Denzapine 50mg/ml Oral Suspension
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Company information
- More information about this medicine
|• with schizophrenia who are non-responsive to or intolerant of antipsychotic drug treatment, or with psychosis in Parkinson's disease when other treatment strategies have failed (see point 4.1)• who have initially normal leukocyte findings (white blood cell count of >3500/mm3 (3.5 x 109 /L), and an absolute neutrophil count (ANC) of >2000/mm3 (2.0 x 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 therapy, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of DENZAPINE.Prescribing physicians should comply fully with the required safety measures. At each consultation, a patient receiving DENZAPINE should 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.DENZAPINE must be dispensed under strict medical supervision in accordance with official recommendations.|
|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. 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. If myocarditis or cardiomyopathy are suspected, DENZAPINE treatment should be promptly stopped and the patient immediately referred to a cardiologist.Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine.|
Treatment-resistant schizophrenic patients
Starting therapy12.5 mg (0.25 ml of suspension) once or twice on the first day, followed by 25 mg (0.5 ml of suspension) or 50mg (1.0 ml of suspension) on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg (0.5 ml to 1.0 ml of suspension) in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg (1.0 ml to 2.0 ml of suspension) at half-weekly or, preferably, weekly intervals.
Use in childrenNot Recommended in Children.
Use in the elderlyInitiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day.
Therapeutic dose rangeIn most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day (4 ml to 9 ml/day) given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. For maintenance dose, see below.
Maximum doseTo obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e. not exceeding 100 mg or 2 ml) are permissible up to 900 mg/day (18 ml). The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day (9 ml/day) must be borne in mind.
Maintenance doseAfter 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 200 mg, once daily administration in the evening may be appropriate.
Ending therapyIn the event of planned termination of DENZAPINE therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation is necessary (e.g. because of leucopoenia), 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.
Re-starting therapyIn patients in whom the interval since the last dose of DENZAPINE suspension exceeds 2 days, treatment should be re-initiated with 12.5 mg (0.25 ml) 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 Special warnings and precautions for use), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.
Switching from a previous antipsychotic therapy to DENZAPINEIt is generally recommended that DENZAPINE should not be used in combination with other antipsychotics, including depot preparations, which may have a myelosuppressive effect. When DENZAPINE 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.
Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failedThe starting dose must not exceed 12.5 mg/day (0.25 ml) taken in the evening. Subsequent dose increases must be by 12.5 mg increments (0.25 ml), with a maximum of two increments a week up to a maximum of 50 mg (1 ml), 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. The mean effective dose is usually between 25 and 37.5 mg/day (0.5 and 0.75 ml/day). In the event that treatment for at least one week with a dose of 50 mg (1 ml) fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week (0.25 ml/week). The dose of 50 mg/day (1 ml/day) should only be exceeded in exceptional cases, and the maximum dose of 100 mg/day (2 ml/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. 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, DENZAPINE dosage may be increased by increments of 12.5 mg/week (0.25 ml/week) up to a maximum of 100 mg/day (2 ml/day), taken in one or two divided doses (see above). Ending therapy: A gradual reduction in dose by steps of 12.5 mg (0.25 ml) over a period of at least one week (preferably two) is recommended. Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis as indicated in section 4.4 (Special warnings and precautions for use). In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
PrecautionsDENZAPINE can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of WBC counts and 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 DENZAPINE, its use is limited to patients in whom therapy is indicated as set out in section 4.1 (Therapeutic indications) and: who have initially normal leukocyte findings (WBC count greater than 3500/mm3 (3.5 x 109/L) and ANC above 2000/mm3 (2.0 x 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 DENZAPINE. 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. Caution should be exercised in patients with cardiovascular disease or a family history of QT prolongation.As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc intervalThe concomitant administration of neuroleptic medicines should be avoided.Prescribing physicians should 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 DENZAPINE is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109 /L) or the ANC is less than 1500/mm3 (1.5 x 109 /L) at any time during DENZAPINE treatment. Patients in whom DENZAPINE has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to DENZAPINE.At each consultation, a patient receiving DENZAPINE should 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 DENZAPINE.Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on DENZAPINE with the agreement of a haematologist.|
WBC Counts and ANC MonitoringWBC and differential blood counts must be performed within 10 days prior to initiating DENZAPINE treatment to ensure that only patients with normal WBC counts (WBC count greater than 3500/mm3 (3.5 x 109/L) and ANC above 2000/mm3 (2.0 x 109/L)) will receive the drug. After the start of DENZAPINE treatment the WBC count and ANC must be 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 DENZAPINE or until haematological recovery has occurred (see below Low WBC count/ANC). At each consultation, the patient should 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/ANCIf, during DENZAPINE therapy, either the WBC count falls to between 3500/mm3 (3.5 x 109/L) and 3000/mm3 (3.0 x 109/L) or the ANC falls to between 2000/mm3 (2.0 x 109/L) and 1500/mm3 (1.5 x 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 x 109/L) and 1500 - 2000/mm3 (1.5 - 2.0 x 109/L), respectively, or higher. Immediate discontinuation of DENZAPINE treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109/L) or the ANC is less than 1500/mm3 (1.5 x 109/L) during DENZAPINE 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, DENZAPINE should be discontinued after the first blood count. Following discontinuation of DENZAPINE, haematological evaluation is required until haematological recovery has occurred.
