Carbamazepine

St. John’s wort may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with St. John’s wort.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of corticosteroids. The dosage of corticosteroids may have to be adjusted to clinical requirement.

Cytochrome P4503A4 (CYP3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine 10, 11-epoxide. Co-administration of CYP3A4 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.

Cytochrome P4503A4 (CYP3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine 10, 11-epoxide. Co-administration of inhibitors of CYP3A4 may result in increased plasma concentrations which could induce adverse reactions.

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.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of tricyclic antidepressants. The dosage of tricyclic antidepressants may have to be adjusted to clinical requirement.

Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.

Grapefruit juice may raise carbamazepine plasma levels. 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 grapefruit juice.

Due to hepatic enzyme induction, carbamazepine may cause failure of the therapeutic effect of oestrogen and/or progestogen containing products. This may result in failure of contraception, recurrence of symptoms or breakthrough bleeding or spotting.

Patients taking carbamazepine and requiring hormonal contraception should receive a preparation containing not less than 50 µg oestrogen or use of some alternative non-hormonal method of contraception should be considered.

Macrolide antibiotics (e.g. erythromycin, clarithromycin) may raise carbamazepine plasma levels. 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 macrolides.

Protease inhibitors may raise carbamazepine plasma levels. 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 protease inhibitors.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of protease inhibitors. The dosage of protease inhibitors may have to be adjusted to clinical requirement.

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.

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of acenocoumarol.

Acetazolamide may raise carbamazepine plasma levels. 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 acetazolamide.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of albendazole. The dosage of albendazole may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of alprazolam.

Aminophylline may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with aminophylline.

Carbamazepine may lower aminophylline concentration in blood serum.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of aprepitant. The dosage of aprepitant may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of aripiprazole. The dosage of aripiprazole may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of bromperidol. The dosage of bromperidol may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of buprenorphine. The dosage of buprenorphine may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of bupropion. The dosage of bupropion may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of ciclosporin. The dosage of ciclosporin may have to be adjusted to clinical requirement.

Cimetidine may raise carbamazepine plasma levels. 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 cimetidine.

Ciprofloxacin may raise carbamazepine plasma levels. 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 ψiprofloxacin.

Cisplatin may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with cisplatin.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of citalopram. The dosage of citalopram may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of clobazam. The dosage of clobazam may have to be adjusted to clinical requirement.

Although the data are partly contradictory, possibly also clonazepam may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with clonazepam.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of clonazepam. The dosage of clonazepam may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of clozapine. The dosage of clozapine may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of cyclophosphamide. The dosage of cyclophosphamide may have to be adjusted to clinical requirement.

Danazol may raise carbamazepine plasma levels. 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 danazol.

Dantrolene may raise carbamazepine plasma levels. 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 dantrolene.

Desipramine may raise carbamazepine plasma levels. 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 desipramine.

Dextropropoxyphene may raise carbamazepine plasma levels.

Dextropropoxyphene may raise carbamazepine plasma levels. 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 dextropropoxyphene.

Diltiazem may raise carbamazepine plasma levels. 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 diltiazem.

Doxorubicin may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with doxorubicin.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of doxycycline.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of ethosuximide. The dosage of ethosuximide may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of everolimus. The dosage of everolimus may have to be adjusted to clinical requirement.

Felbamate may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with felbamate.

Fluconazole may raise carbamazepine plasma levels. 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 fluconazole.

Fluoxetine may raise carbamazepine plasma levels. 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 fluoxetine.

Fluvoxamine may raise carbamazepine plasma levels. 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 fluvoxamine.

Fosphenytoin may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with fosphenytoin.

Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of haloperidol. Combined use of carbamazepine with haloperidol, may also result in an increase in neurological side-effects.

Ibuprofen may raise carbamazepine plasma levels. 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 ibuprofen.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of imatinib. The dosage of imatinib may have to be adjusted to clinical requirement.

Isoniazid may raise carbamazepine plasma levels. 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 isoniazid.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

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

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

Itraconazole may raise carbamazepine plasma levels. 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 itraconazole.

Alternative anti-convulsants may be recommended in patients treated with itraconazole.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of itraconazole. The dosage of itraconazole may have to be adjusted to clinical requirement.

Ketoconazole may raise carbamazepine plasma levels. 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 ketoconazole.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of lamotrigine. The dosage of lamotrigine may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of lapatinib. The dosage of lapatinib may have to be adjusted to clinical requirement.

Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of levothyroxine. The dosage of levothyroxine may have to be adjusted to clinical requirement.

The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range.

Loratadine may raise carbamazepine plasma levels. 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 loratadine.

Mefloquine may antagonise the anti-epileptic effect of carbamazepine. The dose of carbamazepine may have to be adjusted when used concomitantly with mefloquine.

Methsuximide may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with methsuximide.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of methadone. The dosage of methadone may have to be adjusted to clinical requirement.

