TEGRETOL^®

Carbamazepine

Qualitative and Quantitative Composition

Active substance: 5-Carbamoyl-5H-dibenz[b,f]azepin (carbamazepine)

Tablets: 200 mg and 400 mg carbamazepine

CR tablets (modified--release film-coated tablets, divisible): 200 mg and 400 mg carbamazepine

Syrup (viscous suspension, white, caramel flavoured): 5 mL contains 100 mg carbamazepine

Pharmaceutical forms

1. Tablet containing 200mg carbamazepine. Round, white, flat tablet, 9mm in diameter, with bevelled edges. Imprinted CG on one side, and G/K on the scored side.
2. Tablet containing 400mg carbamazepine. White, flat, rod-shaped tablet with bevelled edges. 17mm in length and 5.5mm in width. Imprinted CG/CG on one side and LR/LR on the second side; both sides of the tablet are scored.
3. Syrup containing 100mg/5mL carbamazepine. A viscous white suspension with a caramel odour and taste. It contains sorbitol (875mg/5mL), which is converted slowly into glucose, making the syrup suitable for diabetics.
4. Controlled Release Tablet containing 200mg carbamazepine. Beige-orange, ovaloid-shaped, film-coated divisible tablet with slightly convex faces. Approximate length is 12.2mm, and approximate width is 5.6mm. Both sides are scored; one side is imprinted C/G, and the other side H/C.
5. Controlled Release Tablet containing 400mg carbamazepine. Brown-orange, ovaloid-shaped, film-coated divisible tablet, with slightly convex faces. Approximately 16.7mm in length, and approximately 6.6mm in width. Imprinted CG/CG on one side, and ENE/ENE on the other side; both sides are scored.

Clinical particulars

Therapeutic indications

Epilepsy

• Complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization
• Generalized tonic-clonic seizures. Mixed forms of seizures

Tegretol^® is suitable for both monotherapy and combination therapy.

Tegretol is usually not effective in absences (petit mal) and myoclonic seizures (see. Special warnings and special precautions for use).

Acute mania and maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence.

Alcohol-withdrawal syndrome

Idiopathic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis (either typical or atypical). Idiopathic glossopharyngeal neuralgia.

Painful diabetic neuropathy

Diabetes insipidus centralis. Polyuria and polydipsia of neurohormonal origin.

Dosage and method of administration

The tablets and the syrup (to be shaken before use) may be taken during, after, or between meals. Tablets should be taken with a little liquid, and 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 syrup is particularly suitable for patients who have difficulty in swallowing tablets or need initial careful adjustment of the dosage.

As a result of slow, controlled release of the active substance from the CR tablets these are designed to be taken in a twice-daily dosage regimen.

Since a given dose of Tegretol syrup will produce higher peak levels than the same dose in tablet form, it is advisable to start with low doses and to increase them slowly so as to avoid adverse reactions.

Switching patients from Tegretol tablets to syrup: this should be done by giving the same number of mg per day in smaller, more frequent doses (e.g. syrup t.i.d. instead of tablets b.i.d).

Switching patients from conventional tablets to CR tablets: clinical experience shows that in some patients the dosage in the form of CR tablets may need to be increased.

Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tegretol should be selected with caution in elderly patients.

Epilepsy

When 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.

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 antiepileptic therapy, this should be done gradually while maintaining, or if necessary adapting, the dosage of the other antiepileptic(s) (see. Interaction with other medicinal products and other forms of interaction).

Adults - Oral forms: Initially, 100-200 mg once or twice daily; slowly raise the dosage until - generally at 400 mg 2-3 times daily - an optimum response is obtained. In some patients 1600 mg or even 2000 mg daily may be appropriate.

Children - Oral forms: For children aged 4 years or less, a starting dose of 20- 60 mg/day, increasing by 20- 60 mg every second day, has been recommended. For children over the age of 4 years, therapy may begin with 100 mg/day, increasing at weekly intervals by 100 mg.

Maintenance dosage: 10-20 mg/kg body weight daily in divided doses, e.g.

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.

Alcohol-withdrawal syndrome

Average dosage: 200 mg 3 times daily. In severe cases it can be raised during the first few days (e.g. to 400 mg 3 times daily). At the start of treatment for severe withdrawal manifestations, Tegretol should be given in combination with sedative-hypnotic drugs (e.g. clomethiazole, chlordiazepoxide). After the acute stage has abated, Tegretol can be continued as monotherapy.

