Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Tegretol should be given only under medical supervision. Tegretol should be prescribed only after a critical benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic, or renal damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with Tegretol.

Haematological effects
Agranulocytosis and aplastic anaemia have been associated with Tegretol; however, due to the very low incidence of these conditions, meaningful risk estimates for Tegretol are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2.0 persons per million per year for aplastic anaemia.

Transient or persistent decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Tegretol. However, in the majority of cases these effects prove transient and are unlikely to signal the onset of either aplastic anaemia or agranulocytosis. Nonetheless, complete pretreatment blood counts, including platelets (and possibly reticulocytes and serum iron), should be obtained at baseline, and periodically thereafter.

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. Tegretol should be discontinued if any evidence of significant bone-marrow depression appears.

Patients should be made aware of early toxic signs and symptoms of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult the physician immediately.

Serious dermatologic reactions
Serious dermatologic reactions, including toxic epidermal necrolysis (TEN; also known as Lyell’s syndrome) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol.
Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with Tegretol. These reactions are estimated to occur in 1 to 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. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell’s syndrome/TEN) appear, Tegretol should be withdrawn at once and alternative therapy should be considered.

Pharmacogenomics
There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.


Association with HLA-A*3101
Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of hypersensitivity syndrome and cutaneous adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash (see Warnings and precautions: Hypersensitivity).
Retrospective genome-wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS, TEN, DRESS, AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLA-A*3101 allele in these patients.

The frequency of the HLA-A*3101 allele varies widely between ethnic populations and 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, with some exceptions within 5-12%. Prevalence above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10%-15% in other native ethnicities in these same regions.

The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that 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 nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.

Testing for the presence of HLA-A*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas, Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with Tegretol (see Information for Healthcare professionals in this section). The use of Tegretol should be avoided in patients who are found to be positive for HLA-A*3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current Tegretol users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.

Association with HLA-B*1502
Retrospective studies in patients of Han Chinese and Thai origin found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigene (HLA)-B*1502 allele. The frequency of HLA- B*1502 allele ranges from 2 to 12% in Han Chinese populations and is about 8% in Thai populations. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher frequency of the HLA-B*1502 allele in the population e.g. above 15% in the Philippines and some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in persons of European descent, several African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (< 1%).

The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that 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 nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.

Testing for the presence of HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Tegretol (see Information for Healthcare professionals in this section). The use of Tegretol should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. HLA-B*1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low. Screening is generally not recommended for any current Tegretol users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA-B*1502 status.

The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.

Limitation of genetic screening
Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B*1502 and treated with Tegretol will not develop SJS/TEN and patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A*3101 and treated with Tegretol will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA- A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.

Information for Healthcare professionals
If testing for the presence of the HLA-B*1502 allele is performed, high-resolution “HLA- B*1502 genotyping” is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected. Similarly if testing for the presence of the HLA-A*3101 allele is performed, high-resolution “HLA-A*3101 genotyping” respectively is recommended. The test is positive if either one or two HLA- A*3101 alleles are detected and negative if no HLA- A*3101 alleles are detected.

Other dermatologic reactions
Mild skin reactions, e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it 
may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.
The HLA-A*3101 allele has been found to be associated with less severe adverse cutaneous reactions from carbamazepine and may predict the risk of these reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption). However, The HLA-B*1502 allele has not been found to predict the risk of these aforementioned skin reactions.

Hypersensitivity

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been reported with Tegretol. If a patient develops these reactions after treatment with Tegretol, the drug must be discontinued, and an alternative treatment started.Tegretol may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia     and    Systemic     Symptoms      (DRESS),      a     delayed      multi-organ hypersensitivitydisorder 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), that may occur in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium and colon).(See Adverse drug reactions section).
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptin).

Cross-hypersensitivity can occur between carbamazepine and aromatic antiepileptic drugs (e.g.
phenytoin, primidone and phenobarbital).

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Tegretol should be withdrawn immediately.

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

Hepatic function
Baseline and periodic evaluations of hepatic function must be performed during treatment with Tegretol, particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or active liver disease.

Renal function
Baseline and periodic complete urinalysis and BUN determinations are recommended.


Hyponatremia
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.

Hypothyroidism
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.

Anticholinergic effects
Tegretol has shown mild anticholinergic activity. Patients with increased intraocular pressure and urinary retention should therefore be closely observed during therapy (see Adverse drug reactions).

