Clozapine Tablets USP 100mg Taj Pharma

  1. Name of the medicinal product

Clozapine Tablets USP 25mg.
Clozapine Tablets USP 50mg.
Clozapine Tablets USP 100mg.

UK Clozapine Official Recommendations

As a consequence of a recent European regulatory initiative, the Clozapine Summary of Product Characteristics (SmPC) has been harmonised across Europe. The SmPC states that blood monitoring should be carried out in accordance with national-specific official recommendations. These are reproduced below.

The UK Clozapine Patient Monitoring Service (CPMS) was developed in order to manage the risk of agranulocytosis associated with clozapine. It is available 24 hours a day. When a monitoring service is not used, evidence suggests a mortality rate from agranulocytosis of 0.3% [1]. This is compared to a mortality rate when Clozapine is used in conjunction with the Clozapine Patient Monitoring Service, of 0.01%[2].

The Clozapine Patient Monitoring Service provides for the centralised monitoring of leucocyte and neutrophil counts which is a mandatory requirement for all patients in the UK who are treated with Clozapine. The use of Clozapine is restricted to patients who are registered with the Clozapine Patient Monitoring Service. In addition to registering their patients, prescribing physicians must register themselves and a nominated pharmacist with the Clozapine Patient Monitoring Service. All Clozapine-treated patients must be under the supervision of an appropriate specialist and supply of Clozapine is restricted to hospital and retail pharmacies registered with the Clozapine Patient Monitoring Service. Clozapine is not sold to, or distributed through wholesalers.

In the UK, a white cell count with a differential count must be monitored:

  • At least weekly for the first 18 weeks of treatment
  • At least at 2 week intervals between weeks 18 and 52
  • After 1 year of treatment with stable neutrophil counts, patients may be monitored at least at 4 week intervals
  • Monitoring must continue throughout treatment and for at least 4 weeks after discontinuation

The Clozapine Patient Monitoring Service maintains a database which includes all patients who have developed abnormal leucocyte or neutrophil findings and who should not be re-exposed to Clozapine.

Prescribers and pharmacists should adhere to brand prescribing and dispensing of clozapine in order to prevent the disruption to effective monitoring that may be caused if patients switch brands.

Furthermore, in order to protect patient safety, at any one time patients should only be prescribed one brand of clozapine and only registered with the monitoring service connected to that brand.

 

Clozapine can cause agranulocytosis. Its use should be limited to patients:

– with schizophrenia who are non-responsive to or intolerant of antipsychotic medication, or with psychosis in Parkinson’s disease when other treatment strategies have failed (see section 4.1),

– who have initially normal leukocyte findings (white blood cell count ≥ 3500/mm3(≥ 3.5×109/l), and ANC ≥ 2000/mm(≥ 2.0×109/l)), and

– in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) can be performed as follows: weekly during the first 18 weeks of treatment, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Clozapine (see section 4.4.).

Prescribing physicians must comply fully with the required safety measures. At each consultation, a patient receiving Clozapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention must be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia (see section 4.4).

Clozapine must be dispensed under strict medical supervision in accordance with official recommendations (see section 4.4).

Myocarditis

Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. The increased risk of myocarditis is greatest in the first 2 months of treatment. Fatal cases of cardiomyopathy have also been reported rarely (see section 4.4).

Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first 2 months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction (see section 4.4).

If myocarditis or cardiomyopathy are suspected, Clozapine treatment should be promptly stopped and the patient immediately referred to a cardiologist (see section 4.4).

Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine (see section 4.3 and 4.4).

  1. Qualitative and quantitative composition

25mg tablet:

Each tablet contains 25mg clozapine.

Excipient(s) with known effect: also includes lactose monohydrate 48.0mg per tablet.

For the full list of excipients, see section 6.1.

50mg tablet:

Each tablet contains 50mg clozapine.

Excipient(s) with known effect: also includes lactose monohydrate 48.0mg per tablet.

For the full list of excipients, see section 6.1.

100mg tablet:

Each tablet contains 100mg clozapine.

Excipient(s) with known effect: also includes lactose monohydrate 192.0mg per tablet.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Tablets.

  1. Clinical particulars

4.1 Therapeutic indications

Treatment-resistant schizophrenia

Clozapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.

Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.

Psychosis during the course of Parkinson’s disease

Clozapine is also indicated in psychotic disorders occurring during the course of Parkinson’s disease, in cases where standard treatment has failed.

4.2 Posology and method of administration

Posology

The dosage must be adjusted individually. For each patient the lowest effective dose should be used. For doses not realisable/practicable with one strength, other strengths of this medicinal product are available. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure and sedation.

Initiation of Clozapine treatment must be restricted to those patients with a WBC count ≥ 3500/mm3 (3.5×109/l) and an ANC ≥ 2000/mm3 (2.0×109/l) within standardised normal limits.

Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacodynamic and pharmacokinetic interactions with Clozapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5).

Switching from a previous antipsychotic therapy to Clozapine

It is generally recommended that Clozapine should not be used in combination with other antipsychotics. When Clozapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards.

The following dosages are recommended:

Treatment-resistant schizophrenic patients

Starting therapy

12.5mg once or twice on the first day, followed by 25mg once or twice on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50mg in order to achieve a dose level of up to 300mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100mg at half-weekly or, preferably, weekly intervals.

Therapeutic dose range

In most patients, antipsychotic efficacy can be expected with 200 to 450mg/day given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime.

Maximum dose

To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (not exceeding 100mg) are permissible up to 900mg/day. However, the possibility of increased adverse reactions (in particular seizures) occurring at doses over 450mg/day must be borne in mind.

Maintenance dose

After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200mg, once daily administration in the evening may be appropriate.

Ending therapy

In the event of planned termination of Clozapine therapy, a gradual reduction in dose over a 1 to 2-week period is recommended. If abrupt discontinuation is necessary, the patient should be carefully observed for the occurrence of withdrawal reactions (see section 4.4).

Re-starting therapy

In patients in whom the interval since the last dose of Clozapine exceeds 2 days, treatment should be re-initiated with 12.5mg given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see section 4.4), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.

Psychotic disorders occurring during the course of Parkinson’s disease, in cases where standard treatment has failed

Starting therapy

The starting dose must not exceed 12.5mg/day, taken in the evening. Subsequent dose increases must be by 12.5mg increments, with a maximum of two increments a week up to a maximum of 50mg, a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.

Therapeutic dose range

The mean effective dose is usually between 25 and 37.5mg/day. In the event that treatment for at least one week with a dose of 50mg fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5mg/week.

Maximum dose

The dose of 50mg/day should only be exceeded in exceptional cases, and the maximum dose of 100mg/day must never be exceeded.

Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.

Maintenance dose

When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach results in the recurrence of psychotic symptoms, Clozapine dosage may be increased by increments of 12.5mg/week up to a maximum of 100mg/day, taken in one or two divided doses (see above).

Ending therapy

A gradual reduction in dose by steps of 12.5mg over a period of at least one week (preferably two) is recommended.

Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis (see section 4.4). In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.

Special populations

Hepatic impairment

Patients with hepatic impairment should receive Clozapine with caution along with regular monitoring of liver function tests (see section 4.4).

Paediatric population

No paediatric studies have been performed. The safety and efficacy of Clozapine in children and adolescents under the age of 16 years have not yet been established. It should not be used in this group until further data become available.

