Summary of medicine characteristics - CARBAMAZEPINE CRESCENT 100 MG TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Carbamazepine Crescent 100 mg tablet
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is carbamazepine.
Each tablet contains 100 mg carbamazepine.
For full list of excipients, see section 6.1.
Azo colouring agent (FD & C Red 40)
3 PHARMACEUTICAL FORM
4 CLINICAL PARTICULARS
Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carbamazepine. These reactions are estimated to occur in 1–6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.
There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions (see section 4.2).
HLA-B*1502 allele – in Han Chinese, Thai and other Asian populations
HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine (see section 4.2). If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still very rarely occur.
There are some data that suggest an increased risk of serious carbamazepine-associated TEN/SJS in other Asian populations. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA-B*1502 may be considered.
The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%).
HLA-A*3101 allele - European descent and Japanese populations
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash (see section 4.8) in people of European descent and the Japanese.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine treatment.
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine may be considered if the benefits are thought to exceed risks.
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-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).
Carbamazepine Tablet may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with DRESS, a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), that may occur in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon) see section 4.8 Undesirable Effects.
In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Carbamazepine Tablet should be withdrawn immediately.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25–30 % of these patients may experience hypersensitivity reactions with oxacarbazepine (Trileptal).
Cross-hypersensitivity can occur between carbamazepine and aromatic antiepileptics (e.g. phenytoin, primidone and phenobarbital).
Carbamazepine Tablet should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all these conditions, carbamazepine may exacerbate seizures. In case of exacerbation of seizures, carbamazepine should be discontinued.
Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences.
An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.
Abrupt withdrawal of carbamazepine may precipitate seizures therefore carbamazepine withdrawal should be gradual. If treatment with carbamazepine has to be withdrawn abruptly in a patient with epilepsy, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug.
Endocrinological effects
Breakthrough bleeding has been reported in women taking carbamazepine while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by carbamazepine and women of childbearing potential should be advised to consider using alternative forms of birth control while taking carbamazepine.
Patients taking carbamazepine and requiring hormonal contraception should receive a preparation containing not less than 50^g oestrogen or use of some alternative non-hormonal method of contraception should be considered.
Although correlations between dosages 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 4.5 Interaction with other Medicaments and other forms of Interaction).
Carbamazepine Tablet 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 carbamazepine. Baseline and periodic complete urinalysis and BUN determinations are recommended.
Hyponatremia is known to occur with carbamazepine. In patients with preexisting renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, medicinal products associated with inappropriate ADH secretion), serum sodium levels should be measured prior to initiating carbamazepine therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. If hyponatraemia is observed, water restriction is an important counter-measurement if clinically indicated.
Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction requiring an increase in dose of thyroid replacement therapy in patients with hypothyroidism. Hence thyroid function monitoring is suggested to adjust the dosage of thyroid replacement therapy.
Carbamazepine has shown mild anticholinergic activity; patients with increased intraocular pressure and urinary retention should therefore be closely observed during therapy (see section 4.8).
The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
Co-administration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine can induce adverse reactions (increase of carbamazepine or carbamazepine-10,11 epoxide plasma concentrations respectively). The dosage of Carbamazepine Tablet should be adjusted accordingly and/or the plasma levels monitored.
Co-administration of CYP3A4 inducers with carbamazepine may decrease carbamazepine plasma concentrations and its therapeutic effect, while discontinuation of a CYP3A4 inducer may increase carbamazepine plasma concentrations. The dosage of Carbamazepine Tablet may have to be adjusted.
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 co-medications mainly metabolized by CYP3A4 by induction of their metabolism. See section 4.5 Interactions
Female patients of childbearing potential should be warned that the concurrent use of Carbamazepine Tablet with hormonal contraceptives may render this type of contraceptive ineffective (see sections 4.5 Interactions and 4.6 Pregnancy and lactation). Alternative non-hormonal forms of contraception are recommended when using Carbamazepine Tablet.
Carbamazepine treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state, sedation (see section 4.8 Undesirable effects) which may lead to falls and, consequently fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete risk assessment of fall should be considered recurrently for patients on long-term Tegretol treatment.
Interference with serological testing
Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.
Carbamazepine and the 10, 11-epoxide metabolite may result in false positive tricyclic antidepressant concentration in fluorescence polarized immunoassay method.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.
Azo colouring agent (FD & C Red 40)
May cause allergic reactions
4.5 Interaction with other medicinal products and other forms of interaction
Carbamazepine interacts with many other medicinal products, and caution should always be taken when combining carbamazepine with other medicinal products.
Pharmacokinetic interactions
Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine 10, 11-epoxide. Co-administration of inhibitors of CYP 3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Co-administration of CYP 3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the carbamazepine serum level and 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.
