Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Generics [UK] Limited t/a Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
These have included potentially life-threatening rashes such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome (HSS) (see section 4.8).
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.
If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, lamotrigine 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 lamotrigine, lamotrigine must not be re-started in this patient at any time.
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 epileptic 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.
Additionally the overall risk of rash appears to be strongly associated with:
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.
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 a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema abnormalities of the blood and liver and aseptic meningitis (see section 4.8). 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 dispersible tablets 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.
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 dispersible tablets. Therefore patients receiving lamotrigine dispersible tablets 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 significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two fold resulting in decreased lamotrigine levels (see section 4.5). A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose related adverse events. Patients should be monitored with respect to this.
In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example “pill free week”), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment (see section 4.2). Variations in lamotrigine levels of this order may be associated with adverse effects. Therefore, consideration should be given to using contraception without a pill free week, as first line therapy (for example, continuous hormonal contraceptives or non-hormonal methods).
The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see section 4.5). The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.
Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase, hence there is a possibility of interference with folate metabolism during long term therapy (see section 4.6). However, during prolonged human dosing, lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.
In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.
Lamotrigine dispersible tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.
As with other AEDs, abrupt withdrawal of lamotrigine dispersible tablets may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of lamotrigine dispersible tablets should be gradually decreased over a period of two weeks.
There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of lamotrigine.
A clinically significant worsening of seizure frequency instead of an improvement may be observed. In patients with more than one seizure type, the observed benefit of control for one seizure type should be weighed against any observed worsening in another seizure type.
Myoclonic seizures may be worsened by lamotrigine.
There is a suggestion in the data that responses in combination with enzyme inducers is less than in combination with non-enzyme inducing antiepileptic agents. The reason is unclear.
In children taking lamotrigine for the treatment of typical absence seizures, efficacy may not be maintained in all patients.
Arrhythmogenic ST-T abnormality and typical Brugada ECG pattern has been reported in patients treated with lamotrigine. The use of lamotrigine should be carefully considered in patients with Brugada syndrome.
HLH has been reported in patients taking lamotrigine (see section 4.8). 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.
Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders.
Lamotrigine dispersible tablets contain sulphite ammonia caramel (E150d). May rarely cause severe hypersensitivity reactions and bronchospasm.
Interaction studies have only been performed in adults.
UDP glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGTs, may also enhance the metabolism of lamotrigine.
Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 6. Specific dosing guidance for these drugs is provided in Section 4.2.
Table 6. Effects of other medicinal products on glucuronidation of lamotrigine:
| Medicinal products that significantly inhibit glucuronidation of lamotrigine | Medicinal products that significantly induce glucuronidation of lamotrigine | Medicinal products that do not significantly inhibit or induce glucuronidation of lamotrigine |
|---|---|---|
| Valproate | Phenytoin | Oxcarbazepine |
| Carbamazepine | Felbamate | |
| Phenobarbitone | Gabapentin | |
| Primidone | Levetiracetam | |
| Rifampicin | Pregabalin | |
| Lopinavir/ritonavir | Topiramate | |
| Ethinyloestradiol/levonorgestrel combination** | Zonisamide | |
| Atazanavir/ritonavir* | Lithium | |
| Buproprion | ||
| Olanzapine | ||
| Aripiprazole | ||
| Lacosamide | ||
| Perampanel |
* For dosing guidance (see section 4.2)
** Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters (see sections 4.2 and 4.4).
There is no evidence that lamotrigine causes clinically significant induction or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.
Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly two fold. In patients receiving concomitant therapy with valproate, the appropriate treatment regimen should be used (see section 4.2).
Certain AEDs (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug metabolising enzymes induce the glucuronidation of lamotrigine and enhance the metabolism of lamotrigine. In patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbitone or primidone, the appropriate treatment regimen should be used (see section 4.2).
There have been reports of central nervous system events including dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine following the introduction of lamotrigine. These events usually resolve when the dose of carbamazepine is reduced. A similar effect was seen during a study of lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction was not investigated.
There are reports in the literature of decreased lamotrigine levels when lamotrigine was given in combination with oxcarbazepine. However, in a prospective study in healthy adult volunteers using doses of 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine. Therefore in patients receiving concomitant therapy with oxcarbazepine, the treatment regimen for lamotrigine adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation should be used (see section 4.2).
In a study of healthy volunteers, coadministration of felbamate (1200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
Based on a retrospective analysis of plasma levels in patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
Potential interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg, 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
In a study of patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.
Plasma concentrations of lamotrigine were not affected by concomitant lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures.
In a pooled analysis of data from three placebo-controlled clinical trials investigating adjunctive perampanel in patients with partial-onset and primary generalised tonic-clonic seizures, the highest perampanel dose evaluated (12 mg/day) increased lamotrigine clearance by less than 10%. An effect of this magnitude is not considered to be clinically relevant.
Although changes in the plasma concentrations of other AEDs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant AEDs. Evidence from in vitro studies indicates that lamotrigine does not displace other AEDs from protein binding sites.
The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for six days to 20 healthy subjects were not altered by co administration of 100 mg/day lamotrigine.
Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 subjects and had only a slight increase in the AUC of lamotrigine glucuronide.
In a study in healthy adult volunteers, 15 mg olanzapine reduced the AUC and Cmax of lamotrigine by an average of 24% and 20%, respectively. An effect of this magnitude is not generally expected to be clinically relevant. Lamotrigine at 200 mg did not affect the pharmacokinetics of olanzapine.
Multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of 2 mg risperidone in 14 healthy adult volunteers. Following the co administration of risperidone 2 mg with lamotrigine, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.