Patients 60 years of age and older

Initiation of treatment is recommended at a particularly low dose (12.5mg given once on the first day), with subsequent dose increments restricted to 25mg/day.

Method of administration

Clozapine is administered orally.

4.3 Contraindications

  • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
  • Patients unable to undergo regular blood tests.
  • History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
  • History of Clozapine-induced agranulocytosis.
  • Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged
  • Impaired bone marrow function.
  • Uncontrolled epilepsy.
  • Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.
  • Circulatory collapse and/or CNS depression of any cause.
  • Severe renal or cardiac disorders (e.g. myocarditis).
  • Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
  • Paralytic ileus.

4.4 Special warnings and precautions for use

Agranulocytosis

Clozapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring. The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations.

Because of the risks associated with Clozapine, its use is limited to patients in whom therapy is indicated as set out in section 4.1 and:

  • who have initially normal leukocyte findings (WBC count ≥ 3500/mm3(3.5×109/l) and ANC ≥ 2000/mm(2.0×109/l), and
  • in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks and at least 4-week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Clozapine.

Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that might include an ECG, and the patient treated only if the expected benefits clearly outweigh the risks (see section 4.3). The treating physician should consider performing a pre-treatment ECG.

Prescribing physicians must comply fully with the required safety measures.

Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts.

Immediate discontinuation of Clozapine is mandatory if either the WBC count is less than 3000/mm3 (3.0×109/l) or the ANC is less than 1500/mm3 (1.5×109/l) at any time during Clozapine treatment. Patients in whom Clozapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Clozapine.

At each consultation, a patient receiving Clozapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia. Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients’ blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.

Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting Clozapine.

Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may only be started on Clozapine with the agreement of a haematologist.

White Blood Cell (WBC) counts and Absolute Neutrophil Count (ANC) monitoring

WBC and differential blood counts must be performed within 10 days prior to initiating Clozapine treatment to ensure that only patients with normal WBC counts and ANC (WBC count ≥ 3500/mm(3.5×109/l) and ANC ≥ 2000/mm(2.0×109/l)) will receive Clozapine. After the start of Clozapine treatment regular WBC count and ANC must be performed and monitored weekly for the first 18 weeks, and at least at four-week intervals thereafter.

Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Clozapine or until haematological recovery has occurred (see “Low WBC count/ANC” below). At each consultation, the patient must be reminded to contact the treating physician immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.

Low WBC count/ANC

If, during Clozapine therapy, either the WBC count falls to between 3500/mm3 (3.5×109/l) and 3000/mm3 (3.0×109/l) or the ANC falls to between 2000/mm3 (2.0×109/l) and 1500/mm(1.5×109/l), haematological evaluations must be performed at least twice weekly until the patient’s WBC count and ANC stabilise within the range 3000-3500/mm3 (3.0-3.5×109/l) and 1500-2000/mm(1.5-2.0×109/l), respectively, or higher.

Immediate discontinuation of Clozapine treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0×109/l) or the ANC is less than 1500/mm3 (1.5×109/l) during Clozapine treatment. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Confirmation of the haematological values is recommended by performing two blood counts on two consecutive days; however, Clozapine should be discontinued after the first blood count.

Following discontinuation of Clozapine, haematological evaluation is required until haematological recovery has occurred.

Table 1

Blood cell countAction required
WBC/mm(/l)ANC/mm3 (/l)
≥ 3500 (≥ 3.5×109)≥ 2000 (≥ 2.0×109)Continue Clozapine treatment
Between ≥ 3000 and < 3500 (≥ 3.0×109 and < 3.5×109)Between ≥ 1500 and < 2000 (≥ 1.5×109 and < 2.0×109)Continue Clozapine treatment, sample blood twice weekly until counts stabilise or increase
< 3000 (< 3.0×109)< 1500 (< 1.5×109)Immediately stop Clozapine treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.

If Clozapine has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0×109/l) occurs or the ANC falls below 1000/mm(1.0×109/l), the management of this condition must be guided by an experienced haematologist.

Discontinuation of therapy for haematological reasons

Patients in whom Clozapine has been discontinued as a result of either WBC or ANC deficiencies (see above) must not be re-exposed to Clozapine.

Prescribers are encouraged to keep a record of all patients’ blood results and to take any steps necessary to prevent the patient being accidentally rechallenged in the future.

Discontinuation of therapy for other reasons

Patients who have been on Clozapine for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If Clozapine treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment and the dose should be re-titrated (see section 4.2).

Other precautions

This medicinal product contains lactose monohydrate.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Eosinophilia

In the event of eosinophilia, discontinuation of Clozapine is recommended if the eosinophil count rises above 3000/mm(3.0×109/l); therapy should be restarted only after the eosinophil count has fallen below 1000/mm(1.0×109/l).

Thrombocytopenia

In the event of thrombocytopenia, discontinuation of Clozapine therapy is recommended if the platelet count falls below 50 000/mm(50×109/l).

Cardiovascular disorders

Orthostatic hypotension, with or without syncope, can occur during Clozapine treatment. Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur with concurrent use of a benzodiazepine or any other psychotropic agent (see section 4.5) and during initial titration in association with rapid dose escalation; on very rare occasions they may occur even after the first dose. Therefore, patients starting Clozapine treatment require close medical supervision. Monitoring of standing and supine blood pressure is necessary during the first weeks of treatment in patients with Parkinson’s disease.

Analysis of safety databases suggests that the use of Clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases of myocarditis have been fatal. Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with Clozapine use; these reports also include fatalities. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, Clozapine treatment should be promptly stopped and the patient immediately referred to a cardiologist.

In patients who are diagnosed with cardiomyopathy while on Clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to Clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see section 4.8).

Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to Clozapine.

Myocardial infarction

There have been post marketing reports of myocardial infarction including fatal cases. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.

QT interval prolongation

As with other antipsychotics, caution is advised in patients with known cardiovascular disease or family history of QT prolongation.

As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval.

Cerebrovascular adverse events

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk factors for stroke.

Risk of thromboembolism

Since Clozapine may be associated with thromboembolism, immobilisation of patients should be avoided.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Clozapine and preventive measures undertaken.

Seizures

Patients with a history of epilepsy should be closely observed during Clozapine therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced (see section 4.2) and, if necessary, an anti-convulsant treatment should be initiated.

Anticholinergic effects

Clozapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, Clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstructionfaecal impaction, paralytic ileus, megacolon and intestinal infarction ischaemia (see section 4.8). On rare occasions these cases have been fatal. Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that constipation is recognised and actively treated.

Fever

During Clozapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign. Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infection or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. If the diagnosis of NMS is confirmed, Clozapine should be discontinued immediately and appropriate medical measures should be administered.

Falls

Clozapine may cause seizures, 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.

Metabolic changes

Atypical antipsychotic drugs, including Clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycaemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific profile.

Hyperglycaemia

Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. A mechanism for this possible association has not yet been determined. Cases of severe hyperglycaemia with ketoacidosis or hyperosmolar coma have been reported very rarely in patients with no prior history of hyperglycaemia, some of which have been fatal. When follow-up data were available, discontinuation of clozapine resulted mostly in resolution of the impaired glucose tolerance, and reinstitution of clozapine resulted in its reoccurrence. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. The discontinuation of clozapine should be considered in patients where active medical management of their hyperglycaemia has failed.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including Clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.

