Tegretol Special Precautions

General: Tegretol should only be used under medical supervision.
Tegretol should be prescribed only after critical risk-benefit assessment and under close monitoring in the following situations: Prior or existing haematological disease, history of haematological adverse reactions to other drugs; Impaired sodium metabolism; Patients with current or previous heart, liver or kidney disease (see Adverse Reactions), after interruptions of treatment with Tegretol, or patients who have previously discontinued treatment with carbamazepine.
Haematological events: Agranulocytosis and aplastic anaemia have been associated with Tegretol but their very low frequency makes it difficult to derive a meaningful risk estimate. There are estimates that the incidence is not much higher with Tegretol than that calculated for the untreated general population, in which the probability of occurrence is 4.7 cases per million per year for agranulocytosis and 2.0 cases per million per year for aplastic anaemia.
Slightly decreased platelet or white blood cell counts are uncommon to common in association with Tegretol treatment. However, in the majority of cases they are transient and are unlikely to signal the onset of aplastic anaemia or agranulocytosis.
Nonetheless, complete blood counts, including platelets, reticulocytes and serum iron, should be determined at baseline and at regular intervals thereafter.
If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count must be closely monitored. Tegretol should be discontinued if there is any evidence of significant bone-marrow depression.
Patients should be informed about the signs of incipient intoxication and the symptoms of possible haematological complications, as well as about the symptoms of cutaneous or hepatic hypersensitivity reactions. They should be instructed to consult their doctor immediately in the event of reactions such as fever, sore throat, perineal infection, exanthema, mouth ulcers, easy bruising, petechiae or idiopathic thrombocytopenic purpura.
Serious dermatological reactions: There have been rare reports of severe dermatological reactions, including toxic epidermal necrolysis (TEN, or Lyell syndrome) and Stevens-Johnson syndrome (SJS) following administration of Tegretol. The patients concerned may require hospitalization, as these conditions may be life-threatening or fatal. Most cases of SJS/TEN were reported in the first few months of treatment with Tegretol. These dermatological reactions are estimated to occur in 1 to 6 per 10,000 new patients in countries with mainly Caucasian populations. In some Asian countries, however, the risk is estimated to be around ten times greater.
Tegretol must be withdrawn at once, and an alternative therapy must be considered, as soon as signs or symptoms of severe skin reactions are ascertained.
There is growing evidence that, in predisposed patients, different HLA alleles play a role in connection with immune-mediated adverse reactions.
Association with HLA-A*3101 allele: The human leukocyte antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous adverse reactions such as SJS/TEN, drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and maculopapular rash.
Retrospective genetic studies in the Japanese and Northern European populations showed an association between severe skin reactions (SJS/TEN, DRESS, AGEP) and maculopapular rashes associated with carbamazepine use and the presence of the HLA-A*3101 allele.
The frequency of this allele varies widely in different ethnic populations. Its frequency is about 2 to 5% in European populations and about 10% in the Japanese population. The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations. For Western European populations the frequency of the HLA-A*3101 allele is estimated at up to approximately 6.7%, depending on geographic region. There are some exceptions with a frequency of 5-12%. Frequencies are estimated to be above 15% in the following ethnic groups: South America (Argentina and Brazil), North America (US Navajo and Sioux, and Seri Indians in Sonora, Mexico) and Southern India (Tamil Nadu).
The allele frequencies listed here represent the percentage of chromosomes in the specified populations that carry the allele concerned. The percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e. the "carrier frequency") is thus nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Before initiating treatment with Tegretol it is recommended that patients at risk because of their ancestry (e.g. patients from Japan, Caucasians and the indigenous population of America, patients of Spanish or Portuguese descent, and patients of South Indian or Arab descent) be tested for the presence of the HLA-A*3101 allele (see Dosage & Administration). Tegretol should not be used in patients who test positive unless the benefits clearly outweigh the risks. Screening for HLA-A*3101 is generally not recommended for patients who have already used Tegretol for a prolonged period, as SJS/TEN, AGEP, DRESS and maculopapular rash usually occur only during the first few months of therapy.
Association with HLA-B*1502 allele: Retrospective studies in patients of Han Chinese and Thai ancestry found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the human leukocyte antigen (HLA)-B*1502 allele. The frequency of this allele ranges from 2 to 12% in Han Chinese populations and is about 8% in Thailand. Higher rates of SJS ("uncommon" rather than "rare") are reported in Asian countries (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher frequency of the HLA-B*1502 allele. The frequency of carriers of this allele is over 15% in the Philippines and in some Malay populations. Allele frequencies of up to 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in the Caucasian population, Africans, indigenous peoples of the Americas, Japanese, and Hispanic populations (< 1%).
