LAMOTRIGINE BRISTOL LABS

Posology Lamotrigine tablets should be swallowed whole, and should not be chewed or crushed. If the calculated dose of lamotrigine (for example for treatment of children with epilepsy or patients with hepatic impairment) does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. 2), lamotrigine should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamotrigine Tablets not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk. Epilepsy The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) and for children and adolescents aged 2 to 12 years (Table 2) are given below.

4). 5). 5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used. 6 mg/kg every one to […]

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 (≥1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

System Organ Class Adverse Event Frequency Haematological abnormalities1 including neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis, Haemophagocytic lymphohistiocytosis (HLH) Very rareBlood and lymphatic system disorders Lymphadenopathy1 , Pseudolymphoma Not known Hypersensitivity syndrome2 (including such symptoms as, fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver, disseminated intravascular coagulation, multi organ failure).

4) Rare Nervous System Disorders Unsteadiness, movement disorders, worsening of Parkinson's disease 3, extrapyramidal effects, choreoathetosis†, increase in seizure frequency Very Rare Diplopia†, blurred vision† UncommonEye disorders Conjunctivitis Rare Gastrointestinal disorders Nausea†, vomiting†, diarrhoea†, dry mouth§ Common Hepatobiliary disorders Hepatic failure, hepatic dysfunction4, increased liver function tests Very rare Skin rash5†§ Very common Alopecia, photosensitivity reaction Uncommon Stevens–Johnson Syndrome§ Rare Toxic epidermal necrolysis Very rare Skin and subcutaneous tissue disorders Drug Reaction with Eosinophilia and Systemic Symptoms Very rare Arthralgia§ CommonMusculoskeletal and connective tissue disorders Lupus-like reactions Very rare Renal and urinary disorders Tubulointerstitial nephritis, Tubulointerstitial nephritis and uveitis syndrome Not known General disorders and administration site conditions Tiredness†, pain§, back pain§ Common 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 and 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 Lamotrigine discontinued if an alternative aetiology cannot be established. 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. 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.

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Skin rash:

There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self limiting; however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported.

8). In adults enrolled in studies utilizing the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately half of these cases have been reported as Stevens–Johnson syndrome (1 in 1000).

In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000. The risk of serious skin rashes is higher in children than in adults. 8). In children, the initial presentation of a rash can be mistaken for an infection; physicians should consider the possibility of a reaction to lamotrigine treatment in children that develop symptoms of rash and fever during the first eight weeks of therapy.

2). 2). Caution is also required when treating patients with a history of allergy or rash to other antiepileptic drugs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.

HLA-B*1502 allele in individuals of Asian (primarily Han Chinese and Thai) origin has been shown to be associated with the risk of developing SJS/TEN when treated with lamotrigine. If these patients are known to be positive for HLA-B*1502, use of lamotrigine should be carefully considered.

All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related to lamotrigine treatment. It is recommended that lamotrigine should not be restarted in patients who have discontinued due to rash associated with their prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

If the patient has developed SJS, TEN or DRESS with the use of lamotrigine, treatment with lamotrigine must not be re-started in this patient at any time. Rash has also been reported as part of DRESS; also known as hypersensitivity syndrome.

8). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multiorgan failure. , 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 Lamotrigine discontinued if an alternative aetiology cannot be established.

Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

8). In several cases, the reaction occurred with a high dose (400mg or more), upon dose escalation or rapid up-titration. If lamotrigine-associated photosensitivity is suspected in a patient showing signs of photosensitivity (such as an exaggerated sunburn), treatment discontinuation should be considered.

g. use of protective clothing and sunscreens). 8). HLH is characterised by signs and symptoms, like fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, high serum ferritin, hypertriglyceridaemia and abnormalities of liver function and coagulation.

Symptoms occur generally within 4 weeks of treatment initiation, HLH can be life threatening. Patients should be informed of the symptoms associated with HLH and should be advised to seek medical attention immediately if they experience these symptoms while on lamotrigine therapy.

Immediately evaluate patients who develop these signs and symptoms and consider a diagnosis of HLH. Lamotrigine should be promptly discontinued unless an alternative aetiology can be established.

Clinical worsening and suicide risk:

Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs 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 lamotrigine. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered.

Patients (and caregivers […]

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