Weight gain

Weight gain has been observed with atypical antipsychotic use, including Clozapine. Clinical monitoring of weight is recommended.

Rebound, withdrawal effects

Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea.

Special populations

Hepatic impairment

Patients with stable pre-existing liver disorders may receive Clozapine, but need regular liver function tests. Liver function tests should be performed in patients in whom symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, develop during Clozapine therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if symptoms of jaundice occur, treatment with Clozapine must be discontinued. It may be resumed (see “Re-starting therapy” under section 4.2) only when the results of liver function tests are normal. In such cases, liver function should be closely monitored after re-introduction of Clozapine.

Patients aged 60 years and older

Initiation of treatment in patients aged 60 years and older is recommended at a lower dose (see section 4.2).

Orthostatic hypotension can occur with Clozapine treatment and there have been reports of tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with compromised cardiovascular function, may be more susceptible to these effects.

Patients aged 60 years and older may also be particularly susceptible to the anticholinergic effects of Clozapine, such as urinary retention and constipation.

Increased mortality in elderly people with dementia:

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Clozapine is not approved for the treatment of dementia-related behavioural disturbances.

4.5 Interaction with other medicinal products and other forms of interaction

Contraindication of concomitant use

Substances known to have a substantial potential to depress bone marrow function must not be used concurrently with Clozapine (see section 4.3).

Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Clozapine because these cannot be rapidly removed from the body in situations where this may be required, e.g. neutropenia (see section 4.3).

Alcohol should not be used concomitantly with Clozapine due to possible potentiation of sedation.

Precautions including dose adjustment

Clozapine may enhance the central effects of CNS depressants such as narcotics, antihistamines and benzodiazepines. Particular caution is advised when Clozapine therapy is initiated in patients who are receiving a benzodiazepine or any other psychotropic agent. These patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound and may lead to cardiac and/or respiratory arrest. It is not clear whether cardiac or respiratory collapse can be prevented by dose adjustment.

Because of the possibility of additive effects, caution is essential in the concomitant administration of substances possessing anticholinergic, hypotensive, or respiratory depressant effects.

Owing to its anti-alpha-adrenergic properties, Clozapine may reduce the blood-pressure-increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor effect of epinephrine.

Concomitant administration of substances known to inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for CYP 1A2 inhibitors such as caffeine (see below), perazine and the selective serotonin reuptake inhibitor fluvoxamine. Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine, and, to a lesser degree, sertraline, are CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP 3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin and protease inhibitors are unlikely, although some have been reported. Hormonal contraceptives (including combinations of estrogen and progesterone or progesterone only) are CYP 1A2, CYP 3A4 and CYP 2C19 inhibitors. Therefore initiation or discontinuation of hormonal contraceptives, may require dose adjustment of clozapine according to the individual medical need. Because the plasma concentration of clozapine is increased by caffeine intake and decreased by nearly 50% following a 5-day caffeine-free period, dosage changes of clozapine may be necessary when there is a change in caffeine-drinking habit. In cases of sudden cessation of smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.

Cases have been reported of an interaction between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. The nature of this interaction has not been fully elucidated.

Concomitant administration of substances known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine, leading to reduced efficacy. Substances known to induce the activity of cytochrome P450 enzymes and with reported interactions with clozapine include, for instance, carbamazepine (not to be used concomitantly with clozapine, due to its myelosuppresive potential), phenytoin and rifampicin. Known inducers of CYP1A2, such as omeprazole, may lead to decreased clozapine levels. The potential for reduced efficacy of clozapine should be considered when it is used in combination with these substances.

Other

Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).

Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Clozapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.

Caution is called for in patients receiving concomitant treatment with other substances which are either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic antidepressants, phenothiazines and type 1C anti-arrhythmics, which are known to bind to cytochrome P450 2D6, no clinically relevant interactions have been observed thus far.

As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval, or causing electrolyte imbalance.

An outline of drug interactions believed to be most important with Clozapine is given in Table 2 below. The list is not exhaustive.

Table 2: Reference to the most common drug interactions with Clozapine

DrugInteractionsComments
Bone marrow suppressants (e.g. carbamazepine, chloramphenicol), sulphonamides (e.g. co-trimoxazole), pyrazolone analgesics (e.g. phenylbutazone), penicillamine, cytotoxic agents and long-acting depot injections of antipsychoticsInteract to increase the risk and/or severity of bone marrow suppression.Clozapine must not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see section 4.3).
BenzodiazepinesConcomitant use may increase risk of circulatory collapse, which may lead to cardiac and/or respiratory arrest.Whilst the occurrence is rare, caution is advised when using these agents together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when Clozapine is added to an established benzodiazepine regimen.
AnticholinergicsClozapine potentiates the action of these agents through additive anticholinergic activity.Observe patients for anticholinergic side-effects, e.g. constipation, especially when using to help control hypersalivation.
AntihypertensivesClozapine can potentiate the hypotensive effects of these agents due to its sympathomimetic antagonistic effects.Caution is advised if Clozapine is used concomitantly with antihypertensive agents. Patients should be advised of the risk of hypotension, especially during the period of initial dose titration.
Alcohol, MAOIs, CNS depressants, including narcotics and benzodiazepinesEnhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these substances.Caution is advised if Clozapine is used concomitantly with other CNS active agents. Advise patients of the possible additive sedative effects and caution them not to drive or operate machinery.
Highly protein bound substances (e.g. warfarin and digoxin)Clozapine may cause an increase in plasma concentration of these substances due to displacement from plasma proteins.Patients should be monitored for the occurrence of side effects associated with these substances, and doses of the protein bound substance adjusted, if necessary.
PhenytoinAddition of phenytoin to Clozapine regimen may cause a decrease in the clozapine plasma concentrations.If phenytoin must be used, the patient should be monitored closely for a worsening or recurrence of psychotic symptoms.
LithiumConcomitant use can increase the risk of development of neuroleptic malignant syndrome (NMS).Observe for signs and symptoms of NMS.
CYP1A2 inducing substances (e.g. omeprazole)Concomitant use may decrease clozapine levelsPotential for reduced efficacy of clozapine should be considered.
CYP1A2 inhibiting substances e.g. fluvoxamine, caffeine, ciprofloxacin, perazine or hormonal contraceptives (CYP1A2, CYP3A4, CYP2C19)Concomitant use may increase clozapine levelsPotential for increase in adverse effects. Care is also required upon cessation of concomitant CYP1A2 or CYP3A4 inhibiting medications as there may be a decrease in clozapine levels. The effect of CYP2C19 inhibition may be minimal.

4.6 Fertility, pregnancy and lactation

Pregnancy

For clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancyembryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Neonates exposed to antipsychotics (including Clozapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Breastfeeding

Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving Clozapine should not breast-feed.

Fertility

Limited data available on the effects of clozapine on human fertility are inconclusive. In male and female rats, clozapine did not affect fertility when administered up to 40mg/kg, corresponding to a human equivalence dose of 6.4mg/kg or approximately a third of the maximum permissible adult human dose.

Women of child-bearing potential

A return to normal menstruation may occur as a result of switching from other antipsychotics to Clozapine. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.

