Each tablet contains:

active ingredients: clozapine – 100 mg;

excipients microcrystalline cellulose, lactose monohydrate, maize (corn) starch, povidone, sodium starch glycolate, magnesium stearate.

Antipsychotic; N05AH02.

8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine; 5786-21-0.

Clozapine is a dibenzodiazepine derivative and the prototype of the atypical antipsychotics. It has relatively weak dopamine receptor-blocking activity at D1, D2, D3, and D5 receptors but has a high affinity for the D4 receptor. Clozapine possesses alpha-adrenergic blocking, antimuscarinic, antihistaminic, antiserotonergic, and sedative properties.

Although clozapine is well absorbed from the gastrointestinal tract, its bioavailability is limited to about 50% by first-pass metabolism. Peak plasma concentrations are achieved, on average, about 2.5 hours after oral doses. Clozapine is about 95% bound to plasma proteins and has a mean terminal elimination half-life of about 12 hours at steady state. It is almost completely metabolised and routes of metabolism include N-demethylation, hydroxylation, and N-oxidation; the desmethyl metabolite (norclozapine) has limited activity. The metabolism of clozapine is mediated mainly by the cytochrome P450 isoenzyme CYP1A2. Metabolites and trace amounts of unchanged drug are excreted mainly in the urine and also in the faeces. There is wide interindividual variation in plasma concentrations of clozapine and no simple correlation has been found between plasma concentrations and therapeutic effect. It is distributed into breast milk.

Clozapine use must be accompanied by strict procedures for the monitoring of white blood cell counts. To minimise the incidence of adverse effects, clozapine therapy should be introduced gradually, beginning with low doses and increasing according to response.

In the treatment of schizophrenia, including reducing the risk of suicidal behaviour, the usual dose by mouth is 12.5 mg once or twice on the first day followed by 25 mg once or twice on the second day. Thereafter the daily dosage may be increased gradually in increments of 25 to 50 mg to achieve a daily dose of up to 300 mg within 14 to 21 days. Subsequent increments of 50 to 100 mg may be made once or twice weekly; a daily dosage of 900 mg should not be exceeded. Once a therapeutic response has been obtained, a gradual reduction of dosage to a suitable maintenance dose is recommended; most patients respond to 200 to 450 mg daily. The total daily dose is given in divided doses; a larger portion may be given at night. Daily maintenance doses of 200 mg or less may be given as a single dose in the evening. If clozapine is to be withdrawn, this should be done gradually over a 1- to 2-week period. However, immediate withdrawal with careful observation is essential if neutropenia develops or if myocarditis or cardiomyopathy is suspected.

Elderly patients may require lower doses of clozapine and it is recommended that treatment should start with a dose of 12.5 mg on the first day and that subsequent dose increments should be restricted to 25 mg.

For patients who are restarting treatment after an interval of more than 2 days, 12.5 mg may be given once or twice on the first day. If this dose is well tolerated it may be possible to increase the dosage more quickly than when first starting. However, patients who have had respiratory or cardiac arrest with initial dosing, but were then successfully titrated to a therapeutic dose, should be re-titrated with extreme caution after a break of even 24 hours.

It is recommended that oral therapy with other antipsychotics should be withdrawn gradually before treatment with clozapine is started.

Digestive system: hypersalivation, nausea, vomiting, unpleasant abdominal feeling, heartburn,constipation (which, in a few cases, has led to gastrointestinal obstruction, faecal impaction, and paralytic ileus. There were reports of liver enzymes activity increase and in rare cases of cholestasis.

The respiratory system: pneumonia and lower respiratory tract infection, which can have fatal consequences.

Metabolism: weight gain, hyperglycemia.

Hematopoietic system: reversible neutropenia, granulocytopenia, agranulocytosis (usually develops during the first 18 weeks of treatment); possible development of eosinophilia and leukocytosis of unknown nature (especially during the first weeks of treatment).

CNS:most frequently – drowsiness,fatigue feeling, sedation; can be – dizziness, headache, obsessive-compulsive disorder. Relatively rare – extrapyramidal symptoms, usually mild severity. There are reports on the development of rigidity, tremor, akathisia, and very rare reports the development of neuroleptic malignant syndrome.

