Tegretol

Tegretol^®

PRESCRIPTION ONLY

Composition
Each tablet contains carbamazepine 200 mg.
Each CR (slow release film coated tablets, divisible) tablet contains carbamazepine 200 mg and 400 mg.
Each chewable tablet (scored) contains carbamazepine 100 mg.
Each 5 ml (=1 measuring spoon)(Syrup (viscous suspension, white caramel flavoured)) contains carbamazepine 100 mg.

Indications 
Epilepsy
Partial seizures with complex symptomatology.
Primary generalized epilepsy or secondarily generalized forms of seizure with a tonic-clonic component.

Mixed forms of epilepsy
Tegretol^® is suitable both for monotherapy and combination therapy.
Tegretol^® is usually not effective in absences (petit mal)(see "special warnings and special precautions for use"). Mania and prophylactic treatment in manic-depressive (bipolar) disorders.
Idiophatic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis.
Idiophatic glossopharyngeal neuralgia.
Painful diabetic neurophathy.

Posology and Method of Administration
The tablets or the syrup (to be shaken before use) may be taken during, after, or between meals with a little liquid. Possible remnants of the chewable tablets should be washed down with a little liquid.
The CR tablets (either whole or, if so prescribed, only half a tablet) should be swallowed unchewed with a little liquid. The chewable tablets and the syrup (one measure = 5 ml = 100 mg; half a measure = 2.5 ml = 50 mg) are particularly suitable for patients who have difficulty in swallowing tablets or needs initial careful adjustment of the dosage.
Thank to slow, controlled release of the active substance from the CR tablets they can as a rule be prescribed in a twice-daily dosage. Switching patients from Tegretol^® tablets to CR tablets: clinically experience shows that in some patients the dosage in the form of CR tablets may need to be increased. In elderly subjects the dosage of Tegretol^® should be selected with caution.

Epilepsy
Wherever possible, Tegretol^® should be prescribed as monotherapy. Treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is obtained. After obtaining adequate seizure control, dosage may be reduced very gradually to the minimum effective level. Determination of plasma levels may help in establishing the optimum dosage (see "special warnings and special precautions for use"). When Tegretol^® is added to existing anti epileptic therapy, this should be done gradually while maintaining, of if necessary adapting, the dosage of the other anti epileptic(s) (see "Interaction with other medicament's and other form of interaction").

Adults
Oral forms: initially, 100 - 200 mg once or twice daily; slowly raise the dosage until optimum response obtained generally at 400 mg 2 - 3 times daily. In some patients 1600 mg or even 2000 mg daily may be necessary (in rare instance).

Children
Tegretol^® conventional tablet formulations are not recommended for very young children and Tegretol^® retard is not recommended for children under 5 years.
Oral forms: 10 - 20 mg/kg body weight daily. i.e.
Up to 1 year of age: 100 - 200 mg daily (= 1 - 2 measures of syrup) 1 - 5 years of age: 200 - 400 mg daily (= 2 x 1 - 2 measures of syrup)
6 - 10 years of age: 400 - 600 mg daily (= 2 - 3 x 2 measures of syrup)
11 - 15 years of age: 600 - 1000 mg daily (= 3 x 2 - 3 measures of syrup)
to be taken in several fractional doses.
In children age 4 years or less, a starting dose of 20 to 60 mg/day, increased by 20 to 60 mg every second day, has been recommended. For children over the age of 4 years, therapy may begin with 100 mg/day, increased at weekly intervals by 100 mg.

Trigeminal Neuralgia
Slowly raise the initial dosage of 200 - 400 mg daily until freedom from pain is achieved (normally at 200 mg 3 - 4 times daily). Then gradually reduce the dosage to the lowest possible maintenance level. In elderly patients an initial dose of 100 mg twice daily is recommended.

Painful Diabetic Neuropathy
Average dosage: 200 mg 2 - 4 times daily.
Mania and prophylactic treatment in manic-depressive (bipolar) disorder.
Dosage range: about 400 - 1600 mg daily, the usual dosage being 400 - 600 mg daily given in 2-3 fractional doses. When treating acute mania, the dosage should be increased rather quickly, where as for prophylaxis of bipolar disorders small dosage increments are recommended in order to provide for optimal tolerability.

Contraindications
Known hypersensitivity to carbamazepine or structurally related drugs (e.g.  Tricyclic antidepressants). Patients with atrioventricular block, a history of previous bone-marrow depression, or a history of acute intermittent porphyria. On theoretical grounds (a structural relationship to tricyclic antidepressants) the use of Tegretol^® is not recommended in combination with monoamine-oxidase inhibitors (MAOIs); before administering Tegretol^® MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.

