Antiepileptic, neurotropic and psychotropic agent
COMPOSITION AND PHARMACEUTICAL FORM
Active substance: 5H-dibenzo [b,f] azepine-5-carboxamide
Tablets: 200 mg carbamazepine.
Complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization.
Generalized tonic-clonic seizures. Mixed forms of seizures.
Tecral is suitable for both monotherapy and combination therapy.
Tecral is usually not effective in absences (petit mal) and myoclonic seizures (see section SPECIAL WARNINGS AND 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 giossopharyngeal neuralgia.
• Painful diabetic neuropathy
• Diabetes insipidus centralis. Polyuria and polydipsia of neurohormonal orgin.
DOSAGE AND ADMINISTRATION
The tablets 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. Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tecral should be selected with caution on elderly patients.
When possible. Tecral 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 section SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
When TECRAL 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 section INTERACTIONS)
Initially, 100 to 200 mg once or twice daily; the dosage should be slowly raised until – generally at 400 mg 2 to 3 times daily – an optimum response is obtained. In some patients 1600 mg or even 2000 mg daily may be appropriate.
For children aged 4 years or less, a starting dose of 20 to 60 mg/day, increasing by 20 to 60 mg every second day, is 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 to 20 mg/kg body weight daily in divided doses. e.g.
• Up to 1 year of age 100 to 200 mg daily
• 1 to 5 years of age 200 to 400 mg daily
• 6 to 10 years of age 400 to 600 mg daily
• 11 to 15 years of age 600 to 1000mg daily
Acute mania and maintenance treatment of bipolar affective disorders
Dosage range: about 400 to 1600 mg daily, the usual dosage being 400 to 600 mg daily given in 2 to 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 ensure optimal tolerability.
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. Tecral should be given in combination with sedative-hypnotic drugs (e.g. clomethiazole, chlordiazepoxide). After the acute stage has abated. Tecral can be continued as monotherapy.
The initial dosage of 200 to 400 mg should be slowly raised daily until freedom from pain is achieved (normally all 200 mg 3 to 4 times daily). The dosage should then be gradually reduced 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 to 4 times daily.
Diabetes insipidus centralis
Average dosage for adults: 200 mg 2 to 3 times daily, in children the dosage should be reduced proportionally to the child’s age and body weight.
• Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation
• Patients with atrioventricular block
• Patients with a history of bone-marrow depression
• Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda)
• The use of Tecral is not recommended in combination with monoamine-oxidase inhibitors (MAO/s) (See, section INTERACTIONS).
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Tecral should be given only under medical supervision. Tecral 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 Tecral.
Agranulocytosis and aplastic anaemia have been associated with Tecral; however, due to the very low incidence of these conditions, meaningful risk estimates for Tecral 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 Tecral. 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 at 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. Tecral should be discontinued if any evidence of significant bone-marrow depression appears. 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.
Serious dermatologic reactions
Serious dermatologic reactions, including toxic epidermal necrolysis (TEN; also known as Lyell’s syndrome) and Stevens-Johnson syndrome (SJS), have been reported very rarely with Tecral. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with Tecral. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell’s syndrome/TEN) appear, Tecral should be withdrawn at once and alternative therapy should be considered. There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.
Association with HLA-A *3101
Human Leukocyte Antigen (HLA)3A 3101 may be a risk factor for the development of cutaneous adverse drug reactions such as SJS, TEN, DRESS. AGEP and maculopapular rash. Retrospective genome-wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS. TEN, DRESS. AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLAA*3101 allele in these patients.
The frequency of the HLAA*3101 allele varies widely between ethnic, populations. The frequency of this allele is estimated less than 5% in the majority of European, Australian, Asian, African and North American populations with some exceptions within 5-12%. Prevalence above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10%-15% in other native ethnicities in these same regions.
Testing for the presence of HLAA*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas. Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with Tecral (see section information for Healthcare professionals). The use of Tecral should be avoided in patients who are found to be positive for HLAA*3101: unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current Tecral users as the risk of SJS/TEN, AGEP. DRESS and maculopapular risk is largely confined to the first few, months of therapy, regardless of HLAA*3101 status.
Association with HLA-B*1502
Retrospective studies in patients of Han Chinese ancestry found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigene (HLA)B*1502 allele. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher prevalence of the HLA-B*1502 allele in the population. The prevalence of carriers of this allele in Asian populations is above 15% in the Philippines. Thailand, Hong Kong and Malaysia around 10% in Taiwan around 4% ,in North China around 2 to 4% in South Asia including Indians, and less than 1% in Japan and Korea. The prevalence of the HLAB*1502 allele is negligible in Caucasian, African, indigenous peoples of the Americas and Hispanic populations sampled.
