The P-I-E-N-O Parkinsn's List Drug Database
clozapine / ClozarilTM
antipsychotic
atypical tranquilizer
Description: Clozapine is an oral antipsychotic agent. It is an atypical antipsychotic of dibenzodiazepine derivation, with properties that differ from other antipsychotic agents. Clozapine is structurally related to the antipsychotic loxapine but differs in efficacy and adverse effects. Approximately 35 mg of clozapine is equivalent to 100 mg of chlorpromazine (CPZ EQ), the prototype typical antipsychotic. Clozapine is a second-line agent for patients who have failed treatment with two or more trials of typical antipsychotics either because of ineffectiveness or intolerable adverse effects. Clozapine therapy requires special monitoring and surveillance requirements due to its potential for causing fatal agranulocytosis in ~1% of exposed patients per year. Clozapine was approved by the FDA in February 1990.
Mechanism of Action: The clinical effects of antipsychotics are mostly due to antagonism of dopamine receptors in the central nervous system. The CNS dopaminergic system extends to many regions of the brain and several types of dopamine receptors have been identified. Traditional antipsychotics (e.g., haloperidol, phenothiazines) block type 2 dopamine receptors (DA) to a greater degree than type 1 (DA) receptors. Clozapine mainly blocks DA and DA receptors; its effects on DA receptors are relatively less than traditional antipsychotics. The lower affinity of clozapine for DA receptors may partially explain its lack of extrapyramidal effects. The superior efficacy of clozapine in treating resistant schizophrenic patients may be due to its additional blockade of serotonin type 2 receptors. Antipsychotic activity also may be due to an increased turnover of gamma aminobutyric acid (GABA) in the nucleus accumbens, which inhibits dopaminergic neurons.
Clozapine's blockade of ›A-adrenergic receptors produces sedation, muscle relaxation, and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns. Clozapine strongly binds to muscarinic receptors, often causing problematic anticholinergic effects, predominately constipation and dry mouth. The seizure threshold is lowered more by clozapine than by any other antipsychotic agent, causing seizures in ~10% of patients exposed to higher doses. Clozapine's EEG effects show more similarity to antidepressants than to those of typical antipsychotics.
Pharmacokinetics: Following oral administration, the drug is rapidly absorbed. Only 27-50% of a dose reaches the systemic circulation unchanged due to extensive first-pass metabolism. Food does not appear to affect the amount of drug absorbed. There is extensive enterohepatic recirculation, which is apparently enhanced by food. Clozapine plasma concentrations have been observed to vary widely on the same dose. Various individual patient factors can alter response, such as smoking, hepatic metabolism, gastic absorption, age, and, possibly, gender.
Clozapine is rapidly and extensively distributed; it crosses the blood-brain barrier and is distributed into breast milk. The drug is 95% bound to plasma protein, primarily ›-1-acid glycoprotein. Steady-state plasma concentrations are reached after 7-10 days of dosing. The onset of antipsychotic effect can take several weeks, but maximal effects can require several months because the drug is used for treating refractory patients. Patients have been reported to continue to improve for at least 2 years following the start of clozapine. Metabolism of the drug is extensive. Norclozapine, the desmethyl metabolite, is pharmacologically active, but other metabolites do not appear to have clinically significant activity. Plasma concentrations decline in the biphasic manner typical of oral antipsychotics. Mean terminal elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in the urine and 30% in the feces, but only small amounts consist of unchanged drug.
CONTRAINDICATIONS/PRECAUTIONS: Clozapine should not be used in patients with a fever, history of bone marrow depression, agranulocytosis, granulocytopenia, or myeloproliferative disorders. Clozapine-induced agranulocytosis and fatal infection can result. Psychotic patients who have experienced agranulocytosis (WBC '2000 or ANC '500) must NEVER be rechallenged with clozapine, and the manufacturer maintains a confidential register (1-800-448-5938) that must be checked before initiation of therapy. Issue of weekly supplies of the drug are dependent upon the results of the weekly white blood cell count, which are sent to the national registry. Arrangements can be made through the national registry for patients that are going to be traveling outside of the area served by their home clozapine monitoring system.
Intramuscular injections should not be administered to patients receiving cloazpine. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to clozapine- induced bone marrow depression. Clozapine is classified by the FDA as a Class B teratogen. Its use in pregnancy should be undertaken only when clearly needed. Patients should be told to notify their physician and pharmacist if they become or plan to become pregnant.