Metronidazole may significantly increase serum carbamazepine concentrations. One case of carbamazepine toxicity has been reported.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of mianserin. The dosage of mianserin may have to be adjusted to clinical requirement.

Nefazodone may raise carbamazepine plasma levels. 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 nefazodone.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of nefazodone. The dosage of nefazodone may have to be adjusted to clinical requirement.

Nicotinamide may raise carbamazepine plasma levels. 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 nicotinamide.

Olanzapine may raise carbamazepine plasma levels. 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 olanzapine.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of olanzapine. The dosage of olanzapine may have to be adjusted to clinical requirement.

Omeprazole may raise carbamazepine plasma levels. 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 omeprazole.

Oxcarbazepine may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with oxcarbazepine.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of oxcarbazepine. The dosage of oxcarbazepine may have to be adjusted to clinical requirement.

Oxybutynin may raise carbamazepine plasma levels. 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 oxybutynin.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of paliperidone. The dosage of paliperidone may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of paracetamol. The dosage of paracetamol may have to be adjusted to clinical requirement. Long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity.

Paroxetine may raise carbamazepine plasma levels. 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 paroxetine.

Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.

Phenobarbital may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with phenobarbital.

Phenytoin may decrease carbamazepine plasma levels. 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.

Primidone 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 carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with primidone.

Primidone may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with primidone.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of primidone. The dosage of primidone may have to be adjusted to clinical requirement.

Quetiapine 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 carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with quetiapine.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of quetiapine. The dosage of quetiapine may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of rifabutin. The dosage of rifabutin may have to be adjusted to clinical requirement.

Rifampicin may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with rifampicin.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of risperidone. The dosage of risperidone may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of sertraline.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of sirolimus. The dosage of sirolimus may have to be adjusted to clinical requirement.

Valproic acid 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 carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with valproic acid.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of valproic acid.

Stiripentol may raise carbamazepine plasma levels. 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 stiripentol.

Carbamazepine may reduce blood serum levels of sunitinib.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of tacrolimus. The dosage of tacrolimus may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of tadalafil. The dosage of tadalafil may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of temsirolimus. The dosage of temsirolimus may have to be adjusted to clinical requirement.

Terbinafine may raise carbamazepine plasma levels. 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 terbinafine.

Theophylline may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with theophylline.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of theophylline. The dosage of theophylline may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of tiagabine. The dosage of tiagabine may have to be adjusted to clinical requirement.

A case has been reported in which elevated carbamazepine levels (approximately a 75% increase over 5 weeks) were reported when ticlopidine was added to the patients therapy. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia). The carbamazepine dosage may require reduction.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of topiramate.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of tramadol.

Trazodone may raise carbamazepine plasma levels. 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 trazodone.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of trazodone. The dosage of trazodone may have to be adjusted to clinical requirement.

Valpromide 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 carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with valpromide.

Verapamil may raise carbamazepine plasma levels. 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 verapamil.

Vigabatrin may raise carbamazepine plasma levels. 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 vigabatrin.

Voriconazole may raise carbamazepine plasma levels. 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 voriconazole.

Alternative anti-convulsants may be recommended in patients treated with voriconazole.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of voriconazole. The dosage of voriconazole may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of warfarin. The dosage of warfarin may have to be adjusted to clinical requirement.

Carbamazepine may lower the plasma level, diminish or even abolish the activity of zonisamide. The dosage of zonisamide may have to be adjusted to clinical requirement.

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.

Hyponatremia is known to occur with carbamazepine. In patients with pre-existing 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.

Progabide 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 carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with progabide.

Valnoctamide 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 carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with valnoctamide.

Viloxazine may raise carbamazepine plasma levels. 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 viloxazine.

Phensuximide may decrease carbamazepine plasma levels. The dose of carbamazepine may have to be adjusted when used concomitantly with phensuximide.

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 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 <400 mg 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 foetus.

Carbamazepine passes into the breast milk (about 25-60% of the plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring 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.

Fertility

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

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.

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, <1/10), uncommon (≥1/1.000, <1/100), rare (≥1/10.000, </1.000), very rare (<1/10.000), not known (cannot be estimated from the available data).

Infections and infestations

Not known**: reactivation of Human herpesvirus 6 infection

Blood and lymphatic system disorders

Very common: leukopenia

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, leukopenia, 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, hypogammaglobinaemia

Not known**: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

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: gynaecomastia, galactorrhoea

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: hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusional state

Very rare: 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 movementdisorder, 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

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: nausea, vomiting

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: bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol) leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms

Not know**: 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: gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant

Common: blood alkaline phosphatase increased

Uncommon: transaminases increased

Very rare: intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased. Thyroid function test abnormal: decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased

Not known**: bone density decreased.

* In some Asian countries also reported as rare.
** Additional adverse drug reactions from spontaneous reports (frequency not known).

The following adverse drug reactions have been derived from post-marketing experience with carbamazepine 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.

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.