Testing for the presence of HLAB* 1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Tecral (see section information for Healthcare professionals). The use of Tecral should be avoided in tested patients who are found to be positive for HLAB*1502 unless the benefits clearly outweigh the risks. HLAB* 1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoiding use of other drugs associated with SJS/TEN in HLAB*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which, the prevalence of HLAB*1502 is low. Screening is generally not recommended for any current Tecral users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLAB*1502 status.
The identifications of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in those subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.
Limitation of genetic screening
Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLAB*1502 and treated with Tecral will not develop SJS/TEN and patients negative for HLAB*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A*3101 and treated with Tecral will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of and morbidity from, these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.
Other dermatologic reactions
Mild skin reactions, e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use. The HLA-A*3101 allele has been found to be associated with less severe adverse cutaneous reactions from carbamazepine and may predict the risk of these reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption). However, the HLA-B*1502 allele has not been found to predict the risk of these alone mentioned skin reactions.
Tecral may trigger hypersensitivity reactions, including multi-organ hypersensitivity reactions, which can affect the skin, liver, (including intrahepatic bile ducts) haematopoietic organs and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section UNDESIRABLE EFFECTS). The HLA-A*3101 allele has been found to be associated with the occurrence of hypersensitivity syndrome, including maculopapular rash.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25 to 30 % of these patients may experience hypersensitivity reactions with oxcarbazepine.
Cross-hypersensitivity can occur between carbamazepine and phenytoin. In general if signs and symptoms suggestive of hypersensitivity reactions occur, Tecral should be withdrawn immediately.
Tecral should be used with caution in patients with mixed seizures which includes absences, either typical or atypical all these conditions. Tecral may exacerbate seizures. In the event of exacerbation of seizures, Tecral should be discontinued.
Baseline and periodic evaluations of hepatic function must be performed during treatment with Tecral particularly patients with a history of liver disease and in elderly patients. 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.
Tecral has shown mild anticholinergic activity. Patients with increased intraocular pressure should therefore be closely observed during therapy (see section UNDESIRABLE EFFECTS).
The possibility of activation of a latent psychosis and in elderly patients of confusion or agitation should be borne in mind.
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known.
Therefore patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Breakthrough bleeding has been reported in women taking Tecral while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Tecral and women of childbearing age should be advised to consider using alternative forms of birth control while taking Tecral. Due to enzyme induction, Tecral may cause failure of the therapeutic effect of drugs containing oestrogen and/or progesterone (e.g. failure of contraception).
Monitoring of plasma levels
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 situations, 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 section INTERACTIONS).
Dose reduction and withdrawal
Abrupt withdrawal of Tecral may precipitate seizures. If treatment with Tecral has to be withdrawn abruptly in a patient with epilepsy the switch to the new antiepileptic compound should be made under cover of a suitable drug (e.g. diazepam i.v., rectal; or phenytoin i.v.).
Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalyzing formation of the active metabolite carbamazepine 10, 11 epoxide. Coadministration of inhibitors of CYP3A4 may result in increased carbarmazepine plasma concentrations which could induce adverse reaction. Coadministration of CYP3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to a potential decrease in the 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. Carbamazepine is a potent inducer of CYP3A4 and other phase I and Phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 by induction of their metabolism. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10.11-transdiol derivative from carbamazepine 10.11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine 10.11 epoxide plasma concentrations.
Agents that may raise carbamazepine plasma levels
Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tecral should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with Analgesics, anti-inflammatory drugs: dextropropoxyphene, iburofen, Androgens: danazol, Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin), Antidepressants: possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine: trazodone, viloxazine, Antiepileptics stinpentol, vigabatrin, Antifungais: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole), Anthistamines loratadine terfenadine. Antipsychotics olanzapine, Antituberculosis isoniazid, Antivirals protease inhibitors for HIV treatment (e.g. ritonavir). Carbonic anhydrase inhibitors acetazolamide. Cardiovascular drugs diltiazem, verapamil, Gastrointestinal drugs possibly cimetidine omeprazole, Muscle relaxants oxybutynin, dantrolene. Platelet aggregation inhibitors ticlopidine, Other interactions grapefruit juice, nicotinamide (in adults only in high dosage).
Agents that may raise the active metabolite carbamazepine – 10.11 epoxide plasma levels
Since raised plasma carbamazepine 10.11 epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia) the dosage of Tecral should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
Agents that may decrease carbamazepine plasma levels
The dose of Tecral may have to be adjusted when used concomitantly with Antiepileptics felbamate, methsuximide, oxcarbazepine, phenobarbitone, phensuximide, phenytoin and fosphenytoin, primidone, and although the data are partly contradictory, possibly also clonazepam, Antineoplastics cisplatin or doxorubicin, Antituberculosis, rifampicin, Bronchodilators or anti-asthma drugs, theophylline, aminophylline, Dermatological drugs isotretinoin. Other interactions, herbal preparations containing St. John’s wort (Hypericum perforatum).