Clozapine is excreted into breast milk and should not be used by mothers who are breast-feeding. If the use of the drug is deemed essential, alternative methods of feeding are recommended.
Clozapine lowers the seizure threshold and should be used with extreme caution in patients with a history of seizures. Clozapine has precipitated grand-mal seizures, particularly at doses greater than 600 mg/day or following dosage changes greater than 100 mg/day. Because of the possibility of seizures as well as excessive sedation, patients on clozapine should avoid potentially hazardous activities in which sudden loss of consciousness could result in serious consequences.
Similar to other antipsychotics, in general, clozapine should not be administered to patients with tardive dyskinesia. However, due its relatively lower affinity for DA receptors than traditional antipsychotics (e.g., haloperidol, phenothiazines), clozapine is often substituted when patients develop tardive dyskinesia during therapy with traditional antipsychotics.
Clozapine should be used cautiously in patients with cardiovascular disorders because the drug is likely to induce tachycardia and/or orthostatic hypotension. Such patients should be treated with a low initial dose, followed by a more gradual dosage titration, and they should be warned of the possible adverse effects.
Clozapine should be used with caution in patients with prostatic hypertrophy, closed-angle glaucoma, or urinary retention because clozapine has strong anticholinergic activity that can exacerbate these conditions.
The safe use of clozapine in patients with hepatic disease, renal disease, or cardiac disease has not been fully evaluated, so cautious use is recommended with careful documentation of the benefit-to-risk assessment.
Clozapine should be used with caution in the treatment of elderly patients because they are more likely to have problems associated with increased anticholinergic activity, orthostatic hypotension, and CNS depression. Initial doses should be low, with longer intervals between dosage increases. Until experience with an individual patient has been gained, the dose should be increased in 25 mg increments once or twice a week.
DRUG INTERACTIONS: Ethanol or other drugs that can cause CNS depression, if used concomitantly with clozapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and, possibly, respiratory depression. Besides ethanol, the following drugs should be used cautiously with clozapine: HA-blockers, benzodiazepines, opiate agonists, sedative-hypnotics, and tricyclic antidepressants.
Concomitant use of clozapine with other drugs known to cause bone marrow depression might increase the possibility of developing myelosuppressive effects. Clozapine should be withheld if any weekly absolute white cell count falls below 3,000/mm or if the absolute neutrophil count (ANC) drops below 1,000/mm. If the absolute white cell count falls below 2,000/mm or the ANC falls below 500/mm, then clozapine should NEVER be restarted.
Clozapine has strong anticholinergic activity, and concurrent use with other anticholinergic drugs can increase side effects such as dry mouth, constipation, loss of accommodation, and urinary retention. Drugs to be avoided in patients receiving clozapine include: antimuscarinics, HA-antagonists, phenothiazines, and tricyclic antidepressants.
Carbamazepine, phenytoin and other cytochrome P-450 enzyme inducers can reduce clozapine plasma concentrations, possibly as a result of increased clozapine metabolism. While carbamazepine can significantly reduce clozapine serum concentrations, the clinical impact of this pharmacokinetic interaction has not been determined.
The protein-binding of clozapine is 95%; highly protein-bound medications can displace clozapine from its binding sites, predominately ›A-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of the following drugs: digoxin, heparin, phenytoin, or warfarin.
Drugs such as erythromycin, fluoxetine, or fluvoxamine, can inhibit cytochrome P-450 metabolism and can increase clozapine plasma concentrations. In 1994, a study of 34 schizophrenic patients demonstrated a significant increase in clozapine serum concentrations during concomitant therapy with fluoxetine. Although data are limited, fluvoxamine has also caused substantial increases in clozapine serum concentrations.
Severe hypotension and respiratory depression have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Concomitant benzodiazepine use should be undertaken only when no alternative is acceptable; caution and careful monitoring are recommended. Starting doses of the benzodiazepine should be approximately one-half of the usual dose until experience with the patient has been gained. Other sedative/hypnotic agents have not been used as commonly as concomitant benzodiazepines and could possibly cause greater respiratory depression in predisposed individuals.
A single case report associates the appearance of psychiatric symptoms with caffeine ingestion in a patient taking clozapine. Although clozapine could have inhibited caffeine metabolism and these symptoms could be a result of caffeine excess, it is also possible that caffeine inhibited the therapeutic action of clozapine. Until more data are available, caffeine consumption should be minimized in patients requiring clozapine.