Diabetes insipidus centralis

Average dosage for adults: 200 mg 2-3 times daily. In children the dosage should be reduced proportionally to the child's age and body weight.

Painful diabetic neuropathy

Average dosage: 200 mg 2-4 times daily.

Acute mania and maintenance treatment of bipolar affective disorders

Dosage range: about 400-1600 mg daily, the usual dosage being 400-600 mg daily given in 2-3 divided doses. In acute mania, the dosage should be increased rather quickly, whereas small dosage increments are recommended for maintenance therapy of bipolar disorders in order to provide for optimal tolerability.

Contraindications

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation. Patients with atrioventricular block, a history of bone-marrow depression, or a history of acute intermittent porphyria. Because it is structurally related 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 the very low incidence of these conditions, 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 pretreatment blood counts, including platelets (and possibly reticulocytes and serum iron), should be obtained as a baseline, and periodically thereafter.

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. 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.

Tegretol should be used with caution in patients with mixed seizures which includes absences, either typical or atypical. In all these conditions, Tegretol may exacerbate seizures. In case of exacerbation of seizures, Tegretol should be discontinued.

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.

Patients should be made aware of early toxic signs and symptoms of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage 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 haematological reactions to other drugs, or interrupted courses of therapy with Tegretol.

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 patient should be kept under close surveillance.

Tegretol has shown mild anticholinergic activity; patients with increased intraocular 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 causal relationship has not been established.

Breakthrough bleeding has been reported in women taking Tegretol while using oral contraceptives; the reliability of oral contraceptives may be adversely affected by Tegretol and women of childbearing age should be advised to consider using alternative forms of birth control while taking Tegretol. Due to enzyme induction Tegretol may cause failure of the therapeutic effect of oestrogen and/or progesterone containing drugs (e.g. failure of contraception).

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 in seizure 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 medicinal products and other forms of interaction).

Abrupt withdrawal of Tegretol may precipitate seizures. If treatment with Tegretol has to be withdrawn abruptly in a patient with epilepsy, the change-over to the new antiepileptic compound should be made under cover of a suitable drug (e.g. diazepam i.v., rectal; or phenytoin i.v.).

Cross-hypersensitivity can occur between carbamazepine and oxcarbazepine (Trileptal⁽⁾ in approximately 25-30% of the patients

Cross-hypersensitivity can occur between carbamazepine and phenytoin.There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal Tegretol use. These reactions may represent a neonatal withdrawal syndrome.

Interaction with other medicinal products and other forms of interaction

Cytochrome P4503A4 (CYP3A4) is the main enzyme catalyzing formation of carbamazepine-10,11 epoxide. Coadministration of inhibitors of CYP3A4 may result in increased plasma concentrations which could induce adverse reactions. Coadministration of CYP3A4 inducers might increase the rate of Tegretol metabolism, thus leading to a potential decrease in carbamazepine serum level and potential decrease in the therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels.

Agents that may raise Tegretol plasma levels

Verapamil, diltiazem, dextropropoxyphene, viloxazine, fluoxetine, fluvoxamine, possibly cimetidine, acetazolamide, danazol, possibly desipramine, nicotinamide (in adults, only in high dosage), nefazodone, macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin), azoles (e.g. itraconazole, ketoconazole, fluconazole), terfenadine, loratadine, grapefruit juice, protease inhibitors for HIV treatment (e.g. ritonavir).

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.

Agents that may decrease Tegretol plasma levels

Phenobarbitone, phenytoin, primidone, progabide, or theophylline, methsuximide, phensuximide, rifampicin, cisplatin or doxorubicin and, although the data are partly contradictory, possibly also clonazepam, valproic acid or valpromide. Oxcarbazepine; herbal preparations containing St John's wort (Hypericum perforatum). On the other hand, valproic acid, valpromide and primidone have been reported to raise the plasma level of the pharmacologically active carbamazepine-10,11-epoxide metabolite. The dose of Tegretol may consequently have to be adjusted.

Coadministration of felbamate might decrease the carbamazepine serum concentration associated with an increase in carbamazepine-epoxide concentration and might decrease the felbamate serum concentration.

Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; plasma carbamazepine levels should be monitored.