Special Warnings and Special Precautions for Use
Agranulocytosis and aplastic anaemia have been associated with Tegretol^® ; however, due to very low incidence of these diseases, meaningful risk estimates for Tegretol^® are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anaemia.
Transient or persistent decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Tegretol^®, However, in the majority of cases these effects prove transient and are unlikely to signal the onset of either aplastic anaemia or agranulocytosis. Nonetheless, complete pre-treatment blood counts, including platelet and possibly reticulocytes and serum iron, should be obtained as a baseline. Although the value of haematological monitoring has been challenged, guidelines are suggested by some authorities, e.g weekly for the first month, then monthly for the next 5 months, thereafter 2-4 times a year.
If during treatment definitely low or decreased white blood cell or platelet counts are observed, the patient and the complete blood count should be monitored closely. Tegretol^® should be discontinued if any evidence of significant bone-marrow depression appears.
If signs and symptoms suggestive of severe skin reactions - e.g. Stevens-Johnson syndrome, Lyell' syndrome - appear, Tegretol^® should be withdrawn at once. Tegretol^® should be given only under medical supervision. It should be used with caution in patients with a mixed seizure disorder which includes atypical absence seizures, since Tegretol^® has been associated with increased frequency of generalized convulsions. In case of exacerbation of seizures, Tegretol^® should be discontinued.
An increase in the frequency of seizures may occur during switch over from oral formulations to suppositories.
Patients should be made aware of early toxic signs and symptoms of a potential haematolagical problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash ulcers in mouth, easy bruising, pecthial or purpuric hemorrhage appear, the patient should be advised to consult his physician immediately.
Tegretol^® should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic, or renal damage, adverse haemotological reactions to other drugs, or interrupted courses of therapy with Tegretol^®,
Baseline and periodic evaluations of hepatic function, particularly in patients with a history of liver disease and in elderly patients, must be performed during treatment with Tegretol^®, The drug should be withdrawn immediately in cases of aggravated liver dysfunction or active liver disease. Baseline and periodic complete urinalysis and BUN determinations are recommended.
Mild skin reactions, e.g. isolated macular or maculopapular exanthema, are mostly transient and not hazardous, and they usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage; however, the patients should be kept under close surveillance.
Tegretol^® has shown mild anticholinergic activity; patients with increased intra-ocular pressure should therefore be closely observed during therapy.
The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind. Isolated reports of impaired male fertility and/or abnormal spermatogenesis are on file. A casual relationship has not been established.
Breakthrough bleeding has been reported in women taking oral contraceptives; the reliability of oral contraceptives may be adversely affected by Tegretol^®.
Although correlations between dosage and plasma-levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following conditions; dramatic increase seizures frequency/ verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see "Interaction with other medicaments and other forms of interaction").
If treatment with Tegretol^® has to be withdrawn abruptly, the change-over to the new anti epileptic compound should be made under cover of a suitable drug (e.g. diazepam i.v., rectal; or phenytoin i.v.).

Interaction With Other Medicaments and Other Forms of Interaction
Due to induction of the hepatic mono-oxygenase enzyme system carbamazepine may lower the plasma level and diminish or even abolish the activity of certain drugs that are metabolized by this system. The dosage of the following drugs may have to be adjusted to clinical requirements: clobazam, clonazepam, ethosuximide, pirimidone, valproic acid, alprazolam; corticosteroids, (e.g. prednisolone, dexamethasone); cyclosporin, digoxin, doxycycline, felodipine, haloperidol, imipramine, methadone, oral contraceptives (alternative contraceptive methods should be considered) theophylline, oral anticoagulants (warfarin, phenprocoumon, dicoumarol).
Plasma phenytoin level have been reported both to be raised and to be lowered by carbamazepine, and plasma mephenytoin levels have been reported in rare instances to increase.
The following drugs have been shown to raise plasma carbamazepine levels: erythromycin, troleandomycin, possibly josamycin, isoniazid, verapamil, diltiazem, dextropropoxyphene, viloxazine, fluoxetine possibly cimetidine, acetazolamide, danazol, possibly desipramine, and nicotinamide (in adults, only in high dosage). Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol^® should be adjusted accordingly and/or the plasma levels monitored. Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
Combined use of carbamazepine and lithium or metoclopramide on the one hand and caramazepine and neuroleptics (haloperidol, thioridazine) on the other may lead to increased neurological adverse reactions (with the latter combination even in the presence of "therapeutic plasma levels").
The plasma levels of carbamazepine may be reduced by phenobarbitone, phenytoin, pirimidone, progabide, or theophylline and although the data are partly contradictory, possibly also by clomazepam ,valproic acid or valpromide. On the other hand, valproic acid, val promide and pirimidone have been reported to raise the plasma level of the pharmacologically active CBZ-10, 11-epoxide metabolite. The dose of Tegretol^® may consequently have to be adjusted.
Concomitant medication with Tegretol^® and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia, Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium); their dosage may need to be raised and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.
Isotretinoin has been reported to later the bioavailability andlor clearance of carbamazepine and CBZ-10,11-epoxide; plasma carbamazepine levels should be monitored.
Tegretol^® like other psychoactive drugs, may reduce alcohol tolerance; it is therefore advisable for the patient to abstain from alcohol.

