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Clozapine Actavis

Document: Clozapine Actavis tablet ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT


Clozapine Actavis 25 mg tablets

Clozapine Actavis 100 mg tablets


Clozapine Actavis 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 (3.5x109/l), and ANC ≥2000/mm3 ( 2.0x109/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 Closapine Actavis.


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


Clozapine Actavis must be dispensed under strict medical supervision in accordance with official recommendations.


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.


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, Clozapine Actavis 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.



2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Each tablet contains 25 mg clozapine.

Excipient with known effect: lactose monohydrate 48 mg per tablet


Each tablet contains 100 mg clozapine

Excipient with known effect: lactose monohydrate 192 mgper tablet


For the full list of excipients, see section 6.1.


3. PHARMACEUTICAL form


Clozapine Actavis 25 mg tablets:

The tablet is round, yellow, 6 mm in diameter, dividing score on both sides, marked 'CPN 25'.


Clozapine Actavis 100 mg tablets

The tablet is round, yellow, 10 mm in diameter, dividing score on both sides, . marked 'CPN 100'.


4. Clinical particulars


4.1 Therapeutic indications


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.


Clozapine Actavis 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


The dosage must be adjusted individually. For each patient the lowest effective dose should be used.


Initiation of Clozapine Actavis treatment must be restricted to those patients with a WBC count≥3500/mm3(3.5x109/l) and an ANC ≥2000/mm3(2.0x109/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 Actavis, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5 Interaction with other medicinal products and other forms of interaction).


Posology


The following dosages are recommended:


Treatment-resistant schizophrenic patients


Starting therapy

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


Elderly patients

Initiation 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.


Paediatric population

The safety and efficacy of Clozapine Actavis 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.


Therapeutic dose range

In most patients, antipsychotic efficacy can be expected with 200‑450 mg/day given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. For information about maintenance dose see below.


Maximum dose

To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (not exceeding 100 mg) are permissible up to 900 mg/day. However, the possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/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 200 mg, once daily administration in the evening may be appropriate.


Ending therapy

In the event of planned termination of Clozapine Actavis therapy, a gradual reduction in dose over a 1‑2 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 Special warnings and precautions for use).


Re-starting therapy

In patients in whom the interval since the last dose of Clozapine Actavis exceeds 2 days, treatment should be re-initiated with 12.5 mg (half a 25 mg tablet) 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 Clozapine Actavis

It is generally recommended that Clozapine Actavis should not be used in combination with other antipsychotics. When Clozapine Actavis 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 failed


The starting dose must not exceed 12.5 mg/day (half a 25 mg tablet), taken in the evening. Subsequent dose increases must be by 12.5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, 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 25‑37.5 mg/day. In the event that treatment for at least one week with a dose of 50 mg fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week.


The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of 100 mg/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, Clozapine Actavis dosage may be increased by increments of 12.5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see above).


Ending therapy: A gradual reduction in dose by steps of 12.5 mg 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 Special warnings and precautions for use). In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.


4.3 Contraindications



4.4 Special warnings and precautions for use


Clozapine Actavis 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 Actavis, its use is limited to patients in whom therapy is indicated as set out in section 4.1 and:



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 Actavis is mandatory if either the WBC count is less than 3000/mm3 (3.0x109/l) or the ANC is less than 1500/mm3 (1.5x109/l) at any time during Clozapine Actavis treatment. Patients in whom Clozapine Actavis has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Closapine Actavis.


At each consultation, a patient receiving Clozapine Actavis 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 Closapine Actavis.


Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may only be started on Clozapine Actavis 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 Actavis treatment to ensure that only patients with normal WBC counts and ANC (WBC count ≥3500/mm3(3.5x109/l) and ANC ≥2000/mm3(2.0x109/l)) will receive Clozapine Actavis. After the start of Clozapine Actavis treatment regular WBC count and ANC must be performed and monitored weekly for the first 18 weeks, and at least at 4 weeks intervals thereafter.


Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Clozapine Actavis 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 Actavis therapy, either the WBC count falls to between 3500/mm3 (3.5x109/l) and 3000/mm3 (3.0x109/l) or the ANC falls to between 2000/mm3(2.0x109/l) and 1500/mm3 (1.5x109/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 (3.0-3.5x109/l) and 1500‑2000/mm3 (1.5-2.0x109/l), respectively, or higher.


Immediate discontinuation of Clozapine Actavis treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0x109/l) or the ANC is less than 1500/mm3 (1.5x109/l) during Clozapine Actavis 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 Actavis should be discontinued after the first blood count. Following discontinuation of Clozapine Actavis, haematological evaluation is required until haematological recovery has occurred.


Blood cell count

Action required

WBC/mm3 (/l)

ANC/mm3 (/l)

≥3500 (≥3.5x109)

≥2000 (≥2.0x109)

Continue Clozapine Actavis treatment

Between ≥3000 and

<3500 (≥3.0x109 and

<3.5x109)

Between ≥1500 and

<2000 (≥1.5x109 and

<2.0x109)

Continue Clozapine Actavis treatment, sample blood twice weekly until counts stabilise or increase

<3000 (<3.0x109)

<1500 (<1.5x109)

Immediately stop Clozapine Actavis treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not reexpose the patient.

If Clozapine Actavis has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0x109/l) occurs or the ANC falls below 1000/mm3 (1.0x109/l), the management of this condition must be guided by an experienced haematologist.


Discontinuation of therapy for haematological reasons

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

Discontinuation of Clozapine Actavis is recommended if the eosinophil count rises above 3000/mm3(3.0x109/l); therapy should be restarted only after the eosinophil count has fallen below 1000/mm3(1.0x109/l).


Thrombocytopenia

Discontinuation of Clozapine Actavis therapy is recommended if the platelet count falls below 50,000/mm3(50x109/l).


Orthostatic hypotension

Orthostatic hypotension with or without syncope, can occur during Clozapine Actavis 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 Actavis 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.


Myocarditis

Analysis of safety databases suggests that the use of Clozapine Actavis 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 Actavis 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 Actavis 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 Clozapine Actavis.


An approximately 3‑fold increased risk of cerebrovascular adverse eventshas 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.


QT interval

As clozapine can cause QT prolongation caution is advised in patients with bradycardia, cardiovascular disease and family history of QT prolongation.Concomitant use with other antipsychotics should be avoided.


Epilepsy

Patients with a history of epilepsy should be closely observed during Clozapine Actavis 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.


Liver dysfunction

Patients with stable pre-existing liver disorders may receive Clozapine Actavis, 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 Actavis 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 Actavis must be discontinued. It may be resumed (see 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 Actavis.


Intestinal function

Clozapine Actavis 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 Actavis 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). 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 recognized and actively treated.


Fever and NMS

During Clozapine Actavis 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.


Diabetes

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.


VTE

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 Actavis and preventive measures undertaken.


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.


Elderly patient

Initiation of treatment in elderly patients is recommended at a lower dose (see section 4.2).


Orthostatic hypotension can occur with Clozapine Actavis 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.


Elderly patients may also be particularly susceptible to the anticholinergic effects of Clozapine Actavis, 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 Actavis 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 Actavis (see section 4.3).


Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Clozapine Actavis 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 Actavis due to possible potentiation of sedation.


Precautions including dose adjustment

Clozapine Actavis may enhance the central effects of CNS depressants such as narcotics, antihistamines and benzodiazepines. Particular caution is advised when Clozapine Actavis 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 Actavis 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 plasma levels of clozapine, and the dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for CYP1A2 inhibitors such as caffeine (see below) and the selective serotonin reuptake inhibitor fluvoxamine and (more controversial) paroxetin. Some of the other serotonin reuptake inhibitors such as fluoxetine and sertraline are CYP2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin and protease inhibitors are unlikely, although some have been reported.

Because the plasma concentration of clozapine is increased by caffeine intake (1A2) 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. Azole antimycotics, potent CYP3A4 inhibitors may also increase plasma levels of clozapine.


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.


