Brand name Clozaril among others.
An atypical antipsychotic medication.
Primarily used for schizophrenia that does not improve following the use of other antipsychotic medications.
In schizophrenia and schizoaffective disorder it may decrease the rate of suicidal behavior.
It is more effective than typical antipsychotics.
It is administered by mouth, or by injection into a muscle.
Pregnancy category US: B (No risk in non-human studies)
Bioavailability 60 to 70%
Metabolism Liver, by several CYP isozymes
Elimination half-life 6 to 26 hourswith a mean value 14.2 hours in steady state conditions.
Excretion-80% in metabolized state: 30% biliary and 50% kidney
It is associated with a relatively high risk of agranulocytosis, seizures, inflammation of the heart, high blood sugar levels, and, in older people with psychosis as a result of dementia, and increased risk of death.
Common side effects include drowsiness, decreased or increased saliva production, low blood pressure, blurred vision, dizziness, constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, and weight gain.
The risk of developing tardive dyskinesia is below that of typical antipsychotics.
Tardive dyskinesia occurs in about 5% of patients.
The first atypical antipsychotic.
It is more effective in reducing symptoms of schizophrenia than typical antipsychotics.
Clozapine is an effective treatment for those who respond poorly to other drugs-treatment-resistant or refractory schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.
Usually administered by mouth in tablet or liquid form.
A short-acting intramuscular injectable formulation is available, with a similar duration of action as by mouth.
In a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, clozapine was ranked first and demonstrated very high effectiveness, a lowered
relapse rate and patient acceptability is better.
It may reduce propensity for substance abuse in schizophrenic patients.
It may be better than other antipsychotics in people with both schizophrenia and Parkinson’s disease.
It is not recommended for the treatment of behavior problems in older adults with dementia.
It carries five black box warnings, including warnings for agranulocytosis, central nervous system depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension and lowering the seizure threshold, and seizures.
Cessation of ejaculation during orgasm has been reported.
Agranulocytosis occurs in about 1% of people who take clozapine during the first few months of treatment.
Myocarditis can be a fatal side effect of clozapine.
The first manifestations myocarditis are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection.
C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later.
Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation.
The risk of clozapine-induced myocarditis is increased with increasing dose, increasing age and concomitant sodium valproate.
Gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis may occur.
Colonic hypomotility occurs in up to 80% of people prescribed clozapine when gastrointestinal function is measured using radiopaque markers.
Its induced gastrointestinal hypomotility has a higher mortality rate than agranulocytosis.
Monitoring bowel function and the use of laxatives for all clozapine-treated people improves colonic transit times and reduce serious sequelae.
Its M4 agonist activity is thought to be responsible for the hypersalivation.
CNS side effects include: drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety.
delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, obsessive compulsive symptoms, and neuroleptic malignant syndrome.
It is linked to urinary incontinence.
Withdrawal may lead to cholinergic rebound effects, severe movement disorders as well as severe psychotic decompensation.
When discontinuing the drug, gradual dose reduction is recommended.
Hyperglycemia, and significant weight gain is frequently experienced.
The body develops insulin resistance.
Fatalities have been reported due to overdose.
Carbamazepine is decreases plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine.
Carbamazepine should not be used concurrently with clozapine due to increased risk of agranulocytosis.
The use of benzodiazepines and clozapine concomitantly can result in severe adverse reaction such as respiratory arrest, cardiac arrest and sudden death.
Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate, therefore elevation in clozapine concentration in schizophrenia subjects concurrently taking ciprofloxacin.
It is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.
It is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
N-desmethylclozapine (norclozapine), is its major active metabolite.
Absorption is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism.
Peak concentration time after oral dosing is about 2.5 hours.
Food does not appear to affect its bioavailability.
Elimination half-life is about 14 hours at steady state conditions.
It is extensively metabolized in the liver, via the cytochrome P450 system.
Its major metabolite, norclozapine is pharmacologically active.
Agents that induce CYP1A2, smoking, may increase the drugs metabolism.
Agents that inhibit CYP1A2, theophylline, ciprofloxacin, fluvoxamine, can decrease metabolism.
Smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.
Plasma levels are higher in women and increase with age.