Effects due to anticholinergic activity: can be – dry mouth, accommodation disturbances,constipation, disorders of urination,sweating and thermoregulation, the development of hyperthermia.

Allergic reactions: in rare cases – allergic reactions such as skin rashes, urticaria, erythema multiforme, exfoliative dermatitis,photosensitivity,skin pigmentation disorders.

Others – urinary incontinence and retention, transient fever, dysphagia, parotid gland enlargement, confusion, delirium, thromboembolism, acute pancreatitis, hepatitis and cholestatic jaundice, and very rarely fulminant hepatic necrosis. Isolated cases of acute interstitial nephritis have been reported. Abnormalities of glucose homoeostasis and the onset of diabetes mellitus occur uncommonly; severe hyperglycaemia, sometimes leading to ketoacidosis or hyperosmolar coma, has been reported very rarely. There have also been rare reports of hypercholesterolaemia and hypertriglyceridaemia. Many of the adverse effects of clozapine are most common at the start of therapy and may be minimised by gradual increase in dosage.

Postmarketing Clinical Experience

• Central Nervous System: obsessive compulsive symptoms,
• Respiratory System: pneumonia and lower respiratory tract infection which may be fatal.

Abrupt withdrawal of clozapine may be associated with symptoms that have been described as ‘cholinergic rebound’ although the manifestations, which may include headache, profuse sweating, hypersalivation, bronchoconstriction, agitation, enuresis, and diarrhoea also have some common features with the serotonin syndrome; motor disorders and exacerbation of extrapyramidal disorders have also occurred. In addition, as with other antipsychotics, abrupt withdrawal of clozapine may be associated with rapid relapse of the original psychosis.

In general, overdosage of clozapine may be expected to produce effects that are extensions of pharmacologic and adverse effects.

Symptoms: drowsiness, lethargy, coma, confusion, agitation, delirium, increased reflexes, convulsions, excessive salivation, mydriasis, impaired visual acuity, unstable body temperature, tachycardia, hypotension, collapse, arrhythmias, myocardial conduction abnormalities, respiratory depression, cardiac arrhythmias, pneumonia, and hypersalivation. Seizures have occurred with overdosage in some patients.

Treatment: treatment of clozapine overdosage generally requires symptomatic and supportive care, including monitoring of cardiac and vital signs. There is no specific antidote for the management of clozapine overdosage.

It is recommended establishing and maintaining an airway and ensuring adequate ventilation and oxygenation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or gastric lavage and should be considered in the treatment of clozapine overdosage. Electrolyte and acid-base balance should be monitored and adjusted accordingly. Peritoneal dialysis or hemodialysis is of limited value in the treatment of clozapine overdosage because the drug is almost totally bound to serum protein. Forced diuresis, hemoperfusion, and exchange transfusion also are unlikely to be of benefit. While physostigmine salicylate may be useful as adjunctive treatment if severe anticholinergic toxicity is present, the drug should not be used routinely because of its potential adverse effects.

Epinephrine should not be used for treating clozapine-induced hypotension, since clozapine can reverse epinephrine’s vasopressor effects and cause a further lowering of blood pressure. Because of potential additive anticholinergic effects, quinidine or procainamide should be avoided when treating clozapine-induced arrhythmias. Surveillance of the patient should be continued for several days following overdosage because of the risk of delayed effects. In managing clozapine overdosage, the clinician should consider the possibility of multiple drug involvement.

• Granulocytopenia or agranulocytosis (caused the dysfunction of the bone marrow by intake of preparations, as well as indications of agranulocytosis in medical history of patient ).
• Alcoholic and other toxic psychoses, drug intoxication.
• Comatose states.
• Severe diseases of liver, kidney and heart.
• Angle-closure glaucoma.
• Benign hyperplasia of the prostate gland, atony of the intestine.
• Pregnancy, breast feeding.
• Increased susceptibility to convulsions, epilepsy.

• Clozapine penetrates through the placenta.There are no adequate and well-controlled studies for human beings.There has not been revealed any adverse effect of clozapine on the fetus in experimental studies.It is believed that clozapine may excreted with breast milk and reduced child’s suckling ability, restlessness or irritability, seizures and functional disorders of the cardiovascular system.

