Special Warning : אזהרת שימוש

4.4. Special warnings and precautions for use

Since carbamazepine can cause absences or potentiate existing absences, Timonil retard should not be used in patients suffering from absences or mixed seizures involving absences.
If an exacerbation of convulsions occurs, the treatment with carbamazepine should be discontinued.

Timonil retard may only be used after careful weighing up of the possible benefits against the potential risks, and with appropriate precautionary measures in: -     previous or existing haematological disorders, a history of haematological reactions to other medicinal products
-     abnormal sodium metabolism
-     severe heart disease, hepatic or renal dysfunction (see section 4.2 and 4.8) -     patients with myotonic dystrophy because cardiac conduction anomalies often occur in this patient group
-     concomittant treatment with stiripentol (used in the treatment of severe myoclonic epilepsy in infancy [SMEI]), see section 4.5

Warnings and other precautions
Timonil retard may only be used for children under 6 years of age after a careful risk/benefit analysis. Please note the warnings in the dosage scheme of this Information for Healthcare Professionals.

Haematological disorders
Agranulocytosis and aplastic anaemia are known to be associated with carbamazepine.
However, due to the low frequency it is difficult to evaluate the risk. The probability of occurrence of agranulocytosis is 4.7 cases/million/year and of aplastic anaemia 2.0 cases/million/year within the untreated population.
Under carbamazepine use a temporary or permanent reduction of platelet or white blood cell counts occurs very commonly. In most cases this is only temporary and does not necessarily prognose the beginning of an agranulocytosis or aplastic anaemia. It is recommended to have the blood count (including thrombocytes, reticulocytes and serum iron) checked before beginning treatment with carbamazepine, and then at weekly intervals in the first month of treatment, and subsequently in monthly intervals. After completion of 6 months treatment, 2- 4 controls per year are adequate.
Patients should be made aware of early signs of potential haematological disorders, and of symptoms of dermatological and hepatic reactions. If fever, sore throat, allergic skin reactions such as rashes with lymph node swelling and/or influenza-like symptoms, mouth ulceration, tendency for haematoma, petechiae or purpura occur during treatment with Timonil retard, the patient should be instructed to consult his/her doctor immediately and have the blood count checked. In the case of severe allergic reactions, Timonil retard must be discontinued immediately.

In certain blood picture changes (especially leukocytopenia and thrombocytopenia) it may be necessary to discontinue Timonil retard; this is always the case if complaints such as allergic symptoms, fever, sore throat or skin haemorrhage occur at the same time.

1.    Urgent checks required (within 1 week) if one of the following occurs: -     pyrexia, infection
-     skin rash
-     general asthenia
-     oropharyngeal pain, mouth ulceration
-     increased tendency to bruise
-     rise in transaminases
-     fall in leucocytes below 3,000/µl or in granulocytes to under 1,500/µl -     fall in platelets below 125,000/µl
-     decrease in reticulocytes to under 0.3% = 20,000/µl
-     increase in serum iron to more than 150 µg/dl

2.    Withdrawal of carbamazepine is necessary if one of the following occurs:
-     petechial or purpural bleeding
-     fall in red blood cells below 4 million/µl
-     reduction of haematocrit below 32%
-     fall in haemoglobin to under 11 g/dl
-     fall in leucocytes to under 2,000/µl or of granulocytes to under 1,000/µl or of platelets to under 80,000/µl
-     or symptomatic blood count abnormalities

Liver function
It is recommended that liver function tests be carried out before beginning treatment with Timonil retard, and then at weekly intervals in the first month of treatment, and subsequently at monthly intervals. This especially applies for patients with known liver disorder and elderly patients. After completion of 6 months treatment, 2-4 controls per year are adequate.
The patient is to be instructed to consult his/her doctor straight away if symptoms of hepatitis such as fatigue, decreased appetite, nausea, yellow skin or hepatomegaly occur.
If a liver disorder deteriorates, or a florid liver disorder occurs, treatment with carbamazepine should be discontinued immediately.

Renal function
It is recommended to test the urinary status and the urea nitrogen before and routinely during the treatment with carbamazepine.

Caution should be taking with patients that have problems in the kidnies relate to low level of sodium in the blood, or patients who being treated with diuretics e.g. Hydrochlorothiazide, Furosemide which decrease the sodium levels in the blood.

Hypersensitivity reactions
Carbamazepine can trigger hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), delayed, multi-organ hypersensitivity reactions with fever, skin rash, vasculitis, lymph node swelling, arthralgia, leukopenia, eosinophilia, hepatomegaly and splenomegaly, altered liver function tests and vanishing bile duct syndrome (destruction and loss of intrahepatic bile ducts), which may occur in various combinations. Other organs may also be affected (e.g. lung, kidney, pancreas, heart muscle, colon) (see section 4.8).


In patients with hypersensitivity to oxcarbazepine, phenytoin, phenobarbital or lamotrigine, Timonil retard should only be administered after careful evaluation of the possible risks and expected benefits, since these patients have an increased risk of developing hypersensitivity to carbamazepine as well.
Twenty-five to thirty percent of patients who had hypersensitivity reactions to carbamazepine exhibit cross-reactions with oxarbazepine. The risk of cross-reactions between carbamazepine and phenobarbital or phenytoin is about 75 %. If signs or symptoms of a hypersensitivity reaction occur, carbamazepine should be discontinued immediately.