Pregnancy
In animals (mice, rats, rabbits) oral administration of carbamazepine during organogenesis led to increased embryonic mortality at daily doses which caused maternal toxicity (above 200 mg/kg body weight daily, i.e. 10-20 times the usual human dosage). In the rat there was also some indications of abortion at 300 mg/kg body weight daily.
Near-term rat foetuses showed growth retardation again at maternally toxic doses. There was no evidence of teratogenic potential in the 3 animal species tested, but in one study using mice, carbamazepine (40 -240 mg/kg body weight daily, orally) caused defects (mainly dilatation of cerebral ventricles) in 4.7% of exposed foetuses as compared with 1.3% in controls.
Pregnant women with epilepsy should be treated with special care. In women of childbearing age Tegretol^® should, wherever possible, be prescribed as mono therapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of anti epileptic drugs (e.g. valproic acid plus carbamazepine plus pheno-barbitone and/or phenytoin) is greater than in those of mothers receiving the individual drugs as mono therapy.
Minimum effective doses should be given and monitoring of plasma levels is recommended.
If pregnancy occurs in a women receiving Tegretol^®, or if the problem of initiating treatment with Tegretol^® arises during pregnancy, the drug's potential benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.
Offspring of epileptic mothers are known to be more prone to developmental disorders, including malformations. The possibility that carbamazepine, like all major anti epileptic drugs, increases this risk has been reported, although conclusive evidence from controlled studies with carbamazepine mono therapy is lacking. However, there are rare reports on developmental disorders and malformations, including spina bifida, in association with Tegretol^®. Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
Folic acid deficiency is known to occur in pregnancy. Anti epileptic drugs have been reported to aggravate folic acid deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and during pregnancy.
Vitamin K1, to be given to the mother during the last weeks of pregnancy as well as to the new born to prevent bleeding disorders in the offspring, has also been recommended.

Use during lactation
Carbamazepine passes into the breast milk (about 25-60% of plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Tegretol^® may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence).
One report of a severe hypersensitivity skin reaction in a breastfed baby is on file.

Effects on Ability to Drive and Use Machines
The patient's ability to react may be impaired by dizziness and drowsiness caused by Tegretol^®, especially at the start of treatment or in connection with dose adjustments; patients should therefore exercise due caution when driving a vehicle or operating machinery.
Data on safety and effectiveness in children below the age of 6 years is limited.

Undesirable Effects
Particularly at the start of treatment with Tegretol^®, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur occasionally or frequently, e.g. CNS adverse.
Adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions.
The dose-related adverse reactions usually abate within a few days either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdose or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels and possibly to lower the daily dosage and/or divide it into 3-4 fractional doses.
The most severe adverse reactions have been observed in the homeopoetic system, the skin, and the cardiovascular system.