Effect of Tegretol on plasma levels of concomitant agents

Carbamazepine may lower the plasma level, or diminish, or even abolish the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirements: clobazam, clonazepam, ethosuximide, primidone, 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), felbamate, lamotrigine, zonisamide, tiagabine, topiramate, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine), clozapine, oxcarbazepine; protease inhibitors for HIV treatment, e.g. indinavir, ritonavir, saquinavir; calcium channel blockers (dihydropyridine group), e.g., felodipine; itraconazole; levothyroxine; midazolam; olanzapine; products containing oestrogens and/or progesterones; praziquantel; risperidone; tramadol; ziprasidone.

Plasma phenytoin levels 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.

Combinations to be taken into consideration

Coadministration of carbamazepine and paracetamol may reduce the bioavailability of paracetamol/acetaminophen.

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 carbamazepine 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').

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.

Tegretol, like other psychoactive drugs, may reduce alcohol tolerance; it is therefore advisable for the patient to abstain from alcohol.

Pregnancy and lactation

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 evidence of abortion at 300 mg/kg body weight daily. Near-term rat fetuses 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 fetuses 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 monotherapy, because the incidence of congenital abnormalities in the offspring of women treated with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual drugs as monotherapy.

Minimum effective doses should be given and monitoring of plasma levels is recommended.

If pregnancy occurs in a woman 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 antiepileptic drugs, increases this risk has been reported, although conclusive evidence from controlled studies with carbamazepine monotherapy is lacking. However, developmental disorders and malformations, including spina bifida and also other congenital anomalies, e.g. craniofacial defects, cardiovascular malformations, and anomalies involving various body systems, have been reported 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. Antiepileptic 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 newborn 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, allergic skin reaction).

Effects on ability do 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.

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 very commonly or commonly, e.g. CNS 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 overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels.

Frequency estimate: very common ( 10%; common ( 1% to < 10%; uncommon ( 0.1% to
< 1%; rare ( 0.01% to < 0.1%; very rare < 0.01%.

Central nervous system - Neurological

Very common: dizziness, ataxia, drowsiness, fatigue; common: headache, diplopia, accommodation disorders (e.g. blurred vision); uncommon: abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus; rare: orofacial dyskinesia, oculomotor disturbances, speech disorders (e.g. dysarthria, slurred speech), choreoathetotic disorders, peripheral neuritis, paresthesia, muscle weakness, and paretic symptoms. The causative role of carbamazepine in inducing or contributing to the development of a neuromalignant syndrome, especially in conjunction with neuroleptics, is unclear.

Psychiatric

Rare: hallucinations (visual or acoustic), depression, loss of appetite, restlessness, aggressive behaviour, agitation, confusion; very rare: activation of psychosis.

Skin and appendages

Very common: allergic skin reactions, urticaria which may be severe; uncommon: exfoliative dermatitis and erythroderma; rare: lupus erythematosus-like syndrome pruritus; very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, sweating, hair loss, ; very rare cases of hirsutism have been reported, but the causal relationship is not clear.

Blood

Very common: leukopenia; common thrombocytopenia, eosinophilia; rare: leukocytosis, lymphadenopathy, folic acid deficiency; very rare: agranulocytosis, aplastic anaemia, pure red cell aplasia, megaloblastic anaemia, acute intermittent porphyria, reticulocytosis, and possibly haemolytic anaemia.

Liver

Very common: elevated gamma-GT (due to hepatic enzyme induction), usually not clinically relevant; common: elevated alkaline phosphatase, uncommon: elevated transaminases; rare: hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, jaundice; very rare: granulomatous hepatitis, hepatic failure.

Gastrointestinal tract

Very common: nausea, vomiting; common: dryness of the mouth; with suppositories, rectal irritation may occur. Uncommon: diarrhoea or constipation; rare: abdominal pain; very rare: glossitis, stomatitis, pancreatitis.

Hypersensitivity reactions

Rare: a delayed multiorgan hypersensitivity disorder with fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests, occurring in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon); very rare: aseptic meningitis, with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioedema.

Treatment should be discontinued when such hypersensitivity reactions occur.

Cardiovascular system

Rare: disturbances of cardiac conduction; hypertension or hypotension, very rare: bradycardia, arrhythmias, AV-block with syncope, collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thromboembolism.

Endocrine system and metabolism

Common: oedema, fluid retention, weight increase, hyponatraemia and reduced plasma osmolality due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, mental confusion, neurological abnormalities; very rare: increase in prolactin with or without clinical manifestations such as galactorrhoea, gynecomastia, abnormal thyroid function tests: decreased L-Thyroxin (FT4,T4,T3) and increased TSH, usually without clinical manifestations, disturbances of bone metabolism (decrease in plasma calcium and 25-OH-cholecalciferol), leading to osteomalacia, elevated levels of cholesterol, including HDL cholesterol, and triglycerides.

