INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo CLOMENT 25 mg (tablet)
CLOMENT 100 mg (tablet)

APPROVED PACKAGE INSERT FOR CLOMENT 25 mg & 100 mg TABLETS

WARNINGS
The use of CLOMENT should be limited to severely ill schizophrenic patients who are non-responsive to, or intolerant of classical neuroleptic drug treatment, due to significant risk that CLOMENT can cause fatal agranulocytosis.
Physicians who prescribe this medicine should comply fully with the required safety measures. Each patient who receives CLOMENT should be reminded at every consultation 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 any other evidence of infection, which may be indicative of neutropenia.
Patients who are being treated with CLOMENT must have initially normal leucocyte findings (baseline white blood cell count >3500/mm3 and normal differential blood count) before initiation of treatment. Regular white blood cell (WBC) counts and, if possible, absolute neutrophil counts (ANC) (weekly during the first 18 weeks and at least every two weeks thereafter throughout treatment and for one month after discontinuation of treatment) should be performed.
Orthostatic hypotension, with or without syncope, can occur with CLOMENT treatment. Collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur during initial titration in association with rapid dose escalation; but they may occur even after the first dose. Therefore, patients commencing CLOMENT treatment require close medical supervision. Caution should be used in administering CLOMENT to patients having a history of seizures or other predisposing factors. The dose appears to be an important predictor of a seizure, with a greater likelihood at the higher CLOMENT doses used. Because of the substantial risk of seizure associated with clozapine use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others, e.g. the operation of complex machinery, driving a vehicle, swimming, climbing, etc.

SCHEDULING STATUS
S5

PROPRIETARY NAME
(and dosage form)

CLOMENT 25 mg (tablet)
CLOMENT 100 mg (tablet)

COMPOSITION
Each tablet contains 25 mg or 100 mg
clozapine.

PHARMACOLOGICAL CLASSIFICATION
A 2.6.5 Tranquillisers (miscellaneous structures)

PHARMACOLOGICAL ACTION
Clozapine is classified as an atypical antipsychotic agent.
It has weak dopamine receptor-blocking activity at D
1, D2, D3 and D5 receptors, but shows higher potency for the D4 receptor, in addition to potent noradrenolytic, anti-cholinergic, antihistaminic and arousal reaction inhibiting effects. It has also been shown to possess antiserotoninergic properties.
Pharmacokinetics
The absorption of orally administered clozapine is approximately 90 to 95%; the rate or extent of absorption is not influenced by food.
Clozapine undergoes a moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.
In steady-state conditions, when given twice daily, peak blood level occurs on an average at 2,5 hours (range: 1 to 6 h), and the volume of distribution is 1,6 litre/kg.
Clozapine is approximately 95% bound to plasma proteins. Its elimination is biphasic with a mean terminal half-life of 12 hours (between 4 to 66 h).
Clozapine is almost completely metabolised prior to excretion. One of the main metabolites, the des-methyl metabolite, was found to be active. The pharmacological activity of this metabolite resembles those of clozapine, but are considerably weaker and of short duration. Only trace amounts of unchanged medicine are detected in the urine and faeces.
Approximately 50% of the administered dose is excreted in the urine and 30% in the faeces as metabolites.

INDICATIONS
CLOMENT is indicated for the treatment of severely ill schizophrenic patients, failing to respond adequately to standard acceptable antipsychotic medication, either because of insufficient effectiveness or because of intolerable side effects caused by the medication.
Because of the significant risk of agranulocytosis and seizure associated with its use, CLOMENT should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard antipsychotic medicines, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those medicines (see “WARNINGS”).
It is strongly recommended that a patient be given at least 2 trials, each with a different standard antipsychotic product, at an adequate dose and for an adequate duration.
Because of the significant risk of agranulocytosis and seizure with CLOMENT it presents a continuing risk over time; the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.
In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should periodically be re-evaluated.