Caution should be exercised when clozapine is prescribed with other medicines known to increase QT interval, such as other antipsychotics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium or cisapride. Concomitant use with medicines causing electrolyte imbalance, such as thiazide diuretics (hypokalemia), should be considered as it increase the risk for malignantarrhythmias(see section 4.4). In this regard concomitant treatment with drugs that may increase the concentration of clozapine in the blood should also be considered


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 Actavis 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.


An outline of drug interactions believed to be most important with Clozapine Actavis is given in Table 1 below. The list is not exhaustive.


Table 1: Reference to the most common drug interactions with Clozapine Actavis


Drug

Interactions

Comments

Bone marrow suppressants (e.g. carbamazapine, chloramphenicol), sulphonamides (e.g. cotrimoxazole), 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.

Clozapine Actavis must not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see section 4.3).

Benzodiazepines

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 agents together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when Clozapine Actavis is added to an established benzodiazepine regimen.

Anticholinergics

Clozapine Actavis 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.

Antihypertensives

Clozapine Actavis can potentiate the hypotensive effects of these agents due to its sympathomimetic antagonistic effects.

Caution is advised if Clozapine Actavis 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, benzodiazepines

Enhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these substances.

Caution is advised if Clozapine Actavis 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 Actavis 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.

Phenytoin

Addition of phenytoin to Clozapine Actavis 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.

Lithium

Concomitant use can increase the risk of development of neuroleptic malignant syndrome (NMS).

Observe for signs and symptoms of NMS.

4.6 Fertility, pregnancy and lactation


Pregnancy

For clozapine, there are only limited clinical data on exposed pregnancies. Neonates exposed to antipsychotics (including Clozapine Actavis) 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.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.


Breastfeeding

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


Fertility

A return to normal menstruation may occur as a result of switching from other antipsychotics to Clozapine Actavis. 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 Actavis 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.


Undesirable effects


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.


Blood and lymphatic system

Development of granulocytopenia and agranulocytosis is a risk inherent to Clozapine Actavis 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 2 below summarises the estimated incidence of agranulocytosis for each Clozapine Actavis 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

1) From the UK Clozapine Actavis 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 Actavis 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 Clozaril 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 Actavis treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of Clozapine Actavis 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 Actavis 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 Actavis may experience delirium.


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


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 Actavis.


A minority of Clozapine Actavis-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 Actavis. 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 (see section 4.4), 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 Actavis. 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, that can be caused by cardiac disorders, have been reported very rarely in patients receiving clozapine (see section 4.4).


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 Actavis 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 Actavis 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 Actavis therapy.


Pregnancy, puerperium and perinatal conditions

Neonatal withdrawal syndrome has been reported (see section 4.6).


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 Actavis either alone or in combination with lithium or other CNS-active agents. Acute withdrawal reactions have been reported (see section 4.4).


The table below (Table 3) summarizes 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 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).


Blood and lymphatic system disorders

Common

Leukopenia/decreased WBC/neutropenia, eosinophilia, leukocytosis

Unommon

Agranulocytosis

Very rare

Thrombocytopenia, thrombocythaemia

Metabolism and nutrition disorders

Common

Weight gain

Rare

impaired glucose tolerance and diabetes mellitus

Very rare

Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridemia and hypercholesterolemia

Psychiatric disorders

Rare

Agitation, restlessness

Not known

Obsessive compulsive symptoms.

Nervous system disorders

Very common

Drowsiness/sedation, dizziness

Common

Blurred vision, headache, tremor, rigidity, agitation, akathisia, extrapyramidal symptoms, seizures/convulsions/myoclonic jerks

Uncommon

Confusion, delirium

Very rare

Tardive dyskinesia

Cardiac disorders

Very common

Tachycardia

Common

ECG changes

Rare

Circulatory collapse, ventricular arrhythmias, Ventricular fibrillation, ventricular tachycardia, myocarditis, pericarditis/ pericardial effusion, QT prolongation, Torsade de Pointes, cardiac arrest

Very rare

Cardiomyopathy

Vascular disorders

Common

Hypertension, postural hypotension, syncope

Rare

Venous thromboembolism (including pulmonary embolism and deep vein thrombosis)