Clozapine used concomitantly with other antihypertensive agents can increase the risk and severity of hypotension. Epinephrine should not be used to treat clozapine-induced hypotension due to the unopposed œ-activity, which potentially could worsen the hypotension.
Clozapine used concomitantly with lithium can increase the risk of developing seizures, confusion, dyskinesias, and, possibly, neuroleptic malignant syndrome. Careful attention to the patient's hydration status and lithium serum concentrations can prevent the occurrence of some of these problems when concomitant therapy is indicated.
Evidence suggests that smoking tobacco causes a substantial reduction in plasma concentrations of clozapine. Tobacco smokers may require higher doses of clozapine. However, tobacco smoking is extremely common in patients who may require clozapine, and the usual doses were established in this population. Care should be exercised in treating nonsmoking patients since they may require somewhat lower doses than expected.
ADVERSE REACTIONS: Potentially fatal agranulocytosis can occur during clozapine therapy. A recently published report of data from the ClozarilTM National Registry revealed that agranulocytosis occurred in 73 (0.6%) of 11,555 patients over a period of 15 months.D The risk of developing agranulocytosis increased with age and was higher in women. Close monitoring of white blood cell count (WBC count) must be undertaken before and weekly throughout therapy. Agranulocytosis from clozapine is defined by a WBC count of <500/mm, and leukopenia by a WBC count of <2,000/mm. Because the drug has the potential to raise body temperature, especially in early stages of treatment, patients should be carefully monitored for signs and symptoms of infection, and weekly WBC counts should be taken. If therapy is discontinued for any reason, patients should continue to have WBC counts taken for an additional 4 weeks. There appears to be a widespread incidence of mild leukopenia during initial therapy. If neutropenia develops (absolute neutrophil count of <1,500/mm), and clozapine is stopped, the patients outlook is generally favorable. The patient should be monitored for signs of flu-like symptoms or infection. Patients generally recover from clozapine-induced agranulocytosis within 7-28 days after the clozapine is stopped. Patients who develop agranulocytosis from clozapine must NEVER be rechallenged with clozapine.
Excessive sedation or drowsiness is an extremely common initial adverse effect of clozapine administration. After the initial dosage titration, giving most or all of the dose at bedtime can prevent problems due to continuing sedation. If morning sedation is a problem, then dividing doses, with the majority administered at bedtime, can be helpful. Sedative effects can diminish with continued use of the drug. Some patients develop a disturbed sleep pattern with insomnia and intensification of dreams or nightmares. Confusion is more likely to develop in geriatric patients. Headache occurs in about 7% of patients.
Clozapine lowers the seizure threshold, and seizures may develop. Increasing the dose too rapidly (>100 mg/day) and high dosage (>600 mg/day) seem to be more likely to precipitate a seizure. Slow titration of dosage, both up and down, usually can help to prevent seizures. If seizures develop, dosage reduction or discontinuation of the drug may be indicated if the patient has not obtained significant benefit from clozapine. In patients whose illness has improved substantially while taking clozapine, the benefits and risks of continuing clozapine with a concomitant anticonvulsant must be considered.
Long-term therapy with other antipsychotics can result in tardive dyskinesia, an abnormal-movement disorder. Tardive dyskinesia is less likely to occur with clozapine therapy than with other antipsychotics. To date, no confirmed cases of tardive dyskinesia have been associated with clozapine therapy alone. Clozapine is often used in patients who develop tardive dyskinesia to traditional antipsychotics (e.g., haloperidol, phenothiazines). Many patients with preexisting tardive dyskinesia have significant improvement in their symptoms following therapy with clozapine. However, the condition is irreversible, so patients receiving long-term therapy should be monitored for possible symptoms, such as involuntary movements of the tongue, face, mouth, or jaw, and if any signs develop, the drug should be immediately withdrawn. All patients treated with an antipsychotic should receive informed consent and be monitored at 3-6 month intervals for the possible appearance of abnormal movements. Geriatric patients and females appear to be more prone to development of this syndrome.
Clozapine has been associated with transient benign elevations in body temperature. Extreme caution should be used in patients who develop a fever because temperature elevations can be indicative of infection or granulocytopenia or neuroleptic malignant syndrome. Every patient who develops a fever or any other sign of infection during clozapine therapy should undergo an immediate repeat blood count to rule out agranulocytosis. The incidence of the transient hyperthermia is highest during the first 3 weeks of therapy.