Non-teratogenic Effects

• Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation , hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Clozapine should not be given to patients with uncontrolled epilepsy, alcoholic or toxic psychoses, drug intoxication, or a history of circulatory collapse. It should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. It is contra-indicated in patients with bone-marrow suppression, myeloproliferative disorders, or any abnormalities of white blood cell count or differential blood count. It is also contra-indicated in patients with a history of drug-induced neutropenia or agranulocytosis with the exception of that due to chemotherapy. It should not be used with drugs that carry a high risk of bone-marrow suppression.

Cerebrovascular adverse events

An increased risk of cerebrovascular adverse events has been observed in dementia patients treated with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for dementia patients or other patients treated with clozapine. Clozapine should be used with caution in patients with dementia or risk factors for stroke.

Clozapine is contra-indicated in patients with severe renal impairment; caution is required in mild to moderate renal impairment. It should be used with caution in hepatic impairment and avoided in symptomatic or progressive liver disease or hepatic failure. Patients with a history of cardiac impairment or abnormal cardiac findings on examination should be referred to a specialist for further evaluation, which may include an ECG; treatment with clozapine should only then be started if the potential benefits clearly outweigh any risk. Clozapine should not be used in severe heart failure.

Monitoring of leukocytes carried out once in a week during the first 18 weeks of treatment. Then, at least, once every two weeks during the first year of treatment.If the number of neutrophils is stable, monitoring of the number of leukocytes may be carried out once in every 4 weeks.If the white blood cells count is less than 3000/mm3 and / or absolute count of neutrophil / granulocytes is less than 1500/mm3, Azaleptin should be immediately removed and install a careful observation of the patient.

Clozapine possesses antimuscarinic properties and consequently it is contra-indicated in patients with paralytic ileus; it should also be used with caution in benign prostatic hyperplasia and angle-closure glaucoma.

Clinical monitoring for hyperglycaemia has been recommended, especially in patients with or at risk of developing diabetes.

Monitoring the white blood cell and absolute neutrophil counts is mandatory during clozapine treatment and should be carried out in accordance with official recommendations; these may vary between countries. Patients or their carers should report the development of any infection or signs such as fever, sore throat, or flu-like symptoms which suggest infection.

Patients who develop tachycardia at rest, dyspnoea, arrhythmias, chest pain, or other signs and symptoms of heart failure should be investigated immediately and clozapine treatment stopped if a diagnosis of myocarditis or cardiomyopathy is suspected.

Because of an increased risk of collapse due to orthostatic hypotension associated with rapid dose escalation during initial titration of clozapine dosage, it is recommended that treatment should be begun under close medical supervision. In addition, patients with Parkinson’s disease should have their blood pressure monitored for the first weeks of treatment.

On planned withdrawal, the dose of clozapine should be reduced gradually over at least a 1- to 2-week period in order to avoid the risk of rebound psychosis and other withdrawal symptoms. If abrupt withdrawal is necessary then patients should be observed carefully.

Clozapine may affect the performance of skilled tasks such as driving.

The safety and efficacy of the preparation Azaleptin have not been established for children and adolescents under the age of 16 years.

Effects on ability to drive and use machines

• During the treatment with Azaleptin avoid activities that require high concentration and rapid psychomotor reactions.

Contraindication of concomitant use

• Substances known to have a substantial potential to depress bone marrow function must not be used concurrently with Azaleptine .
• Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Azaleptine because these cannot be rapidly removed from the body in situations where this may be required, e.g. neutropenia .
• Alcohol should not be used concomitantly with Azaleptine due to possible potentiation of sedation.

Precautions including dose adjustment

• Azaleptine may enhance the central effects of CNS depressants such as narcotics, antihistamines, and benzodiazepines. Particular caution is advised when Azaleptine 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, Azaleptine 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) and the selective serotonin reuptake inhibitors 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. 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 Azaleptine 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 tricyclicantidepressants,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.

Yellow biconvex scored tablets.

5 blister packets with 10 tablets in each with insert-leaflet in the cardboard box.

3 years. Do not use after the expiration date.

Store at a room temperature (15-25⁰C), in a dry place, out of the reach of children. Protect from light.