Psychiatric effects
The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

Suicidal ideation and behaviour
An analysis of reports of suicidality (suicidal behaviour or ideation) from placebo-controlled clinical studies of eleven medicines used to treat epilepsy as well as psychiatric disorders, and other conditions revealed that paitens receiving anti-epileptic drugs had approximately twice the risk of suicidal behaviour or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behaviour and suicidal ideation was observed as early as one week after starting the anti-epileptic medicine and continued through 24 weeks. The results were generally consitent among the eleven medicines. Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. The relative risk for suicidality was higher in the paitents with epilepsy compared to patients who were given one of the medicines in the class for psychiatric or other conditions.
All patients who are currently taking or starting on any anti-epileptic drug should be closely monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.
Health Care Professionals should inform patients, their families, and caregivers of the potential for an increase in the risk of suicidality. Prescribers should advise paitents to seek medical advice immediately if they develop any symptoms suggestive of suicidality.


Pregnancy and females of reproductive potential
Carbamazepine may be associated with fetal harm when administered to a pregnant woman (see section 4.6 Fertility, pregnancy and lactation). Tegretol should be used during pregnancy only if the potential benefit justifies the potential risks, following careful consideration of alternative suitable treatment options.
The woman should be fully informed of and understand the risk of potential harm to the foetus if carbamazepine is taken during pregnancy and therefore the importance of planning any pregnancy. Adequate counselling should be made available to all pregnant women and women of childbearing potential, regarding the risks associated with pregnancy due to potential teratogenic risk to the foetus (see section 4.6 Fertility, pregnancy and lactation).
Women of childbearing potential should use effective contraception during treatment with carbamazepine and for 2 weeks after the last dose (see below sub-section “Endocrinological effects” and section 4.5 Interaction with other medicinal products and other forms of interaction and section 4.6 Fertility, pregnancy and lactation). Before the initiation of treatment with carbamazepine in a woman of childbearing potential, pregnancy testing should be considered.
If a woman is planning to become pregnant, all efforts should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to reassess carbamazepine treatment and consider alternative treatment options.

Endocrinological effects
Breakthrough bleeding has been reported in women taking Tegretol while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Tegretol and women of child-bearing potential should be advised to consider using alternative forms of birth control while taking Tegretol.

Monitoring of plasma levels
Although correlations between dosage and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations: dramatic increase in seizure frequency/verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see Interactions).

Dose reduction and withdrawal effects
Abrupt withdrawal of Tegretol may precipitate seizures, therefore carbamazepine should be withdrawn gradually over a 6-month period. If treatment with Tegretol has to be withdrawn abruptly in a patient with epilepsy, the switch to the new antiepileptic compound should be made under cover of a suitable drug.

Falls
Tegretol treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state, sedation (see section 7 Adverse drug reactions) 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.

Non-clinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.

Genotoxicity
Carbamazepine was not found to be genotoxic in various standard bacterial and mammalian mutagenicity studies.

Carcinogenicity
In rats treated with carbamazepine for 2 years, the incidence of tumors of the liver was found to be increased. The significance of these findings relative to the use of carbamazepine in humans is unknown at present.

Excipients with known effect

5 ml syrup contains 2 mg saccharin sodium, 875 mg liquid sorbitol, approximately 0.6 mg sodium and preservatives: Methylparaben 6 mg, Propylparaben 1.5mg, Sorbic acid 5 mg.

Sorbitol: This medicine contains 175mg sorbitol in each milliliter, which is equivalent to 175mg/ ml. Patients with hereditary fructose intolerance (HFI) should not take / be given this medicinal product. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

Propylene glycol: This medicine contains 125mg propylene glycol in each 5ml which is equivalent to 25mg per ml. The excipient propylene glycol (PG), is generally considered safe.
However, Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates. In the neonate, if high doses or prolonged administration are warranted, PG toxicity can occur. Effects such as lactic acidosis, central nervous system depression/toxicity, hyperosmolarity, haemolysis, cardiac arrhythmia and seizures have been observed.

Para hydroxybenzoates: This medicine contains methyl hydroxybenzoate and propyl hydroxybenzoate which may cause allergic reactions (possibly delayed).

This medicine contains less than 1mmol sodium (23mg) per ml, that is to say essentially ‘sodium free’.

Effects on Driving

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 have been reported with Tegretol, especially at the start of 
treatment or in connection with dose adjustments.Patients should therefore exercise due caution when driving a vehicle or operating machinery.