4.7 Effects on ability to drive and use machines

Owing to the ability of Clozapine to cause sedation and lower the seizure threshold, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.

4.8 Undesirable effects

Summary of the safety profile

For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. An important exception is its propensity to cause agranulocytosis (see section 4.4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson’s disease in cases where standard treatment has failed. While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse reactions, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.

The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see section 4.4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation.

Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients (from 7.1 to 15.6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leukopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder.

Blood and lymphatic system

Development of granulocytopenia and agranulocytosis is a risk inherent to Clozapine treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. Because immediate withdrawal of treatment is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see section 4.4). Table 3 below summarises the estimated incidence of agranulocytosis for each Clozapine treatment period.

Table 3: Estimated incidence of agranulocytosis1

Treatment periodIncidence of agranulocytosis per 100,000 person-weeks2 of observation
Weeks 0-1832.0
Weeks 19-522.3
Weeks 53 and higher1.8

From the UK Clozapine Patient Monitoring Service lifetime registry experience between 1989 and 2001.

2 Person-time is the sum of individual units of time that the patients in the registry were exposed to Clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000=100,000), or in 200 patients who were in the registry for 500 weeks (200*500=100,000) before experiencing agranulocytosis.

The cumulative incidence of agranulocytosis in the UK Clozapine Patient Monitoring Service lifetime registry experience (0-11.6 years between 1989 and 2001) is 0.78%. The majority of cases (approximately 70%) occur within the first 18 weeks of treatment.

Metabolic and nutritional disorders

Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. On very rare occasions, severe hyperglycaemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported in patients on Clozapine treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of Clozapine and in a few cases hyperglycaemia recurred when treatment was reinitiated. Although most patients had risk factors for non-insulin-dependent diabetes mellitus, hyperglycaemia has also been documented in patients with no known risk factors (see section 4.4).

Nervous system disorders

The very common adverse reactions observed include drowsiness/sedation, and dizziness.

Clozapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures. These symptoms are more likely to occur with rapid dose increases and in patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant the possibility of a pharmacokinetic interaction should be considered. In rare cases, patients treated with Clozapine may experience delirium.

Very rarely, tardive dyskinesia has been reported in patients on Clozapine who had been treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other antipsychotics have improved on Clozapine.

Cardiac disorders

Tachycardia and postural hypotension with or without syncope may occur, especially in the initial weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and magnitude of dose titration. Circulatory collapse as a result of profound hypotension, in particular related to aggressive titration, with the possible serious consequences of cardiac or pulmonary arrest, has been reported with Clozapine.

A minority of Clozapine-treated patients experience ECG changes similar to those seen with other antipsychotics, including S-T segment depression and flattening or inversion of T waves, which normalise after discontinuation of Clozapine. The clinical significance of these changes is unclear. However, such abnormalities have been observed in patients with myocarditis, which should therefore be considered.

Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion and myocarditis have been reported, some of which have been fatal. The majority of the cases of myocarditis occurred within the first 2 months of initiation of therapy with Clozapine. Cardiomyopathy generally occurred later in the treatment.

Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known, however, whether eosinophilia is a reliable predictor of carditis.

Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest, palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms.

Sudden, unexplained deaths are known to occur among psychiatric patients who receive conventional antipsychotic medication but also among untreated psychiatric patients. Such deaths have been reported very rarely in patients receiving Clozapine.

Vascular disorders

Rare cases of thromboembolism have been reported.

Respiratory system

Respiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see sections 4.4 and 4.5).

Gastrointestinal system

Constipation and hypersalivation have been observed very frequently, and nausea and vomiting frequently. Very rarely ileus may occur (see section 4.4). Rarely Clozapine treatment may be associated with dysphagia. Aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.

Hepatobiliary disorders

Transient, asymptomatic elevations of liver enzymes and, rarely, hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, Clozapine should be discontinued (see section 4.4). In rare cases, acute pancreatitis has been reported.

Renal disorders

Isolated cases of acute interstitial nephritis have been reported in association with Clozapine therapy.

Reproductive and breast disorders

Very rare reports of priapism have been received.

General disorders

Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving Clozapine either alone or in combination with lithium or other CNS-active agents.

Acute withdrawal reactions have been reported (see section 4.4).

Tabulated list of adverse reactions:

The table below (Table 4) summarises the adverse reactions accumulated from reports made spontaneously and during clinical studies.

Table 4: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical trial reports

Adverse reactions are ranked under headings of frequency, using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Infections and infestations
Not known:Sepsis*
Blood and lymphatic system disorders
Common:Leukopenia/decreased WBC/neutropenia, eosinophilia, leukocytosis
Uncommon:Agranulocytosis
Rare:Anaemia
Very rare:Thrombocytopenia, thrombocythaemia
Immune system disorders
Not known:Angioedema*, leukocytoclastic vasculitis*
Endocrine disorders
Not known:Pseudophaeochromocytoma*
Metabolism and nutrition disorders
Common:Weight gain
Rare:Diabetes mellitus, impaired glucose tolerance, obesity*
Very rare:Hyperosmolar coma, ketoacidosis, severe hyperglycaemia, hypercholesterolemia, hypertriglyceridemia
Psychiatric disorders
Common:Dysarthria
Uncommon:Dysphemia
Rare:Agitation, restlessness
Nervous system disorders
Very common:Drowsiness/sedation, dizziness
Common:Seizures/convulsions/myoclonic jerks, extrapyramidal symptoms, akathisia, tremor, rigidity, headache
Uncommon:Neuroleptic malignant syndrome
Rare:Confusion, delirium
Very rare:Tardive dyskinesia, obsessive compulsive symptoms
Not known:Cholinergic syndrome (after abrupt withdrawal)*, EEG changes*, pleurothotonus*, restless leg syndrome*
Eye disorders
Common:Blurred vision
Cardiac disorders
Very common:Tachycardia
Common:ECG changes
Rare:Circulatory collapse, arrhythmias, myocarditis, pericarditis/ pericardial effusion
Very rare:Cardiomyopathy, cardiac arrest
Not known:Myocardial infarction sometimes fatal*, myocarditis sometimes fata*, chest pain/angina pectoris*, atrial fibrillation*, palpitations*, mitral valve incompetence associated with clozapine related cardiomyopathy*
Vascular disorders
Common:Syncope, postural hypotension, hypertension
Rare:Thromboembolism
Not known:Hypotension*, Venous thromboembolism
Respiratory, thoracic and mediastinal disorders
Rare:Aspiration of ingested food, pneumonia and lower respiratory tract infection which may be fatal, sleep apnoea syndrome*
Very rare:Respiratory depression/arrest
Not known:Pleural effusion*, nasal congestion*
Gastrointestinal disorders
Very common:Constipation, hypersalivation
Common:Nausea, vomiting, anorexia, dry mouth
Rare:Dysphagia
Very rare:Intestinal obstruction/paralytic ileus/faecal impaction, parotid gland enlargement
Not known:Megacolon sometimes fatal*, intestinal infarction/ischaemia sometimes fatal*, diarrhoea*, abdominal discomfort/heartburn/dyspepsia*, colitis*
Hepatobiliary disorders
Common:Elevated liver enzymes
Rare:Pancreatitis, hepatitis, cholestatic jaundice
Very rare:Fulminant hepatic necrosis
Not known:Hepatic steatosis*, hepatic necrosis*, hepatotoxicity*, hepatic fibrosis*, hepatic cirrhosis*, liver disorders including those hepatic events leading to life-threatening consequences such as liver injury (hepatic, cholestatic and mixed), liver failure which may be fatal and liver transplant*.
Skin and subcutaneous tissue disorders
Very rare:Skin reactions
Not knownPigmentation disorder*
Musculoskeletal and connective tissue disorders
Not known:Rhabdomyolysis*, muscle weakness*, muscle spasms*, muscle pain*, systemic lupus erythematosus*
Renal and urinary disorders
Common:Urinary retention, urinary incontinence
Very rare:Interstitial nephritis
Not known:Renal failure*, Nocturnal enuresis*
Pregnancy, puerperium and perinatal conditions
Not knownDrug withdrawal syndrome neonatal (see 4.6)
Reproductive system and breast disorders
Very rare:Priapism
Not knownRetrograde ejaculation*
General disorders and administration site conditions
Common:Benign hyperthermia, disturbances in sweating/temperature regulation, fever, fatigue
Very rare:Sudden unexplained death
Not known:Polyserositis*
Investigations
Rare:Increased CPK
Injury, poisoning and procedural complications
Uncommon:Falls (associated with clozapine-induced seizures, somnolence, postural hypotension, motor and sensory instability)*