Respiratory, thoracic and mediastinal disorders

Rare:

Aspiration of ingested food

Very rare

Respiratory depression/arrest

Gastrointestinal disorders

Very common

Constipation, hypersalivation

Common:

Nausea, vomiting, anorexia, dry mouth

Rare

Dysphagia

Very rare

Parotid gland enlargement,intestinal obstruction/paralytic ileus/faecal impaction

Hepatobiliary disorders

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 retention, urinary incontinence

Very rare

Interstitial nephritis

Pregnancy, puerperium and perinatal conditions

Not known

Drug withdrawal syndrome neonatal (see 4.6 Fertility, pregnancy and lactation)

Reproductive system and breast disorders

Very rare

Priapism

General disorders and administration site conditions

Common:

Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation,

Uncommon

Neuroleptic malignant syndrome

Very rare

Sudden unexplained death

Investigations

Rare

Increased creatine kinase (CPK)

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.


4.9 Overdose


In cases of acute intentional or accidental Clozapine Actavis 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 2000 mg. There have been reports of patients recovering from an overdose in excess of 10,000 mg. However, in a few adult individuals, primarily those not previously exposed to Clozapine Actavis, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50‑200 mg 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

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.


5. PHARMACOLOGICAL PROPERTIES


5.1 Pharmacodynamic properties


Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines, ATC code N05A H02


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


Mechanism of action

In pharmacological experiments, the compound does not induce catalepsy or inhibit apomorphine- or amphetamine-induced stereotyped behaviour. It has only weak dopaminereceptor- blocking activity at D1, D2, D3and D5 receptors, but shows high potency for the D4receptor, in addition to potent anti-alpha-adrenergic, anticholinergic, antihistaminic, and arousal-reaction-inhibiting effects. It has also been shown to possess antiserotoninergic properties.


Pharmacodynamic effects

Clinically Clozapine Actavis produces rapid and marked sedation and exerts antipsychotic effects in schizophrenic patients resistant to other drug treatment. In such cases, Clozapine Actavis 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.


Clinical efficacy and safety

Compared to classic antipsychotics, Clozapine Actavis produces fewer major extrapyramidal reactions such as acute dystonia, parkinsonian-like side effects and akathisia. In contrast to classic antipsychotics, Clozapine Actavis 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 Actavis 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 Actavis 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 Therapeutic indications) 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 Actavis is 90‑95%; neither the rate nor the extent of absorption is influenced by food.


Distribution

Clozapine Actavis is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50‑60%. In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4‑4.2 hours), and the volume of distribution is 1.6 l/kg.


Biotransformation

Clozapine Actavis is approximately 95% bound to plasma proteins. Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6‑26 hours). After single doses of 75 mg 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 75 mg for at least 7 days.


Elimination

Clozapine Actavis is almost completely metabolised before excretion. 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. 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 37.5‑75 mg and 150 mg 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


Preclinical 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).


6. PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Lactose monohydrate 48 mg resp. 192 mg

Magnesium stearate

Povidone

Talc

Maize starch

Silica, colloidal anhydrous

Pregelatinised starch


6.2 Incompatibilities


Not applicable.


6.3 Shelf life


5 years.


6.4 Special precautions for storage


This medicinal product does not require any special storage precautions.


Nature and contents of container


25 mg tablets: 50x1 monodose, 100 tabl blisterpack, 100 tabl plastic bottle for dose dispensing and hospital use only

100 mg tablets: 50x1 monodose, 100 tabl blisterpack, 500 tabl plastic bottle for dose dispensing and hospital use only


6.6 Special precautions for disposal <and other handling>


No special requirements.


7. MARKETING AUTHORISATION HOLDER


[To be completed nationally]


8. MARKETING AUTHORISATION NUMBER(S)


[To be completed nationally]


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


25 mg: 1998-12-18/2008-12-18

100 mg: 1998-12-18/2008-12-18


10. DATE OF REVISION OF THE TEXT

2016-07-28


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