Effect of Tecral 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 these drugs may have to be adjusted to clinical requirements. Analgesics, anti-inflammatory agents, methadone, paracetamol, phenazone (antipyrine), tramadol. Antibiotics doxycycline, Anticoagulants oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol and acenocoumarol). Antidepressants, bupropion, citalopram, nefazodone, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine). The use of Tecral is not recommended in combination with monoamine-oxidase inhibitors (MAOIs), before administering Tecral MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.
Antiemetics: Aprepitant, Antiepileptics clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate valproic acid, zonisa mide. Plasma phenytoin levels have been reported both to be raised and to be lowered by carbamazepine and there have been rare reports of an increase in plasma mephenytoin levels. Antifungáls itraconazole, Anthelmintics praziquantel, albendazole, Antineoplastics imatinib cyclophosphamide, lapatinib, temsirolimus. Antipsychotics clozapine, haloperidol and bromperidol, olanzapine quetiapine risperidone ziprasidone aripiprazole, paliperidone. Antivirals protease inhibitors for HIV treatment (e.g. indinavir, ritonavir saquinavir). Anxiolytics, alprazolam, midazolam Bronchodilators or anti-asthma drugs theophylline. Contraceptives hormonal contraceptives (alternative contraceptive methods should be considered). Cardiovascular drugs calcium channel blockers (dihydropyridine group) e.g. felodipine, digoxin, Corticosteroids corticosteroids (e.g. prednisolone dexamethasone), Drugs used in erectile dysfunction. Tadalafil, immunosuppressants ciclosporin, everolimus, tacrolimus, sirolimus. Thyroid agents Ievothyroxine, other drug interactions products containing oestrogens and/or progesterones.
Combinations that require specific consideration
Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity. 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 Tecral and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraomia. 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 recover from neuromuscular blockade than expected.
Carbamazepine 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 to 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 three animal species tested, but in one study using mice, carbamazepine (40 to 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. 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, hypospadias and anomalies involving various body systems, have been reported in association with Tecral.
Taking these data into consideration:
• Pregnant women with epilepsy should be treated with special care.
• If women receiving Tecral become pregnant or plan to become pregnant, or if the problem of initiating treatment with Tecral arises during pregnancy the drug’s potential benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.
• In women of childbearing age Tecral 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.
• Patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
• During pregnancy an effective antiepileptic treatment must not be interrupted since the aggravation of the illness is detrimental to both the mother and the fetus.
Monitoring and prevention
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.
In the neonate
In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1 be given to the mother during the last weeks of pregnancy as well as to the neonate.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tecral and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in associated with maternal Tecral use. These reactions may represent a neonatal withdrawal syndrome.
Carbamazepine passes into the breast milk (about 25 to 60% of plasma concentrations). The benefits of breast feeding should be weighed against the remote possibility of adverse effects occurring in the infants. Mothers taking Tecral may breast feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction).
There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
The patient’s ability to react may be impaired by dizziness and drowsiness caused by Tecral, 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.
Particularly at the start of treatment with Tecral 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 and 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 plasma levels.
Adverse reactions (Table 1) are ranked under heading of frequency the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, <1/1000); very rare (< 1/10,000), including isolated reports.
Blood and lymphatic system disorders
Very common: leukopenia
Common: thrombocytopenia, eosinophilia
Rare: leukocytosis, lymphadenopathy, folic acid deficiency
Very rate: agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia, megaloblastic anaemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda, reticulocytosis, and possibly haemolytic anaemia.
Immune system disorders
Rare: a delayed multiorgan hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophillia, hepato-splenomegaly and abnormal liver function tests, occurring in various combinations. Other organs may also be affected (e.g. lungs, kidney, pancreas, myocardium, colon).
Very rare: aseptic meningitis, with myoclonus and peripheral eosinophilia, anaphylactic reaction angioneurotic oedema.
Common: oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders.
Very rare: Blood prolactin increased with or without clinical manifestations such as galactorrhoea, gynecomastia, abnormal thyroid function tests, decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulation hormone, usually without clinical manifestations, bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol), leading to osteomalacia/osteoporosis, increased blood cholesterol, including HDL cholesterol, and triglycerides.
Rare: hallucinations (visual or auditory), depression, anorexia, restlessness, aggression, agitation, confusional state.
Very rare: activation of psychosis.
Nervous system disorders
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, eye movement disturbances, speech disorders (e.g. dysarthria, slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, and paresis.
Very rare: taste disturbances, neuroleptic malignant syndrome.
Very rare: intraocular opacities, conjunctivities, intraocular pressure increased.