The allele frequencies listed here represent the percentage of chromosomes in the specified populations that carry the allele concerned. The percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e. the "carrier frequency") is thus nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Patients at risk because of their ancestry should be tested before initiating treatment with Tegretol to determine if they are carriers of the HLA-B*1502 allele. Tegretol should not be used in patients who test positive unless the benefits clearly outweigh the risks. When assessing risk, it should be considered that HLA-B*1502 is also a risk factor for other antiepileptic drugs. Screening for HLA-B*1502 is not required in populations with a low allele frequency. Similarly, screening is not appropriate in patients who have already used Tegretol for prolonged periods, as SJS/TEN usually occurs only during the first few months of therapy.
The identification of carriers of the HLA-B*1502 allele, and thus avoidance of carbamazepine therapy in such patients of Han Chinese descent, led to a decrease in the incidence of carbamazepine-induced SJS/TEN.
Genetic screening cannot substitute for close patient monitoring because many patients who are carriers of HLA-B*1502 do not develop SJS/TEN, while other patients not at genetic risk may develop SJS/TEN anyway. The situation is similar for carriers of the HLA-A*3101 allele who are treated with Tegretol. These patients do not necessarily develop SJS/TEN, DRESS, AGEP or maculopapular rash. However, patients who are not carriers of HLA-A*3101 may nevertheless develop serious adverse skin reactions. No studies have thus far been made of the extent to which other factors (such as dose, compliance, comedication and comorbidity) promote the development of such serious adverse skin reactions.
Other skin reactions: Mild cutaneous reactions, such as isolated macular or maculopapular eruptions, are frequently transient and not dangerous. They usually resolve within a few days or weeks, either despite continued treatment or following dose reduction. However, since it is difficult to differentiate the signs of mild and transient dermatological reactions from the early signs of severe dermatological reactions, close monitoring is required, and the product should be withdrawn immediately if the patient's condition worsens or if there are any signs of a systemic hypersensitivity reaction.
The HLA-B*1502 allele has no effect on the risk of mild dermatological reactions to carbamazepine.
An association has been shown between the presence of the HLA-A*3101 allele and mild adverse reactions associated with carbamazepine use. The HLA-A*3101 allele is thus a risk factor for developing severe hypersensitivity syndrome or mild maculopapular rash during carbamazepine treatment.
Hypersensitivity reactions: Tegretol may trigger hypersensitivity reactions that can occur in various combinations, including drug rash with eosinophilia and systemic symptoms (DRESS), a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts). Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon) (see Adverse Reactions).
Approximately 25-30% of patients with a hypersensitivity reaction to carbamazepine show a cross-reaction with oxcarbazepine (Trileptal). A cross-reaction may also occur between carbamazepine and aromatic antiepileptic drugs (e.g. phenytoin, primidone and phenobarbital).
Tegretol should be withdrawn at once if there are signs or symptoms suggestive of a hypersensitivity reaction.
Epileptic seizures: As carbamazepine may cause or exacerbate absences, Tegretol should not be used in patients with absences or mixed seizures, which include typical and atypical absences. In all these conditions, Tegretol may exacerbate seizures. If this happens, Tegretol must be discontinued.
Hepatic function: Baseline and periodic evaluations of hepatic function must be performed before and during Tegretol therapy, particularly in patients with a history of liver disease and in elderly patients. Tegretol should be discontinued immediately if hepatic function deteriorates or active hepatitis develops.
Renal function: Baseline and periodic complete urinalysis and BUN determinations are recommended.
Hyponatremia: Hyponatremia can occur with carbamazepine treatment. 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 two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors (use of diuretics, drug-related hyponatraemia, or patients with concussion, pre-existing low sodium values) must especially be taken into account for elderly patients. If hyponatraemia is observed, water restriction is an important countermeasure if clinically indicated.
Hypothyroidism: Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction. This may make it necessary to increase the dose of thyroid replacement therapy in patients with hypothyroidism. Thyroid function monitoring is therefore recommended in order to determine the dosage of thyroid replacement therapy.
Anticholinergic effects: Tegretol shows slight anticholinergic activity and patients with increased intraocular pressure (glaucoma) and urinary retention should therefore be closely monitored during therapy (see Adverse Reactions).
