Novartis Pharmaceuticals UK Ltd

* In some Asian countries also reported as rare.  See also section 4.4 Special warnings and precautions for use.

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.

Some rewording of the text in following sections:

4.4; suicidal ideation new text:  ' has also show a small increase'  corrected to ' has also shown a small increase'.

4.5; Agents that may raise carbamazepine plasma levels: paroxetine was missing and now inserted.

4.8;* on SJS + Investigation - very rare: hypogammaglobulinaemia + * In some....sentence missing and now inserted

SECTION 4.2

The following paragraph has been added:

Before deciding to initiate treatment, patients of Han Chinese and Thai origin should whenever possible be screened for HLA-B*1502 as this allele strongly predicts the risk of severe carbamazepine-associated Stevens-Johnson syndrome (see section 4.4).

SECTION 4.3

The following has been deleted from the last paragraph in this section:

…..before administering Tegretol, MAOIs should be discontinued for a minimum of 2 weeks or longer if the clinical situation permits.

And has been replaced with:

…(see section 4.5 Interaction with other medicinal products and other forms of interaction). 
 
To read:

The use of Tegretol is not recommended in combination with monoamine oxidase inhibitors (MAOIs) (see section 4.5 Interaction with other medicinal products and other forms of interaction).

SECTION 4.4

Paragraph 8

The following has been added:

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications.  A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also show 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 behaviour emerge.

The following has been deleted:

Mild skin reactions e.g. isolated macular or maculopapular exanthemata, are mostly transient and not hazardous, and they usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage; however, the patient should be kept under close surveillance and a worsening rash or accompanying symptoms are an indication for the immediate withdrawal of Tegretol. 

Paragraph 10

The following has been added:

Serious dermatological reactions, including toxic epidermal necrolysis (TEN: also known as Lyell’s syndrome) and Stevens Johnson syndrome (SJS) have been reported very rarely 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. 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.

HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine.  Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine.  If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option.  Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still very rarely occur.

It is not definitely known whether all individuals of south east-Asian ancestry are at risk due to lack of data.

The allele HLA-B*1502 has been shown not to be associated to SJS in the Caucasian population.

Mild skin reactions e.g. isolated macular or maculopapular exanthema, can also occur and are mostly transient and not hazardous. They usually disappear within a few days or weeks, either during the continued course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with continued use.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).

SECTION 4.5

The following has been added:

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.

Section headed “Agents that may raise carbamazepine….”

The following has been deleted from the heading:

…and/or carbamazepine 10,11 epoxide…”

The following text has been deleted:

….quetiapine…. Quetiapine, primidone and valproic acid were reported to increase concentration of the active metabolite carbamazepine-10,11-epoxide.

…..and/or carbamazepine-10,11-epoxide…..

The following paragraph has been added:

Agents that 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 Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:

Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Section headed: “Agents that may decrease carbemazepine plasma levels”

The following has been deleted:

….valproic acid….

Section headed “Effect of Tegretol on plasma levels of concomitant agents”

The following has been deleted:

 ….nefazodone….

Section headed “Combinations that require specific consideration”

The following paragraph has been added:

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

SECTION 4.8

Skin and subcutaneous tissue disorders

In the following sentence:

Very rare cases of hirsutism have been reported, but the causal relationship is not clear.

The following has been deleted:

Very rare cases of…….have been reported, but the causal relationship is not clear.

SECTION 5.2

Biotransformation

The following has been added to the 2nd paragraph:

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide.

SECTION 9

Date of renewal updated to December 2008

SECTION 10

Date of partial revision of text updated to February 2009