Central nervous system
Neurological-frequent: dizziness, ataxia, drowsiness, fatigue; occasional: headache, diplopia, accommodation disorders (e.g. blurred vision), rare; abnormal involuntary movements (e.g. tremor, asterixis, orofacial dyskinesia, choreoathetotic disorders, dystonis, tics); nystagmus; isolated cases: oculomotor disturbances, speech disorders (e.g. dysarthria or slurred speech), peripheral neuritis, paraesthesiae, muscle weakness, and parethic symptoms.
Psychiatric - isolated cases; hallucinations (visual or acoustic), depression, loss of appetite, restlessness, aggressive behaviour, agitation, confusion, activation of psychosis.
Skin and appendages - occasional or frequent: allergic skin reactions, urticaria, which may be severe; rare: exfoliative dermatitis and erythroderma, Stevens-Johnson syndrome, systemic lupus erythematosus-likes syndrome; isolated cases: toxic epidermal necrolysis, photosensivity, erythema multiforme and nodosum; alterations in skin pigmentation, purpura, pruritus, acne, sweating, hair lost. Isolated cases of hirsutism have been reported, but the causal relationship is not clear.
Blood - occasional or frequent: leucopenia; occasional eosinophilia, thrombocytopenia; rare; leucocytosis, lymphadenopathy; isolated case: agranulocytosis, aplastic anaemia, acute intermittent porphyria, reticulocytosis, folic acid deficiency and possibly haemolytic anaemia.
Liver - frequent: elevated gamma-GT (due to hepatic enzyme induction), usually not clinically relevant; occasional: elevated alkaline phosphatase, rarely transaminases ; rare; jaundice, hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type; isolated cases: granulomatous hepatitis.
Gastrointestinal tract - occasional or frequent: nausea, vomiting; occasional: dryness of the mouth; rare: diarrhoea or constipation; isolated cases: abdominal pain, glossitis, stomatitis.
Treatment should be discontinued when such hypersensitivity reactions occur.
Cardiovascular system - rare: disturbances of cardiac conduction, isolated cases: bradycardia, arrhythmias, AV-block with syncope, collapse, congestive heart failure, hypertension or hypotension, aggravation of coronary artery disease, thrombophlebitis, thromboembolism.
Endocrine system and metabolism - occasional: oedema, fluid retention, weight increase, hyponatraemia and reduced plasma osmolality due to an antidiuretic hormone (ADH)-like effect, leading in isolated cases to water intoxication accompanied by lethargy, vomiting, headache, mental confusion, neurological abnormalities; isolated cases: gynaccomastia or galactorrhoea. Isolated cases: abnormal thyroid function tests; decreased L-thyroxine (FT4,T4,T3) and increased TSH, usually without clinical manifestations.
Isolated cases: disturbances of bone metabolism (decrease in plasma calcium and 25-OH- cholecalciferol), leading in isolated cases to osteomalacia.
Isolated cases: elevated levels of cholesterol, including HDL cholesterol, and triglycerides.
Urogenital system -isolated cases: interstitial nephritis and renal failure, as well as signs of renal dysfunction (e.g. albuminuria, haernaturia, oliguria and elevated BUN/azotaemia) urinary frequency, urinary retention, and sexual disturbances/impotence.
Sens organs -isolated cases: taste disturbances, lens opacities, conjunctivitis, tinnitus, hyperacousia .
Musculoskeletal tract - isolated cases: arthralgia, muscle pain or cramp.
Respiratory tract - isolated cases: pulmonary hypersensitivity characterized by fever, dyspnoea, pneumonitis or pneumonia.

Overdose
Signs and symptoms
The presenting signs and symptoms of overdose usually involve the central nervous, cardiovascular and respiratory systems. Central nervous system: CNS depression; disorientation, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthia, nystagmus, ataxia, dyskinesia, initially hyper-reflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia.
Respiratory system: Respiratory depression, pulmonary oedema.
Cardiovascular system: Tachycardia, hypotension, at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.
Gastrointestinal system: Vomiting, delayed gastric emptying, reduced bowel motility.
Renal function: Retention of urine, oliguria or anuria; fluid retention, water intoxication due to an ADH-like effect of carbamazepine.
Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased nuscle creatinine phosphokinase.

Management
There is no specific antidote.
Management should initially be guided by the patient's clinical condition; admission to hospital. Measurement of the level to confirm carbamazepine poisoning and to ascertain the size of the overdose. Evacuation of the stomach, gastric lavage, and administration of activated charcoal.
Supportive medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance. Special recommendations:
Hypotension: administer dopamine or dobutamine i.v.
Disturbances of cardiac rhythm: to be handled on individual basis.
Convulsions: administer a benzodiazepine (e.g. diazepam) or another anti epileptic e.g phenobarbitone (with caution because of increased respiratory depression) or aldehyde. Hyponatraemia (water intoxication); fluid restriction and slow and careful NaCl 0.9% infusion i.v.
These measures may be useful in preventing brain damage. Charcoal haemoperfusion has been recommended. Forced diuresis, haemodialysis, and peritoneal dialysis have been reported to be not effective.
Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.