CONTRA-INDICATIONS
Hypersensitivity to any of the components in CLOMENT.
Patients with a history of drug-induced, toxic or idiosyncratic granulocytopenia/agranulocytosis or neutropenia.
Should not be given simultaneously with other agents, which have a well-known potential to suppress bone marrow function.
Impaired bone marrow function, myeloproliferative disorders or any abnormalities of white blood cell count or differential blood count.
Uncontrolled epilepsy.
Alcoholic and other toxic psychoses, drug intoxication, comatose conditions and glaucoma.
Circulatory collapse and/or central nervous system depression of any cause.
Severe renal or cardiac disorders.
Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease and hepatic failure.
Safety in children under the age of 16 years has not been established.
Pregnancy and lactation.
Since CLOMENT may cause sedation and weight gain, thereby increasing the risk of thromboembolism, immobilisation of the patient should be avoided.

DOSAGE AND DIRECTIONS FOR USE
The dosage must be adjusted individually for each patient, using the lowest possible effective dose. Dose adjustment is required in patients receiving medicines interacting with CLOMENT such as benzodiazepines and medicines with selective serotonin re-uptake (see “Interactions”).
In the elderly or underweight patients or those suffering from renal, hepatic or cardiovascular disorders, or suffering from cerebral vascular insufficiency or cerebral sclerosis, the initial dose should be low, and any dose titration should be slow.
The following dosages for oral administration are recommended:
Initial dose: 12,5 mg (one-half of a 25 mg tablet) once or twice on the first day, followed by one or two 25 mg tablets on the second day. If well tolerated, the dosage may then be increased slowly in increments of 25 to 50 mg, in order to achieve a dose level of up to 300 mg per day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or preferably weekly intervals.
Use in the elderly: It is recommended to initiate treatment at a particularly low dose (12,5 mg given once on the first day) and to restrict subsequent dose increments to 25 mg per day.
Therapeutic dose range: In most patients, antipsychotic efficacy can be expected with 200 to 450 mg per day given in divided doses. Some patients may require doses up to 600 mg/day. The total daily dose may be divided unevenly, with the larger portion at bedtime. For maintenance dose see below.
Maximum dose: A few patients, however, may require larger doses to obtain maximum therapeutic benefit, in which case judicious increments (not to exceed 100 mg per increment) are permissible to a maximum dose of 900 mg per day. The possibility of increased adverse reactions (in particular seizures) occurring at doses of over 450 mg per day must be considered.
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. With daily doses not exceeding 200 mg, a single administration in the evening may be appropriate.
Ending therapy: In the event of planned termination of CLOMENT therapy, a gradual reduction in dose is recommended over a 1 –2 week period. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms.
Re-starting therapy: In patients in whom the interval since the last dose of CLOMENT exceeds 2 days, treatment should be re-initiated with 12,5 mg (one-half of 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 "Other Precautions"), but was then able to be successfully titrated to a therapeutic dose, re-titration should be done with extreme caution.
Switching from a classical neuroleptic to CLOMENT: It is generally recommended that CLOMENT should not be used in combination with classical neuroleptics. When CLOMENT therapy is to be initiated in a patient undergoing oral neuroleptic therapy, it is recommended that the classical neuroleptic should first be discontinued by tapering the dosage downwards over a period of approximately one week. Once the neuroleptic is completely discontinued for at least 24 hours, CLOMENT treatment can be started as described above.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Haematological: Granulocytopenia and agranulocytosis are risks inherent in CLOMENT treatment. Although generally reversible on withdrawal of the medicine, agranulocytosis may prove fatal. The majority of cases occur in the first 18 weeks of treatment. Because immediate withdrawal of the medicine is required to prevent the development of life-threatening agranulocytosis, monitoring of the white blood cell count (as described under "WARNINGS" and "Special Precautionary Measures") is mandatory.
Unexplained eosinophilia and/or leucocytosis may occur, especially in the initial weeks of treatment.
Central Nervous System: Drowsiness, sedation and fatigue are among the most common side effects observed. Dizziness or headache may also occur.
CLOMENT lowers the seizure threshold in a dose-dependent manner and may cause electro-encephalogram changes, including occurrence of spike and wave complexes. If seizures occur, the dose should be reduced and, if necessary, anticonvulsant treatment initiated. With anticonvulsant medicines the possibility of pharmacokinetic interactions should be considered.
CLOMENT may cause confusion, restlessness, agitation and delirium.
Extrapyramidal symptoms may occur while on CLOMENT therapy. Rigidity, tremor and akathisia have been reported.
Although no reports of tardive dyskinesia attributable to CLOMENT have been received, the occurrence of this complication cannot be excluded.
There have been several reported cases of neuroleptic malignant syndrome (NMS) in patients receiving CLOMENT, either alone or in combination with lithium or other central nervous system-active agents. CLOMENT should immediately be discontinued in these patients.
Autonomic Nervous System: Dry mouth, blurred vision and disturbances in sweating and temperature regulation have been reported. Hypersalivation is a common side-effect.
Cardiovascular: Tachycardia and postural hypotension, with or without syncope, may occur, especially in the initial weeks of treatment. Less commonly, hypertension has been reported. Profound circulatory collapse accompanied by respiratory depression or arrest has been reported. (See "Other Precautions" and "Interactions"). Electrocardiogram changes may occur and cases of cardiac dysrhythmias, pericarditis and myocarditis with or without eosinophilia have been reported, some of which have been fatal. Therefore, in patients on clozapine who develop non-specific cardiac disorders, the diagnosis of myocarditis should be considered, and then clozapine should be discontinued.
Venous and pulmonary thromboembolism have been reported.
Respiratory system: Respiratory depression or arrest has occurred in isolated cases with or without circulatory collapse, (see “Other Precautions” and “Interactions”). Less frequently, aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.
Gastro-Intestinal System: Nausea, vomiting, and constipation may occur. Asymptomatic elevations of liver enzymes and, less frequently, hepatitis and cholestatic jaundice may occur. Fulminant hepatic necrosis has less frequently been reported. If jaundice develops, CLOMENT should be discontinued.
In less frequent cases, acute pancreatitis has been reported.
Genito-Urinary System: Urinary incontinence, urinary retention and priapism have been reported. Care should be taken in prescribing CLOMENT in patients with prostatic enlargement. Isolated cases of acute interstitial nephritis have been reported in association with CLOMENT treatment.
Miscellaneous: Benign hyperthermia may occur, especially in the initial weeks of treatment.
Isolated reports of skin reaction have been received.
Hyperglycemia has been reported in patients on CLOMENT treatment.
Less frequently increases in CPK values have occurred.
With prolonged treatment considerable weight gain has been observed.
Sudden, unexplained deaths are known to occur among psychiatric patients who receive antipsychotic medication. Isolated cases of such deaths have been reported in patients receiving CLOMENT.
Because of its potent anticholinergic effects CLOMENT should be prescribed with care in patients with narrow angle glaucoma.