Psychiatric reactions: The possibility of activation of latent psychosis and, particularly in elderly patients, of confusion and agitation should be borne in mind.
Suicidal ideation and suicidal behaviour: Suicidal ideation and suicidal behaviour have been reported in patients treated with antiepileptic agents in a wide variety of indications. A meta-analysis of placebo-controlled studies has shown a slightly increased risk in this respect. The underlying mechanism is not known.
Patients should therefore be monitored for suicidal ideation and behaviour, and appropriate treatment should be initiated if necessary. Patients and/or their caregivers should be told that they should seek medical advice in such situations.
Pregnancy and women of childbearing potential: Congenital malformations may occur if carbamazepine is used during pregnancy. For the treatment of epilepsy during pregnancy Tegretol should therefore only be taken if the potential benefit justifies the potential risks. Carbamazepine should not be used for psychiatric indications and neuropathic pain and patients should instead be switched to more suitable alternative treatments.
Pregnant women and women of childbearing potential should be adequately advised on pregnancy risks due to the potential teratogenic risk for unborn infants.
Women of childbearing potential should use reliable contraception during treatment with carbamazepine and for 2 weeks after the last dose.
Hormonal contraceptives: Breakthrough bleeding has been reported in women taking oral contraceptives. The efficacy of oral contraceptives may be adversely affected by Tegretol. Women of childbearing potential should therefore be advised to use alternative, non-hormonal methods of contraception during Tegretol therapy.
Endocrinological effects: There have been isolated reports of impaired male fertility and/or abnormal spermatogenesis; a causal relationship has not been established.
Interactions: Due to enzyme induction, Tegretol may abolish the therapeutic effect of drugs containing oestrogens and/or progesterones (e.g. failure of contraception).
Coadministration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine may increase carbamazepine or carbamazepine-10,11 epoxide plasma concentrations, which may induce adverse effects. The dosage of Tegretol should, therefore, be adjusted accordingly, and plasma levels monitored.
Coadministration of CYP3A4 inducers may increase Tegretol metabolism, thereby decreasing carbamazepine serum levels and potentially reducing the therapeutic effect. Discontinuation of a CYP3A4 inducer may reduce carbamazepine metabolism, thereby increasing carbamazepine serum levels. The dosage of Tegretol may therefore have to be adjusted.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzymes in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 (see Interactions).
Concomitant use of carbamazepine with direct-acting oral anticoagulants (rivaroxaban, dabigatran, apixaban, edoxaban) may lead to reduced plasma concentrations of direct-acting oral anticoagulants and thus increase the risk of thrombosis. Therefore, if concomitant use is necessary, close monitoring for possible signs and symptoms of thrombosis is recommended.
Monitoring of plasma levels: Although correlations between dosage and plasma concentrations of carbamazepine, and between plasma concentrations and clinical efficacy or tolerability, are rather tenuous, monitoring of plasma concentrations may be useful in the following circumstances: conspicuous increase in seizure frequency; verification of patient compliance; during pregnancy; in the treatment of children or adolescents; if an absorption disorder is suspected; if toxic effects are suspected in patients concomitantly using several medicinal products (see Interactions).
Change of treatment: Abrupt withdrawal of Tegretol may lead to seizures, therefore carbamazepine should be withdrawn gradually over a 6-month period. Epilepsy patients who have to switch from Tegretol therapy must not change abruptly, but transfer to treatment with another antiepileptic while tapering off Tegretol.
If Tegretol therapy has to be withdrawn abruptly in epilepsy patients, the switch to an alternative antiepileptic should be made under cover of a suitable drug (e.g. diazepam i.v. or rectal, phenytoin i.v.).
Falls: Tegretol treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state or sedation (see Adverse Reactions) which may lead to falls and consequently to fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete risk assessment for falls should be regularly considered during long-term Tegretol treatment.
Others: Tegretol oral suspension contains parahydroxybenzoates, which may cause allergic reactions (possibly delayed). It also contains sorbitol and therefore should not be administered to patients with rare hereditary problems of fructose intolerance.
During treatment with carbamazepine, patients should protect themselves from intense sunlight due to the risk of photosensitization.
Effects on ability to drive and use machines: The patient's reactions may be impaired by seizures caused by the medical condition, and by Tegretol-induced adverse effects including dizziness, drowsiness, ataxia, diplopia, impaired accommodation and blurred vision, especially at the start of treatment or following dose adjustment. Patients should therefore exercise due caution when driving or when using machines.