10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure.

Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥10% in the clozapine or olanzapine group)

	Clozapine	Olanzapine
	N=479	N=477
Adverse Reactions	% Reporting	% Reporting
Salivary hypersecretion	48%	6%
Somnolence	46%	25%
Weight increased	31%	56%
Dizziness (excluding vertigo)	27%	12%
Constipation	25%	10%
Insomnia	20%	33%
Nausea	17%	10%
Vomiting	17%	9%
Dyspepsia	14%	8%

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System

Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, and periorbital edema.

Endocrine System

Pseudopheochromocytoma

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling.

Hepatobiliary System

Cholestasis, hepatitis, jaundice, 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 System

Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure.

Skin and Subcutaneous Tissue Disorders

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

Musculoskeletal System and Connective Tissue Disorders

Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.

Respiratory System

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection.

Hemic and Lymphatic System

Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders

Narrow-angle glaucoma.

Miscellaneous

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

Treatment-Resistant Schizophrenia

The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions – Severity Scale score of at least 4 (moderately ill).

In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6 week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with clozapine (N=126) or chlorpromazine (N=142). The maximum daily clozapine dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg.

The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤3 (mildly ill), or (2) a BPRS score of ≤35, at the end of 6 weeks of treatment. Approximately 88% of patients from the clozapine and chlorpromazine groups completed the 6-week trial. At the end of six weeks, 30% of the clozapine group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p <0.001). The mean change in total BPRS score was -16 and -5 in the clozapine and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the clozapine and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the clozapine and chlorpromazine group, respectively. These changes in the clozapine group were statistically significantly greater than in the chlorpromazine group (p <0.001 in each analysis).

Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder

The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of clozapine (Clozaril®) versus olanzapine (Zyprexa®, a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met one of the following criteria:

• They had attempted suicide within the three years prior to their baseline evaluation. • They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation.

Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200 to 900 mg/day for clozapine and 5 to 20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group.

The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data.

A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18 to 69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races.

Patients treated with clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine.

The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for clozapine patients than for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 1).

Figure 1: Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality