Adverse reactions : תופעות לוואי

4.8   Undesirable effects

The undesirable effects for epilepsy and bipolar disorder indications are based on available data from controlled clinical studies and other clinical experience and are listed in the table below. Frequency categories are derived from controlled clinical studies (epilepsy monotherapy (identified by†) and bipolar disorder (identified by §)). Where frequency categories differ between clinical trial data from epilepsy and bipolar disorder the most conservative frequency is shown. However, where no controlled clinical trial data are available, frequency categories have been obtained from other clinical experience.

The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1 000 to <1/100); rare (>1/10 000 to <1/1 000); very rare (<1/10 000), not known (cannot be estimated from the available data).



System Organ Class      Adverse Event                                            Frequency Blood and lymphatic     Haematological abnormalities1 including neutropenia, system disorders        leucopenia, anaemia, thrombocytopenia, pancytopenia,     Very rare aplastic anaemia, agranulocytosis

Haemophagocytic lymphohistiocytosis (see section 4.4)    Very rare

Lymphadenopathy1, Pseudolymphoma
Not known
Immune System           Hypersensitivity syndrome2                               Very rare Disorders
Hypogammaglobulinaemia                                   Unknown
Psychiatric Disorders   Aggression, irritability                                 Common 
Confusion, hallucinations, tics (motor and/or phonic     Very rare tics)

Nightmares                                               Not known
Nervous System          Headache†§                                               Very common Disorders
Somnolence†§, dizziness†§, tremor†, insomnia†            Common agitation§

Ataxia†                                                  Uncommon

Nystagmus†, aseptic meningitis (see section 4.4)         Rare
Unsteadiness, movement disorders, worsening of           Very rare
Parkinson's disease 3, extrapyramidal effects,
choreoathetosis†, increase in seizure frequency


Eye disorders           Diplopia†, blurred vision†                               Uncommon 
Conjunctivitis                                           Rare
Gastrointestinal        Nausea†, vomiting†, diarrhoea†, dry mouth§               Common disorders
Hepatobiliary           Hepatic failure, hepatic dysfunction4, increased liver   Very rare disorders               function tests
Skin and                Skin rash5†§                                             Very common subcutaneous tissue disorders               Alopecia, photosensitivity reaction                      Uncommon 
Erythema multiforme, Stevens–Johnson Syndrome §          Rare

Toxic epidermal necrolysis                               Very rare
Drug Reaction with Eosinophilia and Systemic2            Very rare
Symptoms


Musculoskeletal and     Arthralgia§                                              Common connective tissue disorders               Lupus-like reactions                                     Very rare 
Renal and urinary        Tubulointerstitial nephritis, tubulointerstitial nephritis   Not known disorders                and uveitis syndrome
General disorders and Tiredness†, pain§, back pain§                                   Common administration site conditions
Description of selected adverse reactions
1
Haematological abnormalities and lymphadenopathy may or may not be associated with the Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / hypersensitivity syndrome (see Special warnings and precautions for use and Immune system disorders).
2
Rash has also been reported as part of this syndrome, also known as DRESS. This condition is associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, and abnormalities of the blood, liver and kidney. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present, the patient should be evaluated immediately and Lamictal discontinued if an alternative aetiology cannot be established (see section 4.4).


3
These effects have been reported during other clinical experience. There have been reports that lamotrigine may worsen parkinsonian symptoms in patients with pre-existing Parkinson’s disease, and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.
4
Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.
5
In clinical trials in adults, skin rashes occurred in up to 8-12% of patients taking lamotrigine and in 5-6% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lamictal (see section 4.4).

Serious potentially life-threatening skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell’s Syndrome) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Although the majority recover on withdrawal of lamotrigine treatment, some patients experience irreversible scarring and there have been rare cases of associated death (see section 4.4).

The overall risk of rash, appears to be strongly associated with:

-   high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2)
-   concomitant use of valproate (see section 4.2).


There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with lamotrigine. The mechanism by which lamotrigine affects bone metabolism has not been identified.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il
Additionally, you should also report to GSK Israel (il.safety@gsk.com).