* Adverse drug reactions derived from post-marketing experience via spontaneous case reports and literature cases.

Very rare events of ventricular tachycardia and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

In cases of acute intentional or accidental Clozapine overdose for which information on the outcome is available, mortality to date is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000mg. There have been reports of patients recovering from an overdose in excess of 10 000mg. However, in a few adult individuals, primarily those not previously exposed to Clozapine, the ingestion of doses as low as 400mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 to 200mg resulted in strong sedation or coma without being lethal.

Signs and symptoms

Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.

Treatment

There are no specific antidotes for Clozapine.

Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a ‘reverse epinephrine’ effect.

Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines

Mechanism of action

Clozapine has been shown to be an antipsychotic agent that is different from classic antipsychotics.

In pharmacological experiments, the compound does not induce catalepsy or inhibit apomorphine- or amphetamine-induced stereotyped behaviour. It has only weak dopamine-receptor-blocking activity at D1, D2, D3 and D5 receptors, but shows high potency for the Dreceptor.

Pharmacodynamic effects

Clozapine has potent anti-alpha-adrenergic, anticholinergic, antihistaminic, and arousal-reaction-inhibiting effects. It has also been shown to possess antiserotoninergic properties.

Clinical efficacy and safety

Clinically Clozapine produces rapid and marked sedation and exerts antipsychotic effects in schizophrenic patients resistant to other drug treatment. In such cases, Clozapine has proven effective in relieving both positive and negative schizophrenic symptoms mainly in short-term trials. In an open clinical trial performed in 319 treatment resistant patients treated for 12 months, a clinically relevant improvement was observed in 37% of patients within the first week of treatment and in an additional 44% by the end of 12 months. The improvement was defined as about 20% reduction from baseline in Brief Psychiatric Rating Scale Score. In addition, improvement in some aspects of cognitive dysfunction has been described.

Compared to classic antipsychotics, Clozapine produces fewer major extrapyramidal reactions such as acute dystonia, parkinsonian-like side effects and akathisia. In contrast to classic antipsychotics, Clozapine produces little or no prolactin elevation, thus avoiding adverse effects such as gynaecomastia, amenorrhoea, galactorrhoea and impotence.

A potentially serious adverse reaction caused by Clozapine therapy is granulocytopenia and agranulocytosis occurring at an estimated incidence of 3% and 0.7%, respectively. In view of this risk, the use of Clozapine should be limited to patients who are treatment-resistant or patients with psychosis in Parkinson’s disease when other treatment strategies have failed (see section 4.1) and in whom regular haematological examinations can be performed (see sections 4.4 and 4.8).

5.2 Pharmacokinetic properties

Absorption

The absorption of orally administered Clozapine is 90 to 95%; neither the rate nor the extent of absorption is influenced by food.

Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.

Distribution

In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 l/kg. Clozapine is approximately 95% bound to plasma proteins.

Biotransformation/metabolism

Clozapine is almost completely metabolised before excretion by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Of the main metabolites only the demethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of short duration.

Elimination

Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). After single doses of 75mg the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75mg for at least 7 days.

Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.

Linearity/non-linearity

Dosage increases from 37.5mg to 75mg and 150mg given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see section 4.6).

  1. Pharmaceutical particulars

6.1 List of excipients

Magnesium stearate, Silica, colloidal anhydrous, Povidone, Talc

Maize starch, Lactose monohydrate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage precautions.

6.5 Nature and contents of container

PVC/PVDC/Aluminium or PVC/PE/PVDC/Aluminium blister

Pack size: 7, 14, 20, 28, 30, 40, 50, 60, 84, 98, 100 tablets.

Hospital pack size: 500 (10×50) and 5000 (100×50) tablets.

PVC/PVDC/Aluminium or PVC/PE/PVDC/Aluminium perforated unit-dose blister:

Pack size: 7×1, 14×1, 20×1, 28×1, 30×1, 40×1, 50×1, 60×1, 84×1, 98×1, 100×1 tablets.

Hospital pack size: 500 (10x50x1) and 5000 (100x50x1) tablets.

White polyethylene (PE) bottles with polypropylene (PP), inner sealed and child-resistant closures.

Pack size: 100 tablets.

Hospital pack size: 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

 

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com

 

Clozapine Tablets USP 25mg, 50mg and 100mg Taj Pharma

 

Package Leaflet: Information for the user

Clozapine

Clozapine 25mg tablets USP
Clozapine 50mg tablets USP

Clozapine 100mg tablets USP

Clozapine

 

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

 

What is in this leaflet:

  1. What Clozapine is and what it is used for
  2. What you need to know before you take Clozapine
  3. How to take Clozapine
  4. Possible side effects
  5. How to store Clozapine
  6. Contents of the pack and other information

 

What Clozapine is and what it is used for

The active ingredient of Clozapine is clozapine which belongs to a group of medicines called antipsychotics (medicines that are used to treat specific mental disorders such as psychosis).

Clozapine is used to treat people with schizophrenia in whom other medicines have not worked. Schizophrenia is a mental illness which affects how you think, feel and behave. You should only use this medicine if you have already tried at least two other antipsychotic medicines, including one of the newer atypical antipsychotics, to treat schizophrenia, and these medicines did not work, or caused severe side effects that cannot be treated.

Clozapine is also used to treat severe disturbances in the thoughts, emotions and behaviour of people

with Parkinson’s disease in whom other medicines have not worked.