Carbamazepine induces many active substance metabolizing enzymes and transporters, e.g. CYP3A, CYP2C8, 9 and 19, CYP2B6, UGTs (glucuronidation) and the transport protein p-glycoprotein (Pgp). Therefore, concomitant treatment with carbamazepine may increase the elimination of a large number of active substances whose metabolism is catalyzed by these enzymes. The plasma levels of such active substances can therefore be reduced with reduced or no effect as a result. Induction of Pgp can lead to lowered plasma levels and reduced distribution of drugs transported by this protein e.g. digoxin, fexofenadine, dabigatran, etexilate and sofosbuvir. The inducing effect of carbamazepine reaches its maximum after about 2 weeks of treatment with carbamazepine and may persist for at least 2 weeks after finishing treatment.
The use of carbamazepine is contraindicated in combination with monoamineoxidase inhibitors (MAOIs); before administering carbamazepine MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits (see contraindications).
Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:
Analgesics, anti-inflammatory drugs: dextropropoxyphene.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g. erythromycin, clarithromycin), ciprofloxacine.
Antidepressants: fluoxetine, fluvoxamine, paroxetine, trazodone.
Antiepileptics: vigabatrin.
Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihistamines: loratadine.
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.
Other interactions: grapefruit juice, nicotinamide (only in high dosage).
Since raised plasma carbamazepine-10, 11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Carbamazepine Tablet should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:
Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
The dose of carbamazepine may have to be adjusted when used concomitantly with the substances described below:
Antiepileptics: oxcarbazepine, phenobarbital, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment) and fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam.
Antineoplastics: cisplatin or doxorubicin.
Antituberculosis: rifampicin.
Bronchodilatators or anti-asthma drugs: theophylline,aminophylline.
Other interactions: herbal preparations containing St John's wort (Hypericum perforatum).
Due to potential interactions during combination therapy of epilepsy, plasma levels should be regularly monitored, and dosage adjusted accordingly as required. Blood assays of their respective plasma levels may vary from one patient to another, and moreover are usually bidirectional.
Serum levels of carbamazepine can be reduced by concomitant use of the herbal preparation St John's wort (Hypericum perforatum). This is due to induction of active substance metabolising enzymes, which may persist for at least 2 weeks after cessation of treatment with St. John’s wort. Products with St John’s wort should not be combined with carbamazepine. For patients already taking St John’s wort, serum levels of carbamazepine should be monitored before stopping treatment with St. John’s wort in case of switching between different St John’s wort products. Carbamazepine levels may increase on stopping St. John’s wort. The dose of carbamazepine may need adjusting.
Carbamazepine may lower the plasma level, diminish or even abolish the activity of certain medicinal products, due to its inducing effect on metabolising enzymes and the transport porotein P-gp.
The dosage of the following drugs may have to be adjusted to clinical requirement:
Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g. warfarin, acenocoumarol, rivaroxaban, dabigatran, apixaban and edoxaban).
Antidepressants: bupropion, citalopram, mianserin, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).
Antiemetics: aprepitant
Antiepileptics: clobazam, clonazepam, ethosuximide, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment. There have been rare reports of an increase in plasma mephenytoin levels.
Antifungals: itraconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihelmintics: albendazole.
Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.
Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, aripiprazole, paliperidone.
Antivirals: protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam.
Bronchodilatators 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, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).
Drugs used in erectile dysfunction: tadalafil.
Immunosuppressants: ciclosporin, everolimus, tacrolimus, sirolimus.
Thyroid agents: levothyroxine.
Other drug interactions: products containing oestrogens and/or progesterones.
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.
The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range. Combined use of carbamazepine with metoclopramide or major tranquillisers, e.g. haloperidol, thioridazine, may also result in an increase in neurological side-effects.
Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.
Carbamazepine may antagonise the effects of non-depolarising muscle relaxants (e.g. pancuronium). Their dosage should be raised and patients monitored closely for a more rapid recovery 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.
Concomitant use of carbamazepine with direct acting oral anti-coagulants (rivaroxaban, dabigatran, apixaban and edoxaban) may lead to reduced plasma concentrations of direct acting oral anti-coagulants, which carries the risk of thrombosis. Therefore, if a concomitant use is necessary, closer monitoring of signs and symptoms of thrombosis is recommended.
4.6 Fertility, Pregnancy and lactation
Women of child-bearing potential and contraceptive
Due to enzyme induction, Carbamazepine Tablet may result in a failure of the therapeutic effect of oral contraceptive drugs containing oestrogen and/or progesterone. Women of child bearing potential should be advised to use alternative contraceptive methods while on treatment with Carbamazepine and for 2 weeks following the last dose.
Carbamazepine should only be used during pregnancy after a careful risk/benefit evaluation (if the potential benefit to the mother justifies the potential risk to the fetus).