General anaesthesia
If the patient needs to go through surgical procedure which involves general anaesthesia, the anesthesiologist should be informed about the treatment with Timonil.

Hyponatraemia
Hyponatraemia is known to occur in patients taking carbamazepine. In patients with pre- existing renal disorders associated with low serum sodium concentration, or in patients treated concomitantly with medicines that lower sodium concentrations (e.g. diuretics, medicinal products associated with inadequate ADH secretion), the serum sodium concentration should be determined prior to treatment. Thereafter, serum sodium concentrations should initially be determined after about two weeks and then during the first three months of treatment at monthly intervals or according to clinical need. The above- mentioned risk factors occur particularly in elderly patients. If hyponatraemia is detected, fluid restriction is an important countermeasure, if clinically indicated.

Hypothyroidism
Carbamazepine can reduce serum concentrations of thyroid hormones through enzyme induction, thus necessitating an increase in the dose of thyroid hormone replacement therapy in patients with hypothyroidism. Therefore, monitoring of thyroid function is recommended, in order to adjust the dosage of thyroid hormone replacement therapy.

Anticholinergic effects
Carbamazepine has weak anticholinergic activity. Patients with glaucoma and urinary retention should therefore be carefully monitored during treatment (see section 4.8 Undesirable effects).
Caution should be taking with patients that have no ability to retain the urine.

Transfer of patients to another therapy
An abrupt withdrawal of carbamazepine treatment may lead to convulsions. Carbamazepine should therefore be withdrawn gradually over a period of 6 months. If it is necessary to transfer patients with epilepsy from Timonil retard to another form of therapy, the switch to treatment with another antiepileptic must not be abrupt, but gradual.
If an abrupt switch from carbamazepine to another antiepileptic agent is required in patients with epilepsy, this should take place under the safeguard of a suitable antiepileptic.

Alcohol withdrawal syndrome
Warning: Timonil retard may only be used under inpatient conditions for the indication “Prevention of seizures in alcohol withdrawal syndrome”.

It should be noted that the adverse reactions to carbamazepine in the treatment of alcohol withdrawal syndrome are themselves similar to, and can be confused with, the withdrawal symptoms.

Coadministration of lithium
In order to prevent undesirable interactions (see "Interaction with other medicinal products and other forms of interaction") when, in exceptional cases, Timonil retard is to be given together with lithium because lithium alone is inadequate for the prophylaxis of manic- depressive phases, it must be ensured that a specific carbamazepine plasma concentration 
(8 µg/mL) is not exceeded, that the lithium level is kept in the lower therapeutic range (0.3 to 0.8 mval/L) and that any treatment with neuroleptics has been discontinued at least 8 weeks previously and not given simultaneously.

Photosensitivity reaction
Due to the possibility of photosensitisation, patients should protect themselves from strong sunlight during treatment with carbamazepine.

Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised, placebo-controlled studies of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour.
The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for carbamazepine.

Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.

Hormonal contraceptives
Breakthrough bleeding has been reported in patients treated with carbamazepine who concomitantly use hormonal contraceptives (“the Pill”). The reliability of hormonal contraception with oestrogen and/or progesterone derivatives may be adversely affected or even abolished due to the enzyme-inducing properties of carbamazepine. Therefore, other non-hormonal methods of contraception are recommended for women of childbearing potential (see section 4.6).

Monitoring of plasma level
Although the correlation between carbamazepine dosage and plasma level and the correlation between plasma level and clinical efficacy or drug tolerability is extremely doubtful, monitoring of plasma level may be beneficial in the following cases: noticeable increase in frequency of convulsions, monitoring of patient compliance, during pregnancy, during treatment of children and adolescent, if malabsorption or if toxic effects are suspected in the presence of concomitant medication (see 4.5 Interaction with other medicinal products and other forms of interaction).

Cutaneous reactions
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of carbamazepine. Patients should be advised of the signs and symptoms and monitored closely for skin reactions.
The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, carbamazepine treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
If the patient has developed SJS or TEN with the use of carbamazepine, carbamazepine must not be re-started in this patient at any time.

Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) 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-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 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.

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 severe cutaneous reactions known as 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 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%).

Other dermatologic reactions
Mild skin reactions, e.g. isolated macular and maculopapular exanthema may occur. Usually, these are temporary and not serious, and they disappear within a few days or weeks, either without changes in therapy or after reducing the dosage. Since it may be difficult to distinguish the first symptoms of a serious dermatological reaction from those of mild and temporary reactions, the patient should be monitored in short time intervals. Treatment with carbamazepine should be discontinued immediately, if reactions exacerbate with continuing therapy.

Investigations
On the basis of the above-mentioned possible adverse reactions and hypersensitivity reactions, it is essential, especially for long term therapy, to carry out regularblood counts and tests of liver and kidney function. Carbamazepine levels and, in the case of combination therapy, also plasma concentrations of the other antiepileptics should be routinely monitored and daily doses reduced if necessary.

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