 

What you need to know before you take Clozapine

Do not take Clozapine if you:

  • are allergic (hypersensitive) to clozapine or any of the other ingredients of Clozapine (listed in section 6).
  • are not able to have regular blood tests.
  • have ever been told you have a low white blood cell count (e.g. leucopenia or agranulocytosis), especially if this was caused by medicines. This does not apply if you have had low white blood cell count caused by previous chemotherapy.
  • had to stop using Clozapine previously because of severe side effects (e.g. agranulocytosis or heart problems).
  • are being or have been treated with long-acting depot injections of antipsychotics.
  • suffer from bone marrow disease or have ever suffered from bone marrow disease.
  • suffer from uncontrolled epilepsy (seizures or fits).
  • have an acute mental illness caused by alcohol or drugs (e.g. narcotics).
  • suffer from reduced consciousness and severe drowsiness.
  • suffer from circulatory collapse which may occur as a result of severe shock.
  • suffer from any severe kidney disease.
  • suffer from myocarditis (an inflammation of the heart muscle).
  • suffer from any other severe heart disease.
  • have symptoms of active liver disease such as jaundice (yellow colouring of the skin and eyes, feeling sick and loss of appetite).
  • suffer from any other severe liver disease.
  • suffer from paralytic ileus (your bowel does not work properly and you have severe constipation).
  • use any medicine that stops your bone marrow from working properly.
  • use any medicine that reduces the number of white cells in your blood.

If any of the above applies to you, tell your doctor and do not take Clozapine. Clozapine must not be given to anyone who is unconscious or in a coma.

 

Warnings and Precautions

 

The safety measures mentioned in this section are very important. You must comply with them to minimise the risk of serious life-threatening side effects.

Before you start treatment with Clozapine, tell your doctor if you have or ever had:

  • blood clots or family history of blood clots, as medicines like these have been associated with formation of blood clots.
  • glaucoma (increased pressure in the eye).
  • Elevated (sometimes considerably) blood sugar levels, has occurred in patients with or without diabetes mellitus in their medical history (see section 4).
  • prostate problems or difficulty in urinating.
  • any heart, kidney or liver disease.
  • chronic constipation or if you are taking medicines which cause constipation (such as anticholinergics).
  • galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
  • controlled epilepsy.
  • large intestine diseases.
  • abdominal surgery.
  • a heart disease or family history of abnormal conduction in the heart called “prolongation of the QT interval”.
  • a risk for having a stroke, for example if you have high blood pressure, cardiovascular problems or blood vessel problems in the brain.

 

Tell your doctor immediately before taking the next Clozapine tablet if you:

  • get signs of a cold, fever, flu-like symptoms, sore throat or any other infection. You will have to have an urgent blood test to check if your symptoms are related to your medicine.
  • have a sudden rapid increase in body temperature, rigid muscles which may lead to unconsciousness (neuroleptic malignant syndrome) as you may be experiencing a serious side effect which requires immediate treatment.
  • have fast and irregular heartbeat, even when you are at rest, palpitations, breathing problems, chest pain or unexplained tiredness. Your doctor will need to check your heart and if necessary refer you to a cardiologist immediately.
  • experience nausea (feeling sick), vomiting (being sick) and/or loss of appetite. Your doctor will need to check your liver.
  • experience constipation, abdominal pain, abdominal tenderness, fever, bloating and/or bloody diarrhoea. Your doctor will need to examine you.

 

Medical check-ups and blood tests

Before you start taking Clozapine, your doctor will ask about your medical history and do a blood test to ensure that your white blood cells count is normal. It is important to find this out, as your body needs white blood cells to fight infections.

Make sure that you have regular blood tests before you start treatment, during treatment and after you stop treatment with Clozapine.

  • Your doctor will tell you exactly when and where to have the tests. Clozapine may only be taken if you have a normal blood count.
  • Clozapine can cause a serious decrease in the number of white cells in your blood (agranulocytosis). Only regular blood tests can tell the doctor if you are at risk of developing agranulocytosis.
  • During the first 18 weeks of treatment, tests are needed once a week. Afterwards, tests are needed at least once a month.
  • If there is a decrease in the number of white blood cells, you will have to stop Clozapine treatment immediately. Your white blood cells should then return to normal.

You will need to have blood tests for another 4 weeks after the end of Clozapine treatment.

Your doctor will also do a physical examination before starting treatment. Your doctor may do an electrocardiogram (ECG) to check your heart, but only if this is necessary for you, or if you have any special concerns.

If you have a liver disorder you will have regular liver function tests as long as you continue to take Clozapine. If you suffer from high levels of sugar in the blood (diabetes) your doctor may regularly check your level of sugar in the blood.

Clozapine may cause alteration in blood lipids. Clozapine may cause weight gain. Your doctor may monitor your weight and blood lipid level.

If you already suffer from feeling or if Clozapine makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position as these may increase the possibility of falling.

If you have to undergo surgery or if for some reason you are unable to walk around for a long time, discuss with your doctor the fact that you are taking Clozapine. You may be at risk of thrombosis (blood clotting within a vein).

 

Children and adolescents under 16 years

If you are under 16 years of age you should not use Clozapine as there is not enough information on its use in that age group.

 

Older people (aged 60 years and over)

Older people (aged 60 years and over) may be more likely to have the following side effects during treatment with Clozapine: faintness or light-headedness after changing position, dizziness, fast heartbeat, difficulty in passing urine, and constipation.

Tell your doctor or pharmacist if you suffer from a condition called dementia.

 

Other medicines and Clozapine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription or herbal therapies. You might need to take different amounts of your medicines or to take different medicines.

 

Do not take Clozapine together with medicines that stop the bone marrow from working properly and/or decrease the number of blood cells produced by the body, such as:

  • carbamazepine, a medicine used in epilepsy.
  • certain antibiotics: chloramphenicol, sulphonamides such as co-trimoxazole.
  • certain painkillers: pyrazolone analgesics such as phenylbutazone.
  • penicillamine, a medicine used to treat rheumatic joint inflammation.
  • cytotoxic agents, medicines used in chemotherapy.
  • long-acting depot injections of antipsychotic medicines.

These medicines increase your risk of developing agranulocytosis (lack of white blood cells).

 

Taking Clozapine at the same time as another medicine may affect how well Clozapine and/or the other medicine works. Tell your doctor if you plan to take, if you are taking (even if the course of treatment is about to end) or if you have recently had to stop taking any of the following medicines:

  • medicines used to treat depression such as lithium, fluvoxamine, tricyclic antidepressants, MAO inhibitors, citalopram, paroxetine, fluoxetine, and sertraline.
  • other antipsychotic medicines used to treat mental illnesses such as perazine.
  • benzodiazepines and other medicines used to treat anxiety or sleep disturbances.
  • narcotics and other medicines which can affect your breathing.
  • medicines used to control epilepsy such as phenytoin and valproic acid.
  • medicines used to treat high or low blood pressure such as adrenaline and noradrenaline.
  • warfarin, a medicine used to prevent blood clots.
  • antihistamines, medicines used for colds or allergies such as hay fever.
  • anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness.
  • medicines used to treat Parkinson’s disease.
  • digoxin, a medicine used to treat heart problems.
  • medicines used to treat a fast or irregular heartbeat.
  • some medicines used to treat stomach ulcers, such as omeprazole or cimetidine.
  • some antibiotic medicines, such as erythromycin and rifampicin.
  • some medicines used to treat fungal infections (such as ketoconazole) or viral infections (such as protease inhibitors, used to treat HIV infections).
  • atropine, a medicine which may be used in some eye drops or cough and cold preparations.
  • adrenaline, a medicine used in emergency situations.
  • hormonal contraceptives (birth-control tablets).