Special Precautionary Measures
Because of the association of CLOMENT with agranulocytosis the following precautionary measures are mandatory:
CLOMENT should not be used concurrently with medicines associated with a substantial potential to depress bone marrow function. In addition, the concomitant use of long-acting depot antipsychotics should be avoided because of the inability of these medications, which may have the potential to be myelosuppressive, to be rapidly removed from the body in situations where this may be required, e.g. granulocytopenia.
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 CLOMENT.
Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on CLOMENT after agreement of a haematologist.
WBC counts and ANC monitoring: Before starting CLOMENT treatment, a WBC count and a differential blood count must be performed within 10 days prior to CLOMENT treatment to ensure that only patients with normal leucocyte count and normal absolute neutrophil count (WBC count >3 500/mm3 and ANC >2 000/mm3) will receive the medicine. After the start of CLOMENT treatment the WBC count and, if possible, ANC must be monitored weekly for 18 weeks and thereafter at least every two weeks throughout treatment, and for one month after discontinuation of CLOMENT.
At each consultation, the patient should be reminded to contact the treating physician immediately if any kind of infection, or fever, sore throat or other flu-like symptoms develop. An immediate differential blood count must be performed if any symptoms or signs of an infection occur.
In case of low WBC count/ANC: During the first 18 weeks of CLOMENT therapy, if the WBC count falls to between 3 500/mm3 and 3 000/mm3 and/or the ANC falls to between 2 000/mm3 and 2 500/mm3 and/or the ANC falls to between 1 500/mm3 and 1 000/mm3, WBC and ANC counts should be done twice a week as well as in the event of where the WBC count has dropped by a substantial amount from baseline. A substantial drop is defined as a single drop of 3 000/mm3 or more in the WBC count or a cumulative drop of 3 000/mm3 within 3 weeks.
Immediate discontinuation of CLOMENT treatment is mandatory if the WBC count is less than 3 000/mm3 or the ANC is less than 1 500/mm3 during the first 18 weeks of CLOMENT therapy, and if the WBC count is less than 2 500/mm3 or the ANC count is less than 1 000/mm3 after the first 18 weeks of CLOMENT therapy. 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. Following discontinuation of CLOMENT, haematological evaluation is required until haematological recovery has occurred.
If CLOMENT has been withdrawn and a further fall of WBC count below 2 000/mm3 occurs and/or neutrophil granulocytes decrease below 1 000/mm3, the patient should be referred immediately to a specialised centre.
Patients in whom CLOMENT has been discontinued as a result of white blood cell deficiencies (see above), must not be re-exposed to CLOMENT.
Confirmation of the haematological values is recommended by performing two blood counts done on two consecutive days; however, CLOMENT should be discontinued after the first blood count.
In the event of interruption of therapy for non-haematological reasons: Patients who have been on CLOMENT for more than 18 weeks and have had the treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and, if possible, ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If CLOMENT treatment has been interrupted for 4 weeks or longer, weekly monitoring is required as for patients never exposed to CLOMENT.
Information for patients
Physicians are advised to discuss the following issues with patients for whom they prescribe CLOMENT.
1. Patients who are to receive CLOMENT should be warned about the significant risk of developing agranulocytosis. They should be informed that weekly blood tests are required to monitor for the occurrence of agranulocytosis. Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
2. Patients should be informed of the significant risk of seizure during CLOMENT treatment and they should be advised to avoid driving and any other potentially hazardous activity while taking CLOMENT.
3. Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose instructions.
4. Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter medicines or alcohol.
5. Patients should notify their physician if they become pregnant or intend to become pregnant during therapy.
6. Female patients should not breast feed whilst taking CLOMENT.
7. Patients should be informed that if they stop taking CLOMENT for more than 2 days, they should not start their medication at the same dosage, but should contact their physician for dosing instructions.