Offspring of epileptic mothers with untreated epilepsy are known to be more prone to developmental disorders, including malformations. Developmental disorders and malformations, including spina bifida, and also other congenital anomalies e.g. craniofacial defects such as clept lip/palate, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with the use of Carbamazepine. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening. Based on data in a North American pregnancy registry, the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, diagnosed within 12 weeks of birth was 3.0% (95% CI 2.1 to 4.2%) among mothers exposed to carbamazepine monotherapy in the first trimester and 1.1% (95% CI 0.35 to 2.5%) among pregnant women not taking any antiepileptic drug (relative risk 2.7, 95% CI 1.1 to 7.0).
Taking these data into consideration:
– Pregnant women with epilepsy should be treated with special care.
– If women receiving Carbamazepine become pregnant or plan to become pregnant, or if the problem of initiating treatment with Carbamazepine Tablet arises during pregnancy, the drug's expected benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.
– In women of childbearing potential Carbamazepine 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. The risk of malformations following exposure to carbamazepine as polytherapy may vary depending on the specific drugs used and may be higher in polytherapy combinations that include valproate.
– Minimum effective doses should be given and monitoring of plasma levels is recommended. The plasma concentration could be maintained in the lower side of the therapeutic range 4 to 12 micrograms/mL provided seizure control is maintained. There is evidence to suggest that the risk of malformation with carbamazepine may be dose-dependent i.e. at a dose < 400mg per day, the rates of malformation were lower than with higher doses of carbamazepine.
– 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 should not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate 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 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 Carbamazepine and other concomitant antiepileptic drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal Carbamazepine use. These reactions may represent a neonatal withdrawal syndrome.
Animal studies have shown reproductive toxicity (see section 5.3).
Carbamazepine passes into the breast milk (about 25–60% of the plasma concentrations). The benefits of breast-feeding should be weighed against the the risk of adverse effects in the infant. Mothers taking Carbamazepine may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, allergic skin reaction). There have been some reports of cholestatic hepatitis in neonates exposed to carbamazepine during antenatal and or during breast feeding. Therefore breast-fed infants of mothers treated with carbamazepine should be carefully observed for adverse hepatobiliary effects.
There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.
4.7 Effects on ability to drive and use machines
The patient's ability to react may be impaired by the medical condition resulting in seizures and adverse reactions including dizziness, drowsiness, ataxia, diplopia, impaired accommodation and blurred vision reported with carbamazepine, 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
4.8 Undesirable effects
Summary of the safety profile
Particularly at the start of treatment with carbamazepine, 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 and divide the daily dosage into smaller (i.e. 3–4) fractional doses.
Tabulated summary of adverse drug reactions compiled from clinical trials and from spontaneous reports
Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000).
| Blood and lymphatic system |
| disorders | |
| Very common : | leucopenia. |
| Common: | thrombocytopenia, eosinophilia. |
| Rare: | leucocytosis, lymphadenopathy. |
| Very rare: | agranulocytosis, aplastic anaemia, pancytopenia, aplasia pure red cell, anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia. |
| Not known: | bone marrow depression. |
| Immune system disorders | |
| Rare: | a delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon). |
| Very rare: | anaphylactic reaction, oedema angioedema, |
| Not known: | hypogammaglobulinaemia. |
| Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). | |
| Infections and infestations | |
| Not known: | reactivation of Human herpesvirus 6 infection. |
| Endocrine disorders | |
| 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: | galactorrhoea, gynaecomastia, |
| Metabolism and nutrition disorders | |
| Rare: | folate deficiency, decreased appetite. |
| Very rare: | porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda). |
| Psychiatric disorders | |
| Rare: Very rare: | hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusional state. activation of psychosis. |
| Nervous system disorders | |
| Very common: | ataxia, dizziness, somnolence. |
| Common: | diplopia, headache. |
| Uncommon: | abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics), nystagmus. |
| Rare: | dyskinesia, eye movement disorder, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, and paresis. |
| Very rare: | neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia. |
| Not known: | sedation, memory impairment |
| Eye disorders | |
| Common: | accommodation disorders (e.g. blurred vision) |
| Very rare: | lenticular opacities, conjunctivitis. |
| Ear and labyrinth disorders | |
| Very rare: | hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception. |
| Cardiac disorders | |
| Rare: | cardiac conduction disorders. |
| Very rare: | arrhythmia, atrioventricular block with syncope, bradycardia, cardiac failure congestive, coronary artery disease aggravated. |
| Vascular disorders | |
| Rare: | hypertension or hypotension, vasodilatation. |
| Very Rare: | circulatory collapse, embolism (e.g. pulmonary embolism), thrombophlebitis. |
| Respiratory, thoracic and mediastinal disorders | |
| Very rare: | pulmonary hypersensitivity characterised e.g. by fever, dyspnoea, pneumonitis or pneumonia. |
| Gastro-intestinal disorders | |