This list is not complete. Your doctor and pharmacist have more information on medicines to be careful with or to avoid while taking Clozapine. They will also know if the medicines you are taking belong to the listed groups. Speak to them.

 

Taking Clozapine with food and drink

Do not drink alcohol during treatment with Clozapine.

Tell your doctor if you smoke and how often you have drinks containing caffeine (coffee, tea, cola). Sudden changes in your smoking habits or caffeine drinking habits can also change the effects of Clozapine.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will discuss with you the benefits and possible risks of using this medicine during pregnancy. Tell your doctor immediately if you become pregnant during treatment with Clozapine.

The following symptoms may occur in newborn babies, of mothers that have used Clozapine in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor.

Some women taking some medicines to treat mental illnesses have irregular or no periods. If you have been affected in this way, your periods might return when your medicine is changed to Clozapine. This means you should use effective contraception.

Do not breast-feed during treatment with Clozapine. Clozapine, the active substance of Clozapine, may pass into your milk and affect your baby.

 

Driving and using machines

Clozapine might cause tiredness, drowsiness and seizures, especially at the beginning of treatment. You should not drive or operate machines while you have these symptoms.

 

Clozapine contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars, discuss this with your doctor before taking Clozapine.

 

How to take Clozapine

In order to minimise the risk of low blood pressure, seizures and drowsiness it is necessary that your doctor increases your dose gradually. Always take Clozapine tablets exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

It is important that you do not change your dose or stop taking Clozapine without asking your doctor first. Continue taking the tablets for as long as your doctor tells you. If you are 60 years or older, your doctor may start you on a lower dose and increase it more gradually because you might be more likely to develop some unwanted side effects (see section 2 “Before you take Clozapine”).

If the dose you are prescribed cannot be achieved with this strength tablet, other strengths of this medicinal product are available to achieve the dose.

 

Treatment of schizophrenia

The usual starting dose is 12.5mg (one half of a 25mg tablet) once or twice on the first day followed by 25mg once or twice on the second day. Swallow the tablet with water. If tolerated well, your doctor will then gradually increase the dose in steps of 25-50mg over the next 2-3 weeks until a dose up to 300mg per day is reached. Thereafter, if necessary, the daily dose may be increased in steps of 50 to 100mg half-weekly or, preferably, at weekly intervals.

The effective daily dose is usually between 200mg and 450mg, divided into several single doses per day. Some people might need more. A daily dose of up to 900mg is allowed.

Increased side effects (in particular seizures) are possible at daily doses over 450mg. Always take the lowest effective dose for you. Most people take part of their dose in the morning and part in the evening. Your doctor will tell you exactly how to divide your daily dose. If your daily dose is only 200mg, then you can take this as a single dose in the evening. Once you have been taking Clozapine with

successful results for some time, your doctor may try you on a lower dose. You will need to take Clozapine for at least 6 months.

 

Treatment of severe thought disturbances in patients with Parkinson’s disease

The usual starting dose is 12.5mg (one half of a 25mg tablet) in the evening. Swallow the tablet with water. Your doctor will then gradually increase the dose in steps of 12.5mg, not faster than two steps a week, up to a maximum dose of 50mg by the end of the second week. Increases in the dosage should be stopped or postponed if you feel faint,

light-headed or confused. In order to avoid such symptoms your blood pressure will be measured during the first weeks of treatment.

The effective daily dose is usually between 25mg and 37.5mg, taken as one dose in the evening. Doses of 50mg per day should only be exceeded in exceptional cases. The maximum daily dose is 100mg. Always take the lowest effective dose for you.

 

If you take more Clozapine than you should

If you think that you may have taken too many tablets, or if anyone else takes any of your tablets, contact a doctor immediately or call for emergency medical help.

The symptoms of overdose are:

Drowsiness, tiredness, lack of energy, unconsciousness, coma, confusion, hallucinations, agitation, incoherent speech, stiff limbs, trembling hands, seizures (fits), increased production of saliva, widening of the black part of the eye, blurred vision, low blood pressure, collapse, fast or irregular heartbeat, shallow or difficult breathing.

 

If you forget to take Clozapine

If you forget to take a dose, take it as soon as you remember. If it is almost time for your next dose, leave out the forgotten tablets and take the next dose at the right time. Do not take a double dose to make up for a forgotten dose. Contact your doctor as soon as possible if you have not taken any Clozapine for more than 48 hours.

 

If you stop taking Clozapine

Do not stop taking Clozapine without asking your doctor, because you might get withdrawal reactions. These reactions include sweating, headache, nausea (feeling sick), vomiting (being sick) and diarrhoea. If you have any of the above signs, tell your doctor straight away. These signs may be followed by more serious side effects unless you are treated immediately. Your original symptoms might come back. A gradual reduction in dose in steps of 12.5mg over one to two weeks is recommended, if you have to stop treatment. Your doctor will advise you on how to reduce your daily dose. If you have to stop Clozapine treatment suddenly, you will have to be checked by your doctor.

If your doctor decides to re-start the treatment with Clozapine and your last dose of Clozapine was over two days ago, this will be with the starting dose of 12.5mg.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

 

Possible side effects

Like all medicines, Clozapine can cause side effects, although not everybody gets them.

Some side effects can be serious and need immediate medical attention:

Tell your doctor immediately before taking the next Clozapine tablet if you experience any of the following:

Very common (affects more than 1 in 10 people):

  • severe constipation. Your doctor will have to treat this in order to avoid further complications.
  • fast heart beat

 

Common (affects up to 1 in 10 people):

  • signs of a cold, fever, flu-like symptoms, sore throat or any other infection. You will have to have an urgent blood test to check if your symptoms are related to your medicine.
  • sudden fainting or sudden loss of consciousness with muscle weakness (syncope).

 

Uncommon (affects up to 1 in 100 people):

  • if you have a sudden rapid increase in body temperature, rigid muscles which may lead to unconsciousness (neuroleptic malignant syndrome) as you may be experiencing a serious side effect which requires immediate treatment.
  • light-headedness, dizziness or fainting, when getting up from a sitting or lying position as it may increase the possibility of falling.

 

Rare (affects up to 1 in 1,000 people):

  • signs of a respiratory tract infection or pneumonia such as fever, coughing, difficulty breathing, wheezing.
  • severe, burning, upper abdominal pain, extending to the back accompanied by nausea and vomiting due to inflammation of the pancreas.
  • fainting and muscle weakness due to a significant drop in blood pressure (Circulatory collapse).
  • difficulty in swallowing (which may cause inhalation of food).
  • nausea (feeling sick), vomiting (being sick) and/or loss of appetite. Your doctor will need to check your liver.
  • interruption in breathing with or without snoring during sleep
  • signs of becoming obese or increasing obesity

 

Rare (affects up to 1 in 1,000 people) or very rare (affects up to 1 in 10,000 people):

  • fast and irregular heartbeat, even when you are at rest, palpitations, breathing problems, chest pain or unexplained tiredness. Your doctor will need to check your heart and if necessary refer you to a cardiologist immediately.