Ear and labyrinth disorders
Very rare: hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.
Rare: cardiac conduction disorders; hypertension or hypotension.
Very rare: bradycardia, arrythmia, atrioventricular block with syncope, circulatory collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thromboembolism (e.g. pulmonary embolism).
Respiratory, thoracic and madiastinal disorders
Very rare: pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or penumonia.
Very common: nausea, vomiting.
Common: dry mouth: with suppositories, rectal irritation may occur.
Uncommon: diarrhoea, constipation.
Rare: abdominal pain
Very rare: glossitis, stomatitis, pancreatitis
Very common: increased gamma-GT (due to hepatic enzyme induction), usually not clinically relevant.
Common: increased blood alkaline phosphatase.
Uncommon: increased transaminases.
Rare: hepatitis of cholestatic, parenchyma (hepatocellular) or mixed type, jaundice.
Very rare: granulomatous hepatitis, hepatic failure.
Skin and subcutaneous tissue disorders
Very common: dermatitis allergic, urticaria which may be severe.
Uncommon: exfoliative dermatitis and erythroderma.
Rare: systemic lupus erythematosus, pruritus.
Very rare: toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodosum alterations in skin pigmentation, purpura, acne, hyperhydrosis, hair loss, hirsutism.
Musculoskeletal, connective tissue and bone disorders
Rare: muscular weakness.
Very rare: arthralgia, muscle pain, muscle spasms.
Renal and urinary disorders
Very rare: interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria, and blood urea increased/azotemia), urinary frequency, urinary retention.
Very rare: sexual dysfunction/impotence, spermatogenesis abnormal (with decreased sperm count and/or motility).
Very rare: hypogammaglobulinaemia.
* In some Asian countries also reported as rare. See also section SPECIAL WARNINGS AND PRECAUTIONS FOR USE.
Adverse drug reactions from spontaneous reports and literature cases (frequency not known)
The following adverse drug reactions have been derived from post-marketing experience with Tecral via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.
Immune system disorders
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).
Skin and subscutaneous tissue disorders
Acute Generalized Exanthematous Pustulosis (AGEP).
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, hypothemia, mydriases.
Respiratory depression, pulmonary oedema.
Tachycardia, hypotension at times hypertension, conduction disturbance with widening of QRS complex, syncope in association with cardiac arrest.
Vomiting, delayed gastric emptying, reduced bowel motility.
Retention of urine, oliguria or anuria: fluid retention, water intoxication due to an ADH-Iike effect of carbamazepine.
Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.
There is no specific antidote.
Management could 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 until with cardiac monitoring and careful correction of electrolyte imbalance.
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 NaCI 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.
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 Tecral 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 Tecral is clinically effective in a number of neurological disorders, e.g. it prevents paroxysmal attacks of pain in idopathic and secondary trigeminal neuralgia: In addition, it is used for the relief of neurogenic pain in a variety of conditions, including labes forsalls, post-traumatic paresthesia and post-herpetic rteuralgia: in alcohol-withdrawal syndrome it raises the lowered convulsion threshold and improves withdrawal symptoms (e.g hyperexcitability, tremor, impaired gait): in diabetes insipidus centralis, Tecral reduces the urinary volume and relieves the feeling of thirst.
As a psychotropic agent Tecral 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 Tecral, 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.
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.
Steady-state plasma concentrations of carbamazepine are attained within about 1 to 2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-including drugs, as well as on pretreatment status, dosage, and duration, of treatment.
The steady-state plasma concentrations of carbamazepine considered as therapeutic range vary considerably interindividually for the majority of patients a range between 4 to 12 micrograms/mL corresponding to 17 to 50 micromol/L has been reported. Concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite) about 30% of carbamazepine levels.
Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Tecral.
Assurring complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg. Carbamazepine crosses the placental barrier. Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in the plasma (20 to 30%). Concentrations in breast milk were found to be equivalent to 25 to 80% of the corresponding plasma levels.
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 P450 3A4 has been identified as the major isoform responsible for the formation of the pharmacologically active carbamazepne 10,11 epoxide from carbamazepirie. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11 -transdiol derivative from carbamazepine 10,11 epoxide. 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 produced by UGT2B7.
The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16 to 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 to 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 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 phamacologically active 10,11-epoxide metabolite.
Characteristics in patients
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 finding relative to the use of carbamazepine in humans is unknown at present. Bacterial and mammalian mutagenicity studies yielded negative results.
Tablet: Protect from heat, light and moisture.
INSTRUCTIONS FOR HANDLING
Tecral must be kept out of the reach and sight of children.
If you have any questions about the medicinal product please contact your doctor.
ROCK PHARMACEUTICALS (PVT) LTD.
134-B & 135-B Nowshera
Industrial Estate Risalpur Pakistan.