Other Precautions
In the event of eosinophilia, it is recommended to discontinue CLOMENT if the eosinophil count rises above 3 000/mm3 and to re-start therapy only after the eosinophil count has fallen below 1 000/mm3 (good medical practice as recommended by haematologists).
In the event of thrombocytopenia, it is recommended to discontinue CLOMENT therapy if the platelet count falls below 50 000/mm3.
Owing to the ability of CLOMENT to cause sedation and lower the seizure threshold, activities of driving or operating machinery should be avoided, especially during the initial weeks of treatment.
In patients with a history of seizures, or suffering from cardiovascular or renal disorders (note: severe renal or cardiovascular disorders are contra-indications) the initial dose should be 12,5 mg given once on the first day, and dosage increase should be slow and in small increments.
CLOMENT exerts anticholinergic activity; therefore, careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma.
During CLOMENT therapy patients may experience transient temperature elevations above 38ºC, with the peak incidence within the first 3 weeks of treatment. The 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.
Patients with stable pre-existing liver disorders may receive CLOMENT, but need regular liver function test monitoring. In patients whom, during CLOMENT treatment, symptoms of possible liver dysfunction such as nausea, vomiting and/or anorexia develop, liver function tests should be performed immediately. If the elevation of the values is clinically relevant or if symptoms of jaundice occur, treatment with CLOMENT must be discontinued. It may be resumed (see “Re-starting therapy”) only when the liver function tests have returned to normal values. In such cases, liver function should be closely monitored after the re-introduction of the medicine.
Since CLOMENT may cause sedation and weight gain, thereby increasing the risk of thromboembolism, immobilisation of the patient should be avoided.

Use in elderly: It is recommended to initiate treatment at a particularly low dose (12,5 mg given once on the first day) and to restrict subsequent dose increments to 25 mg/day.

Use in pregnancy, lactation and children: (See “CONTRA-INDICATIONS”).