 

Very rare (affects up to 1 in 10,000 people):

  • persistent painful erection of the penis, if you are a man. This is called priapism. If you have an erection which lasts more than 4 hours immediate medical treatment may be needed in order to avoid further complications.
  • spontaneous bleeding or bruising, which might be signs of a decrease in numbers of blood platelets.
  • symptoms due to uncontrolled blood sugar (such as nausea or vomiting, abdominal pain, excessive thirst, excessive urination, disorientation or confusion.
  • abdominal pain, cramping, swollen abdomen, vomiting, constipation and failure to pass gas which may be signs and symptoms of bowel obstruction.
  • loss of appetite, swollen abdomen, abdominal pain, yellowing of the skin, severe weakness and malaise. These symptoms may be signs that you are starting to develop a liver disorder that may advancement fulminant liver necrosis.
  • nausea, vomiting, fatigue, weight loss which may be symptoms of inflammation of the kidney.

 

Unknown (frequency cannot be estimated from the available data)

  • crushing chest pain, sensation of chest tightness, pressure or squeezing (chest pain may radiate to the left arm, jaw, neck and upper abdomen), shortness of breath, sweating, weakness, light headedness, nausea, vomiting and palpitations (symptoms of heart attack). You should seek emergency medical treatment immediately.
  • chest pressure, heaviness, tightness, squeezing, burning or choking sensation (signs of insufficient blood flow and oxygen to the heart muscle). Your doctor will need to check your heart.
  • intermittent “thumping”, “pounding” or “fluttering” sensation in the chest (palpitations).
  • rapid and irregular heartbeats (atrial fibrillation). There may be occasional heart palpitations, fainting, shortness of breath, or chest discomfort. Your doctor will need to check your heart.
  • symptoms of low blood pressure such as light-headedness, dizziness, fainting, blurred vision, unusual fatigue, cold and clammy skin or nausea.
  • signs of blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing.
  • proven or strongly suspected infection along with fever or low body temperature, abnormally rapid breathing, rapid heart rate, change in responsiveness and awareness, drop in blood pressure (sepsis).
  • profuse sweating, headache, nausea, vomiting and diarrhoea (symptoms of cholinergic syndrome).
  • severely decreased urine output (sign of kidney failure).
  • an allergic reaction (swelling mainly of the face, mouth and throat, as well as, the tongue, which may be itchy or painful).
  • loss of appetite, swollen abdomen, abdominal pain, yellowing of the skin, severe weakness and malaise. This may indicate possible liver disorders that involve replacement of normal liver tissue with scar tissue leading to loss of liver function, including those liver events leading to life threatening consequences such as liver failure (which may lead to death), liver injury (injury of liver cells, bile duct in the liver, or both) and liver transplant.
  • constipation, abdominal pain, abdominal tenderness, fever, bloating, bloody diarrhoea. This may indicate possible megacolon (enlargement of the intestines) or intestinal infarction/ischaemia. Your doctor will need to examine you.
  • sharp chest pain with shortness of breath and with or without coughing
  • increased or new muscle weakness, muscle spasms, muscle pain. This may indicate possible a muscle disorder (rhabdomyolysis). Your doctor will need to examine you.
  • sharp chest or abdominal pain with shortness of breath and with or without coughing or fever.

 

If any of the above apply to you, please tell your doctor immediately before taking the next Clozapine tablet.

 

Other side effects:

Very common (affects more than 1 in 10 people): Drowsiness, dizziness, increased production of saliva. Common (affects up to 1 in 10 people):

High level of white blood cells (leukocytosis), high level of a specific type of white blood cell (eosinophilia), weight gain, blurred vision, headache, trembling, stiffness, restlessness, convulsions, jerks, abnormal movements, inability to initiate movement, inability to remain motionless, changes in ECG heart machine, high blood pressure, faintness or light-headedness after changing position, nausea (feeling sick), vomiting (being sick), loss of appetite, dry mouth, minor abnormalities in liver function tests, loss of bladder control, difficulty in passing urine,

tiredness, fever, increased sweating, raised body temperature, speech disorders (e.g. slurred speech).

 

Uncommon (affects up to 1 in 100 people):

Lack of white blood cells (agranulocytosis), speech disorders (e.g. stuttering).

 

Rare (affects up to 1 in 1,000 people):

Low level of red blood cells (anaemia), restlessness, agitation, confusion, delirium, irregular heart beat, inflammation of the heart muscle (myocarditis) or the membrane surrounding the heart muscle (pericarditis), fluid collection around the heart (pericardial effusion), high level of sugar in the blood, diabetes mellitus, blood clot in the lungs (thromboembolism), inflammation of the liver (hepatitis), liver disease causing yellowing of the skin/dark urine/itching, raised levels of an enzyme called creatinine phosphokinase in the blood.

 

Very rare (affects up to 1 in 10,000 people):

Increase in numbers of blood platelets with possible clotting in the blood vessels, uncontrollable movements of mouth/tongue and limbs, obsessive thoughts and compulsive repetitive behaviours (obsessive compulsive symptoms), skin reactions, swelling in front of the ear (enlargement of saliva glands), difficulty in breathing, very high levels of triglycerides or cholesterol in the blood, disorder of the heart muscle (cardiomyopathy), stopped heart beat (cardiac arrest), sudden unexplained death.

 

Unknown (frequency cannot be estimated from the available data)

Changes in brain waves machine (electroencephalogram/EEG), diarrhoea, stomach discomfort, heartburn, stomach discomfort after a meal, muscle weakness, muscle spasms, muscle pain, stuffy nose, nocturnal bedwetting, sudden, uncontrollable increase in blood pressure (pseudophaeochromocytoma), uncontrolled bending of the body to one side (pleurothotonus), ejaculatory disorder if you are a male, in which semen enters the bladder instead of ejaculating through the penis (dry orgasm or retrograde ejaculation), rash, purplish-red spots, fever or itching due to inflammation of blood vessel, inflammation of the colon resulting in diarrhoea, abdominal pain, fever, change in skin colour, “butterfly” facial rash, joint pain, muscle pain, fever and fatigue (lupus erythematous), restless legs syndrome (irresistible urge to move your legs or arms, usually accompanied by uncomfortable sensations during periods of rest, especially in the evening or at night and temporarily relieved by movement).

In elderly people with dementia, a small increase in the number of people dying has been reported for patients taking antipsychotics compared with those not taking antipsychotics.

 

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

 

How to store Clozapine

Keep this medicine out of the sight and reach of children.

Do not use Clozapine after the expiry date which is stated on the blister/bottle and the carton. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

 

Contents of the pack and other information

What Clozapine contains

The active substance is clozapine. Each tablet contains 25mg or 100mg clozapine.

The other ingredients are magnesium stearate, anhydrous colloidal silica, povidone K30, talc, maize starch, lactose monohydrate.

 

What Clozapine looks like and contents of the pack

Leponex tablets are available in PVC/PVDC/Aluminium or PVC/PE/PVDC/Aluminium blister packs containing 7, 14, 20, 28, 30, 40, 50, 60, 84, 98, 100, 500 (10×50) or 5000 (100×50) tablets,

PVC/PVDC/Aluminium or PVC/PE/PVDC/Aluminium perforated unit-dose blister packs containing 7×1, 14×1, 20×1, 28×1, 30×1, 40×1, 50×1, 60×1, 84×1, 98×1, 100×1, 500 (10x50x1) and 5000

(100x50x1) tablets, and in white plastic bottles containing 100 or 500 tablets. Not all pack sizes may be marketed.

 

  1. Manufactured in India by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com