Urogenital system

Very rare: interstitial nephritis, renal failure, renal dysfunction (e.g. albuminuria, haematuria, oliguria, and elevated BUN/azotemia), urinary frequency, urinary retention, sexual disturbances/impotence.

Sense organs

Very rare: taste disturbances, lens opacities, conjunctivitis hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.

Musculoskeletal system

Very rare: arthralgia, muscle pain or cramp.

Respiratory tract

Very rare: pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or pneumonia.

Overdose

Signs and symptoms

The presenting signs and symptoms of overdosage usually involve the central nervous, cardiovascular, and respiratory systems.

Central nervous system

CNS depression; disorientation, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyper-reflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.

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 muscle 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 plasma level to confirm carbamazepine poisoning and to ascertain the size of the overdose.

Evacuation of the stomach, gastric lavage, and administration of activated charcoal. Delay in evacuating the stomach may result in delayed absorption, leading to relapse during recovery from intoxication. 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 an individual basis.

Convulsions: administer a benzodiazepine (e.g. diazepam) or another antiepileptic, e.g. phenobarbitone (with caution because of increased respiratory depression), or paraldehyde.

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 hemoperfusion 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: antiepileptic, neurotropic, and psychotropic agent; (ATC Code: N03 AX01).

Dibenzazepine derivative.

As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalization; generalized tonic-clonic seizures, as well as combinations of these types of seizures.

In clinical studies Tegretol given as monotherapy to patients with epilepsy - in particular children and adolescents - has been 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 and secondary trigeminal neuralgia; in addition, it is used for the relief of neurogenic pain in a variety of conditions, including tabes dorsalis, post-traumatic paresthesia, and post-herpetic 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 for acute mania as well as for maintenance treatment of (manic-depressive) bipolar affective disorders, when given either as monotherapy or in combination with neuroleptics, antidepressants, or lithium, in excited schizo-affective disorder and excited mania in combination with other neuroleptics, and in rapid cycling episodes.

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 prevention of repetitive firing of sodium-dependent action potentials in depolarized neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.

Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.

Pharmacokinetic properties

Absorption

Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The conventional tablets yield mean peak plasma concentrations of the unchanged substance within 12, 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 in the plasma is approx. 4.5 micrograms/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 a twice daily dosage regimen is low. The bioavailability of Tegretol CR tablets is about 15% lower than that of the other 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 saliva 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 (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other liver-enzyme inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9-10 hours have been found.

The mean elimination half-life of the 10,11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.

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-transdiol derivative and its glucuronide as the main metabolites. Cytochrome P4503A4 has been identified as the major isoform responsible for the formation of carbamazepine-10,11 epoxide from carbamazepine. 9-Hydroxy-methyl-10-carbamoyl 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 micrograms/mL corresponding to 17-50 micro mol/L has been reported. Concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.

Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults.

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.

Preclinical safety data

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

Pharmaceutical Particulars

List of excipients

Tablets: Aerosil 200 (silica aerogel), Avicel PH 102 (cellulose) magnesium

stearate, Nymcel ZSB-10 modified (sodium carboxymethylcellulose)

CR tablets: Aerosil 200 (silica aerogel), Aquacoat ECD solid (solid residue of aqueous polymeric dispersion of ethylcellulose), Avicel PH 102 (cellulose), Eudragit ED solid (copolymer based on polyacrylic / methacrylic esters), magnesium stearate, sodium CMC XL, talc. Coating: Cellulose -HP- M 603 (hydroxypropyl methylcellulose), Cremophor RH 40 (glyceryl polyoxyethylene glycol stearate), iron oxide red 17266, iron oxide yellow 17268, talc, titanium dioxide.

Syrup: Avicel RC 581 (cellulose + sodium CMC), caramel aroma 52929 A, methylparaben, Natrosol 250 G (hydroxyethyl cellulose), propylene glycol dist., polyethylene glycol 400 stearate, propylparaben, saccharin sodium cryst., sorbic acid, sorbitol solution, water deionized.

Incompatibilities

None known.

Shelf life

Special precautions for storage

Medicines should be kept out of the reach of children.

Nature and contents of the container

Instructions for use/handling

There is no specific instruction for use/handling.

   Inhouse Pharmacy (UK)