Interactions
Medicines which are known to potentially depress bone marrow function significantly, such as carbamazapine, co-trimoxazole, chloramphenicol, penicillamine, sulphonamides, antineoplastics and azapropazone should not be used concomitantly with CLOMENT (see also "Special Precautionary Measures").
The possibility of a pharmacokinetic interaction should be considered with anticonvulsant medicines. Valproic acid however did not increase CLOMENT blood levels significantly.
CLOMENT may enhance the central effects of alcohol, mono-amine oxidase inhibitors and central nervous system depressants such as narcotics, antihistamines and benzodiazepines.
Concomitant use of CLOMENT and lithium or other central nervous system-agents may increase the risk of development of neuroleptic malignant syndrome.
Long acting depot antipsychotics should not be used with CLOMENT as they cannot be withdrawn rapidly should neutropenia occur.
Particular caution is advised when CLOMENT therapy is initiated in patients who are receiving (or have recently received) a benzodiazepine, or any other psychotrophic agent, as these patients may have an increased risk of circulatory collapse, which less frequently can be profound and may lead to cardiac and/or respiratory arrest.
Because of the possibility of additive effects, caution in the concomitant administration of medicines with anticholinergic, hypotensive, or respiratory depressant effects is essential.
Since clozapine is highly bound to plasma proteins, the administration of CLOMENT to a patient taking another medicine, which is highly bound to protein (e.g. warfarin) may cause an increase in plasma concentrations of this medicine, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein-bound clozapine by other highly protein-bound medicines.
Concomitant administration of CLOMENT with cimetidine or erythromycin, (medicines known to inhibit the cytochrome P450 enzyme system), may increase the plasma levels of clozapine, possibly resulting in adverse effects.
Since the metabolism of clozapine is mainly mediated by cytochrome P450 1A2 and, probably to a minor extent, by cytochrome P450 2D6, the concomitant administration of medicines which possess affinity for one or both of these enzymes may result in an increase in the plasma levels of clozapine and/or the co-administered medicine. However, 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. On theoretical grounds, however, it is possible that the plasma levels of such medicines are increased by clozapine, so it may be appropriate to use them at doses lower than usually prescribed.
Elevated serum levels of clozapine (sometimes massive) have been reported in patients receiving the medicine in combination with fluvoxamine (up to tenfold), or other selective serotonin re-uptake inhibitors such as paroxetine, sertraline or fluoxetine.
Concomitant administration of phenytoin, and possibly other medicines known to induce the cytochrome P450 enzyme system, may reduce the plasma levels of clozapine and may be associated with the recurrence of psychotic symptoms.
Owing to its noradrenolytic action, CLOMENT may reduce the blood pressure-increasing effect of noradrenalin or the predominantly alpha–adrenergic agents and reverse the pressure effect of adrenaline.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Fatal overdosages have been reported with CLOMENT, mostly at doses above 2000 mg.
Signs and symptoms: Drowsiness, lethargy, coma, areflexia, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, convulsions, hypersalivation, mydriasis, blurred vision, thermolability, tachycardia, hypotension, collapse, cardiac arrhythmias (in particular AV-block, extrasystoles), aspiration, pneumonia, dyspnea, heart block, respiratory depression or failure.
Treatment: Gastric lavage followed by 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 adrenaline and its derivatives should be avoided in the treatment of hypotension because of the possibility of "reverse adrenaline effect". Close medical supervision is necessary for several days because of the possibility of delayed reactions.

IDENTIFICATION
CLOMENT 25 mg: A round, yellow flat bevel-edged tablet with ‘25’over a pressure sensitive breakline on one side, and plain on the other side.
CLOMENT 100 mg: A round, yellow flat bevel-edged tablet with ‘100’over a pressure sensitive breakline on one side, and plain on the other side.

PRESENTATION
CLOMENT 25 mg: Clear transparent PVC/PVDC/PE/Aluminium blister packs of 100 tablets.
CLOMENT 100 mg: Clear transparent PVC/ PVDC/PE/Aluminium blister packs of 100 tablets.

STORAGE INSTRUCTIONS
Store below 25ºC. Protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
CLOMENT 25 mg: 35/2.6.5/0373
CLOMENT 100 mg: 35/2.6.5/0374

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Pharmaplan (Pty) Ltd
106 16th Road
MIDRAND

DATE OF PUBLICATION OF THIS PACKAGE INSERT
8 August 2002

New addition to this site: May 2014
Source: Pharmaceutical Industry

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