| Very common: | vomiting, nausea. |
| Common: | dry mouth, with suppositories rectal irritation may occur. |
| Uncommon: | diarrhoea, constipation. |
| Rare: | abdominal pain. |
| Very rare: | Pancreatitis, glossitis, stomatitis,. |
| Not known: | colitis. |
| Hepatobiliary disorders | |
| Rare: | hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice. |
| Very rare: | hepatic failure, granulomatous liver disease. |
| Skin and subcutaneous tissue disorders: | |
| Very common: | urticaria, which may be severe dermatitus allergic, |
| Uncommon: | dermatitis exfoliative. |
| Rare: | systemic lupus erythematosus, pruritus. |
| Very rare: | Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme, erythema nodosum, pigmentation disorder, purpura, acne, hyperhydrosis, alopecia, hirsutism. |
| Not known: | Acute Generalized Exanthematous Pustulosis (AGEP), lichenoid keratosis, onychomadesis. |
| Musculoskeletal, connective tissue and bone disorders | |
| Rare: | muscular weakness. |
| Very rare: Not known: | bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol) leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms. fracture. |
| Renal and urinary disorders | |
| Very rare : | tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/ azotaemia), urinary retention, urinary frequency. |
| Reproductive System | |
| Very rare: | sexual disturbances/erecticle dysfunction spermatogenesis abnormal (with decreased sperm count and/or motility). |
| General disorders and administration site conditions | |
| Very common: | fatigue. |
| Investigations | |
| Very common: Common: Uncommon: Very rare: Not known: | gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant. blood alkaline phosphatase increased. transaminases increased. intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased. Thyroid function test abnormal: decreased L-Thyroxin (free thyroxine, thyroxine, triiodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased, bone density decreased. |
| Injury, poisoning and procedural complications | |
| Not known | Fall (associated with carbamazepine treatment induced ataxia, dizziness, somnolence, hypotension, confusional state, sedation) (see section 4.4 warning and precautions) |
* In some Asian countries also reported as rare. See also section 4.4 Special warnings and precautions for use.
Additional adverse drug reactions from spontaneous reports (frequency not known)
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism has not been identified.
There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash. In Japanese and European patients, these reactions have been reported to be associated with the use of carbamazepine and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN among individuals of Han Chinese, Thai and some other Asian ancestry (see sections 4.2 and 4.4 for further information).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
The presenting signs and symptoms of overdosage involve the central nervous, cardiovascular, respiratory systems and the adverse drug reactions mentioned under section 4.8.
Central nervous system: CNS depression; disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: Respiratory depression, pulmonary oedema.
Cardiovascular system: Tachycardia, hypotension and at times hypertension, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.
Gastro-intestinal system: Vomiting, delayed gastric emptying, reduced bowel motility.
Musculoskeletal system: There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity.
Renal function: Retention of urine, oliguria or anuria; fluid retention, water intoxication due to ADH-like effect of carbamazepine.
Laboratory findings: Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, increased muscle creatine phosphokinase.
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.
5 PHARMACOLOGICAL PROPERTIES
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 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 400mg 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.
Characteristics in patients
The steady-state plasma concentrations of carbamazepine considered as “therapeutic range” vary considerably inter-individually; for the majority of patients a range between 4–12^g/ml corresponding to 17–50^mol/l has been reported. Concentrations of carbamazepine 10, 11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.
Special populations
Paediatric population
Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults to maintain therapeutic concentrations.
Elderly
There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.
Renal and Hepatic impairment
No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, local tolerance, genotoxicity and carcinogenic potential. Reproductive toxicity studies in animals were insufficient to rule out a teratogenic effect of carbamazepine in humans.
Carcinogenicity
In rats treated with carbamazepine for two years, there was an increased incidence of hepatocellular tumours in females and benign testicular tumours in males. However, there is no evidence to date that these observations are of any relevance to the therapeutic use of carbamazepine in humans.
Reproductive toxicity
In animals studies in mice, rats and rabbits oral administration of carbamazepine during organogenesis led to increased embryo-fetal mortality and fetal growth retardation at daily doses which were associated with maternal toxicity (above 200mg/kg/day). Carbamazepine was teratogenic in a number of studies, particularly in mice, however showed no or only minor teratogenic potential at doses relevant to humans.
Animal data
The cumulative evidence from various animal studies in mice, rats and rabbits indicates that carbamazepine has no or only minor teratogenic potential at doses relevant to man. However, the animal studies were insufficient to rule out a teratogenic effect of carbamazepine. In a reproduction study in rats, nursing offspring demonstrated a reduced weight gain at a maternal dosage level of 192 mg/kg/day
Fertility
In chronic toxicity studies dose related testicular atrophy and aspermatogenesis occurred in rats receiving carbamazepine. The safety margin for this effect is not known.