LAMOTRIGINE MILPHARM

Posology Lamotrigine tablets should be swallowed whole. If the tablets require halving ( to facilitate ease of swallowing), the halves should also be swallowed whole and not be chewed or crushed Use a tablet cutter to halve tablets.

Alternatively, keeping the score-line side facing upwards, hold both the upper and lower sides of the tablet, on either side of the score-line, using the thumb and index finger of both hands (Fig. A) and halve the tablet by pressing down and away from the score-line so that the tablet opens at the score-line side.

Do not hold on to the shoulder (end) of the tablet, on either side of the score-line (Fig. B), when halving since this may cause the tablet to crumble. 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.

For doses not realisable/practicable with this medicinal product, other strengths of this medicinal product or other pharmaceutical forms and products are available. 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 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).

Table 1:

Adults and adolescents aged 13 years and above - recommended treatment regimen in epilepsy Treatment regimen Weeks 1+2 Weeks 3+4 Usual maintenance dose Monotherapy: 25 mg/day (once a day) 50 mg/day (once a day) 100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50-100 mg every one to two weeks until optimal response is achieved.

500 mg/day has been required by some patients to achieve desired response. 5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used. 6 mg/kg/day every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200mg/day.

6 mg/kg/day […]

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 utilized 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).

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 Erythema multiforme, Stevens–Johnson Syndrome § Rare Toxic epidermal necrolysis Very rare Skin and subcutaneous tissue disorders Drug Reaction with Very rare Eosinophilia and Systemic2 Symptoms Arthralgia§ CommonMusculoskeletal and connective tissue disorders Lupus-like reactions Very rare Renal and urinary disorders Tubulointerstitial nephritis, tubulointerstitial nephritis and uveitissyndrome 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, 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.

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 longterm 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.

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Skin rash There have been reports of adverse skin reactions, which have generally occurred within the first eight 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) 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. 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 in children is higher than in adults.

Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in children is from 1 in 300 to 1 in 100. 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). Caution is also required when treating patients with a history of allergy or rash to other AEDs 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 related to lamotrigine treatment. It is recommended that lamotrigine 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.

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 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. 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 (400 mg or more), upon dose escalation or rapid uptitration.

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). 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 of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including lamotrigine. Therefore patients receiving lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.

Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a […]

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