Pharmacological Properties
Pharmacodynamic properties
Therapeutic class: anti epileptic, neurotropic, and psychotropic agent, dibenzazepine derivative.
As an anti epileptic agent its spectrum of activity embraces: partial seizures (simple and complex).
With and without secondary generalization: generalized tonic-clonic seizures (grand mal) as well as combinations of these types of epilepsy. In clinical studies Tegretol^® given as mono therapy to patients with epilepsy - in particular children and adolescents - has reported to exert a psychotropic action, including a positive effect on symptoms of anxiety and depression as well as a decrease in irritability and aggressiveness. As regards cognitive and psychomotor performance, in some studies equivocal or negative effects, depending also upon dosages administered, were reported. In other studies, a beneficial effect on attentiveness, cognitive performance/memory was observed.
As a neurotropic agent Tegretol^® is clinically effective in a number of neurological disorders, e.g. it prevents paroxysmal attacks of pain in idiopathic trigeminal neuralgia; in alcohol withdrawal syndrome it raises the lowered convulsion threshold and improves withdrawal symptoms (e.g. hyperexcitability, tremor, impaired gait); in diabetes insipidus centralis, Tegretol^® reduces the urinary volume and relieves the feeling of thirst.
As a psychotropic agent Tegretol^® proved to have clinical efficacy in affective disorders i.e. as treatment form mania as well as for the prevention of manic-depressive (bipolar) disorders when given either as mono therapy or in combination with neuroleptics, antidepressants, or lithium.
The mechanism of action of carbamazepine, the active substance of Tegretol^®, has only been partially elucidated. Carbamazepine stabilizes hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that blockade of voltage-sensitive sodium channels may be one or even the main primary mechanism of action of carbamazepine. The aforementioned effects, as well as the depressant action of carbamazepine on catecholamine turnover and on glutamate release, could possibly result from this primary effect.
Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the anti epileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the properties of carbamazepine.

Pharmacokinetic properties
Absorption
Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The Conventional tablets and the chewable tablets yield mean peak plasma concentrations of the unchanged substance within 12 and 6 hours, respectively, following single oral doses. With the syrup, mean peak plasma concentrations are attained within 2 hours.
With respect to the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage forms. After a single oral dose of 400 mg carbamazepine (tablets) the mean peak concentration of unchanged carbamazepine (CBZ) in the plasma is approx. 4.5 mg/ml.
When CR tablets are administered singly and repeatedly, they yield about 25% lower peak concentrations of active substance in plasma than the conventional tablets; the peaks are attained within 24 hours. The CR tablets provide a statistically significant decreased fluctuation index, but not a significant decreased Cmin at steady-state. The fluctuation of the plasma concentrations with twice daily dosage regimen is low.
The bioavailability of Tegretol^® CR tablet is about 15% lower than that of the oral dosage forms.
Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Tegretol^®,
Steady-state plasma concentrations of carbamazepine are attained within about 1-2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as well as on pretreatment status, dosage, and duration of treatment.

Distribution
Carbamazepine is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and salive reflects the non-protein bound portion in the plasma (20-30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.
Carbamazepine crosses the placental barrier. Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg .

Elimination
The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (autoinduction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other liver-enzymes inducing drugs (e.g. phenytoin, phenobarbitone) half-life values averaging 9-10 hours have been found. After administration of a single oral dose of 400 mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10, 11-epoxide metabolite. Carbamazepine is metabolized in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10, 11-trans-diol derivative and its glucuronide as the main metabolites. 9-hydroxy-methyl-10-carabamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway. Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine.

Characteristics in Patients
The steady-state plasma concentrations of carbamazepine considered as "therapeutic range" vary considerably interindividually: for the majority of patients a range between 4-12 mg/ml corresponding to 17-50 mmol/L has been reported. Concentrations of CBZ-10, 11-epoxide (pharmacologically active metabolite): about 30% of CBZ levels.
There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.
No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.

Preclincial Safety Data
In rats treated with carbamazepine for 2 years, the incidence of tumours of the liver was found to be increased. The significance of these findings relative to the use of carbamazepine in humans, is, at persent, unknown. Bacterial and mammalian mutagenicity studies yielded negative results.

Storage
Chewable tablets,Store below 30°C, protect from heat and moisture.
Tablets, Store below 30°C, protect from moisture.
CR tablets: Store below 25°C, protect from moisture.
Syrup: Store below 30°C, protect from heat and light
Drugs should be kept out of the reach of children.

Packages
200 mg tablets:
pack of 5 blisters of 10 tablets, Reg.No.DKL 9930410310Al

CR tablets:
pack of 5 blisters of 1 0 tablets, Reg.No. DKL 993041 0414Al

Chewable tablets:
pack of 5 strips of 1 0 tablets, Reg.No. DKL 993041 0263Al

2% syrup:
bottle of 120 ml, Reg.No. DKL 993041 0537 Al

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Manufactured by PT Novartis Indonesia, Citeureup, Bogor, Indonesia under license of Novartis Pharma AG, Basel, Switzerland

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