|Blood cell count||Action required|
|WBC/mm3 (/L)||ANC/mm3 (/L)|
|>3500 (3.5 x 109)||>2000 (2.0 x 109)||Continue DENZAPINE treatment|
|3000- 3500 (3.0 x 109 - 3.5 x 109)||1500-2000 (1.5 x 109 - 2.0 x 109)||Continue DENZAPINE treatment, sample blood twice weekly until counts stabilise or increase|
|< 3000 ( < 3.0 x 109)||< 1500 ( < 1.5 x 109)||Immediately stop DENZAPINE treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.|
Discontinuation of therapy for haematological reasonsPatients in whom DENZAPINE has been discontinued as a result of either WBC or ANC deficiencies (see above) must not be re-exposed to DENZAPINE. 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 reasonsPatients who have been on DENZAPINE 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 DENZAPINE 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 Posology and method of administration).
Other precautionsIn the event of eosinophilia, discontinuation of DENZAPINE is recommended if the eosinophil count rises above 3000/mm3 (3.0 x 109/L); therapy should be restarted only after the eosinophil count has fallen below 1000/mm3 (1.0 x 109/L). In the event of thrombocytopenia, discontinuation of DENZAPINE therapy is recommended if the platelet count falls below 50 000/mm3 (50 x 109/L). Orthostatic hypotension, with or without syncope, can occur during DENZAPINE 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 benzodiazepines or any other psychotropic agent (see section 4.5 Interaction with other medicinal products and other forms of interaction) and during initial titration in association with rapid dose escalation; on very rare occasions they may occur even after the first dose. Therefore, patients commencing DENZAPINE 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 are suspected, DENZAPINE treatment should be promptly stopped and the patient immediately referred to a cardiologist. Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to DENZAPINE. Patients with a history of epilepsy should be closely observed during DENZAPINE therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced (see section 4.2 Posology and method of administration) and, if necessary, an anti-convulsant treatment should be initiated. Patients with stable pre-existing liver disorders may receive DENZAPINE, 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 DENZAPINE therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if symptoms of jaundice occur, treatment with DENZAPINE 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 the drug. DENZAPINE 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 obstruction, faecal impaction and paralytic ileus (see section 4.8 Undesirable effects). 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. During DENZAPINE 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. 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. The discontinuation of clozapine should be considered in patients where active medical management of their hyperglycaemia has failed. Since DENZAPINE 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 DENZAPINE and preventive measures undertaken
Use in the elderlyInitiation of treatment in the elderly is recommended at a lower dose (see section 4.2 Posology and method of administration). Orthostatic hypotension can occur with DENZAPINE treatment and there have been reports of tachycardia, which may be sustained. Elderly patients, particularly those with compromised cardiovascular function, may be more susceptible to these effects. Elderly patients may also be particularly susceptible to the anticholinergic effects of DENZAPINE, such as urinary retention and constipation.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.
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.DENZAPINE is not approved for the treatment of dementia-related behavioural disturbances.
Bone marrow suppressants (e.g. carbamazapine, chloramphenicol, sulphonamides (e.g. co-trimoxazole), pyrazolone analgesics (e.g. phenylbutazone), penicillamine, cytotoxic agents and long-acting depot injections of antipsychotics
Interact to increase the risk and/or severity of bone marrow suppression
DENZAPINE should not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see Section 4.3 Contraindications )
Concomitant 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 drugs together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when DENZAPINE is added to an established benzodiazepine regimen.
DENZAPINE potentiates the action of these drugs through additive anticholinergic activity
Observe patients for anticholinergic side - effects, e.g. constipation, especially when using to help control hypersalivation
DENZAPINE can potentiate the hypotensive effects of these drugs due to its sympathomimetic antagonistic effects
Caution is advised if DENZAPINE 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 benzodiazepines
Enhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these drugs
Caution is advised if DENZAPINE 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 drugs
(e.g. warfarin and digoxin)
DENZAPINE may cause an increase in plasma concentration of these drugs due to displacement from plasma proteins
Patients should be monitored for the occurrence of side effects associated with these drugs, and doses of the protein bound drug adjusted, if necessary
Addition of phenytoin to DENZAPINE drug 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
Concomitant 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 levels
Potential for reduced efficacy of clozapine should be considered.
CYP1A2 inhibiting substances (e.g. fluvoxamine, caffeine, ciprofloxacin)
Concomitant use may increase clozapine levels
Potential for increase in adverse effects. Care is also required upon cessation of concomitant CYP1A2 inhibiting medications as there will be a decrease in clozapine levels.