The possible development of dystonia is much lower with clozapine therapy than with other antipsychotic drugs because of its low propensity for causing extrapyramidal effects. However, muscle rigidity, tremor, agitation, restlessness, akinesia, hypokinesia and akathisia have been reported. There also have been fewer reports of neuroleptic malignant syndrome (NMS) with clozapine therapy than with other antipsychotics, but it has occurred in a few patients. Because this syndrome can be fatal and its symptoms can go unrecognized, careful patient monitoring should be undertaken. Combined use of clozapine and lithium increases the risk of NMS developing (see Drug Interactions). Clozapine causes NMS-like symptoms (e.g., fever, CK elevations, muscle stiffness, and sinus tachycardia) which may complicate diagnosis of NMS.
Hypotension is a fairly common adverse reaction during therapy with clozapine, especially during the initial titration or dosage increase. Tolerance to this effect can develop in long- term therapy. Patients should be warned of possible orthostatic hypotension and syncope, which may present a continuing risk. Rarely collapse may be severe with respiratory and/or cardiac arrest (Product literature). Concomitant therapy with benzodiazepines and other psychotropic drugs may potentiate this problem. Dizziness and vertigo occur in about 19% of patients treated with clozapine.
Sinus tachycardia occurs in about 25% of patients receiving clozapine but can decrease once a stable dosage regimen has been attained. Patients with cardiac dysfunction may be at most risk from this side effect, and the possibility of NMS should be excluded.
ECG changes from clozapine are clinically benign in most patients and are reversed upon discontinuation. However, some patients experienced serious, and sometimes fatal, adverse cardiovascular events, which may or may not be attributed to clozapine therapy. Patients should be monitored for cardiac symptoms during therapy with clozapine, including hypertension, ST-T wave changes, angina, and myocardial infarction.
Anticholinergic effects, such as xerostomia (dry mouth) and urinary retention, can occur during therapy with clozapine, although an unexplained paradoxical reaction of hypersalivation (sialorrhea) also occurs frequently. Salivation can be excessive and troublesome during sleep. Reduction of dosage occasionally improves the condition and should be attempted if the patient can tolerate the dosage reduction. Frequently, administration of an anticholinergic agent (typically benztropine mesylate) is helpful in reducing the sialorrhea. Worsening constipation and other signs of excessive anticholinergic activity can significantly complicate attempts to treat sialorrhea and should be monitored closely. Other gastrointestinal effects include nausea/vomiting, and general abdominal discomfort or heartburn. Other autonomic nervous system complaints include diaphoresis and visual impairment.
Priapism, a potentially serious adverse reaction, has been reported with clozapine.
PATIENT INFORMATION
What do clozapine tablets do?
Clozapine (ClozarilTM ) helps to treat schizophrenia. Clozapine can help you to keep in touch with reality and reduce hallucinations or other mental problems. Clozapine is used to help people that have not responded to other medications. It is available only through a monitoring and dispensing system (contracted doctors, pharmacists, and laboratories) that requires weekly blood testing before allowing dispensing of the next weeks supply of tablets. Generic clozapine tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take clozapine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take clozapine tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If clozapine upsets your stomach, take it with food or milk. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 16 years old.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with clozapine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking clozapine?
Serious side effects with clozapine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with clozapine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take clozapine?
Visit your doctor for regular checks on your progress. You must have a weekly blood test. Your name will go on a national registry of patients that take this medicine, to make sure that you have never had a serious reaction to it. Do not suddenly stop taking clozapine. You may need to gradually reduce the dose. Only stop taking clozapine on your doctor's advice.
You may get dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how clozapine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase dizziness and drowsiness. Avoid alcoholic drinks.
Do not treat yourself for colds, fever, diarrhea or allergies. Ask your doctor or pharmacist for advice, some nonprescription medicines may increase possible side effects.
Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help. Be careful when brushing and flossing your teeth to avoid mouth infections or damage to your gums. See your dentist regularly. Sometimes clozapine can make your mouth water a lot, especially at night.
If you are going to have surgery tell your doctor or dentist that you are taking clozapine.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature below 30C (86F). Throw away any unused medicine after the expiration date.
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