PregnancyFor clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3). Caution should be exercised when prescribing to pregnant women.Neonates exposed to antipsychotics (including Denzapine) 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.
LactationAnimal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving DENZAPINE should not breast-feed.
Women of child-bearing potentialA return to normal menstruation may occur as a result of switching from other antipsychotics to DENZAPINE. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
Blood and lymphatic systemDevelopment of granulocytopenia and agranulocytosis is a risk inherent to DENZAPINE treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see section 4.4 Special warnings and precautions for use). Table 2 below summarises the estimated incidence of agranulocytosis for each DENZAPINE treatment period. Table 2: Estimated incidence of agranulocytosis1
|Treatment period||Incidence of agranulocytosis per 100,000 person-weeks2 of observation|
|Weeks 0 - 18||32.0|
|Weeks 19 - 52||2.3|
|Weeks 53 and higher||1.8|
Metabolic and Nutritional DisordersImpaired 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. Special warnings and precautions for use).
Nervous System DisordersThe very common adverse events observed include drowsiness/sedation, and dizziness. DENZAPINE 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 drugs the possibility of a pharmacokinetic interaction should be considered. In rare cases, patients treated with DENZAPINE 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 DisordersTachycardia 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 of the drug, 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 antipsychotic drugs, 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. 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 medicineSudden, 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 DisordersRare cases of thromboembolism have been reported. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown
Respiratory SystemRespiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see sections 4.4 Special warnings and precautions for use and 4.5 Interaction with other medicinal products and other forms of interaction).
Gastrointestinal SystemConstipation and hypersalivation have been observed very frequently, and nausea and vomiting frequently. Very rarely ileus may occur (see section 4.4 Special warnings and precautions for use). Rarely DENZAPINE 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 DisordersTransient, asymptomatic elevations of liver enzymes and rarely, hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, DENZAPINE should be discontinued (see section 4.4. Special warnings and precautions for use). In rare cases, acute pancreatitis has been reported.
Renal DisordersIsolated cases of acute interstitial nephritis have been reported in association with DENZAPINE therapy.
Reproductive and Breast DisordersVery rare reports of priapism have been received. Pregnancy, puerperium and perinatal conditionsDrug withdrawal syndrome neonatal (see section 4.6 Fertility, pregnancy and lactation) has been reported. The frequency of this is not known.
General DisordersCases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving clozapine either alone or in combination with lithium or other CNS-active agents. The table below (Table 3) summarises the adverse reactions accumulated from reports made spontaneously and during clinical studies. Table 3: 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, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare ( < 1/10,000), including isolated reports.
|Blood and lymphatic system disorders|
|Common||Leucopoenia/decreased WBC/neutropenia, eosinophilia, leukocytosis|
|Very rare||Thrombocytopenia Thrombocythaemia|
|Metabolism and nutrition disorders|
|Rare||Impaired glucose tolerance, diabetes mellitus|
|Very rare||Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia|
|Nervous system disorders|
|Very common||Drowsiness/sedation, dizziness|
|Common||Blurred vision, headache, tremor, rigidity, akathisia, extra pyramidal symptoms, seizures/convulsions/myoclonic jerks|
|Very rare||Tardive dyskinesia, obsessive compulsive disorder|
|Rare||Circulatory collapse, Ventricular arrhythmias (VF, VT), myocarditis, pericarditis/pericardial effusion|
|Very rare||Cardiomyopathy, cardiac arrest, QT prolongation, Torsades de pointes|
|Common||Hypertension, postural hypotension, syncope|
|Rare||Aspiration of ingested food, pneumonia and lower respiratory tract infection which may be fatal|
|Very rare||Respiratory depression/arrest|
|Very common||Constipation, hypersalivation|
|Common||Nausea, vomiting, anorexia, dry mouth|
|Very rare||Parotid gland enlargement, intestinal obstruction/paralytic ileus/faecal impaction|
|Common||Elevated liver enzymes|
|Rare||Hepatitis, cholestatic jaundice, pancreatitis|
|Very rare||Fulminant hepatic necrosis|
|Skin and subcutaneous tissue disorders|
|Very rare||Skin reactions|
|Renal and urinary disorders|
|Common||Urinary incontinence, urinary retention|
|Very rare||Interstitial nephritis|
|Reproductive system disorders|
|Pregnancy, puerperium and perinatal conditions|
|Not known||Drug withdrawal syndrome neonatal|
|Common||Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation|
|Uncommon||Neuroleptic malignant syndrome|
|Very rare||Sudden unexplained death|
Signs and symptomsDrowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extra pyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.
TreatmentGastric 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.
Park View House, 65 London Road, Newbury, Berkshire, RG14 1JN
Telephone : +44 (0)1635 568 400
Fax : +44 (0)1635 568 401
Customer Care direct line : +44 (0)1635 568 445
Medical Information Direct Line : +44 (0)870 851 0207
Medical Information Fax : +44 (0)1793 710 387
Medical Information e-mail : email@example.com