In a study of 18 adult patients with bipolar I disorder, receiving an established regimen of lamotrigine (100-400 mg/day), doses of aripiprazole were increased from 10 mg/day to a target of 30 mg/day over a 7 day period and continued once daily for a further 7 days. An average reduction of approximately 10% in Cmax and AUC of lamotrigine was observed. An effect of this magnitude is not expected to be of clinical consequence.
In vitro experiments indicated that the formation of lamotrigine’s primary metabolite, the 2-N-glucuronide, was minimally inhibited by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol or lorazepam. These experiments also suggested that metabolism of lamotrigine was unlikely to be inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone. In addition, a study of bufuralol metabolism using human liver microsome preparations suggested that lamotrigine would not reduce the clearance of medicinal products metabolised predominantly by CYP2D6.
In a study of 16 female volunteers, dosing with 30 μg ethinyloestradiol/150 μg levonorgestrel in a combined oral contraceptive pill caused an approximately two fold increase in lamotrigine oral clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and Cmax, respectively. Serum lamotrigine concentrations increased during the course of the week of inactive treatment (including the “pill free” week), with pre-dose concentrations at the end of the week of inactive treatment being, on average, approximately two-fold higher than during co-therapy (see section 4.4). No adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of hormonal contraceptives, but the maintenance dose of lamotrigine will need to be increased or decreased in most cases when starting or stopping hormonal contraceptives (see section 4.2).
In a study of 16 female volunteers, a steady state dose of 300 mg lamotrigine had no effect on the pharmacokinetics of the ethinyloestradiol component of a combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax, respectively. Measurement of serum FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance, and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see section 4.4). The effects of doses of lamotrigine other than 300 mg/day have not been studied and studies with other female hormonal preparations have not been conducted.
In a study in 10 male volunteers, rifampicin increased lamotrigine clearance and decreased lamotrigine half-life due to induction of the hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the appropriate treatment regimen should be used (see section 4.2).
In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine, probably by induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the appropriate treatment regimen should be used (see section 4.2).
In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/100 mg) administered for 9 days reduced the plasma AUC and Cmax of lamotrigine (single 100 mg dose) by an average of 32% and 6%, respectively. In patients receiving concomitant therapy with atazanavir/ritonavir, the appropriate treatment regimen should be used (see section 4.2).
Data from in vitro assessment demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT2, with an IC50 value of 53.8 μM. Co-administration of lamotrigine with renally excreted medicinal products which are substrates of OCT2 (e.g. metformin, gabapentin and varenicline) may result in increased plasma levels of these medicines.
The clinical significance of this has not been clearly defined, however care should be taken in patients co-administered with these medicinal products.
Specialist advice should be given to women who are of childbearing potential. The antiepileptic treatment should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child.
Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.
A large amount of data on pregnant women exposed to lamotrigine monotherapy during the first trimester of pregnancy (more than 8700) do not suggest a substantial increase in the risk for major congenital malformations, including oral clefts. Animal studies have shown developmental toxicity (see section 5.3).
If therapy with lamotrigine is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended.
Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase and could therefore theoretically lead to an increased risk of embryofoetal damage by reducing folic acid levels (see section 4.4). Intake of folic acid when planning pregnancy and during early pregnancy may be considered.
Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine plasma levels during pregnancy with a potential risk of loss of seizure control. After birth lamotrigine levels may increase rapidly with a risk of dose related adverse events. Therefore lamotrigine serum concentrations should be monitored before, during and after pregnancy, as well as shortly after birth. If necessary, the dose should be adapted to maintain the lamotrigine serum concentration at the same level as before pregnancy, or adapted according to clinical response. In addition, dose related undesirable effects should be monitored after birth.
Lamotrigine has been reported to pass into breast milk in highly variable concentrations, resulting in total lamotrigine levels in infants of up to approximately 50% of the mother’s. Therefore, in some breast-fed infants, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur.
The potential benefits of breast-feeding should be weighed against the potential risk of adverse effects occurring in the infant. Should a woman decide to breast feed while on therapy with lamotrigine, the infant should be monitored for adverse effects, such as sedation, rash and poor weight gain.
Animal experiments did not reveal impairment of fertility by lamotrigine (see section 5.3).
As there is individual variation in response to all AED therapy, patients taking lamotrigine to treat epilepsy should consult their physician on the specific issues of driving and epilepsy.
No studies on the effects on the ability to drive and use machines have been performed. Two volunteer studies have demonstrated that the effect of lamotrigine on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine adverse reactions of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how lamotrigine dispersible tablets therapy affects them before driving or operating machinery.
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, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Very rare: Haematological abnormalities1 including neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis, haemophagocytic lymphohistiocytosis (HLH)
Not known: Lymphadenopathy1
Very rare: Hypersensitivity syndrome2** (including such symptoms as, fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver, disseminated intravascular coagulation, multi organ failure)
Not known: Hypogammaglobulinaemia
Common: Aggression, irritability
Very rare: Confusion, hallucinations, tics
Not known: Nightmares
Very common: Headache§
Common: Somnolence†§, dizziness†§, tremor†, insomnia†, agitation§
Uncommon: Ataxia†
Rare: Nystagmus†, Aseptic meningitis (see section 4.4)
Very rare: Unsteadiness, movement disorders, worsening of Parkinson’s disease3, extrapyramidal effects, choreoathetosis†, increase in seizure frequency
Uncommon: Diplopia†, blurred vision†
Rare: Conjunctivitis
Common: Nausea†, vomiting†, diarrhoea†, dry mouth§
Very rare: Hepatic failure, hepatic dysfunction4, increased liver function tests
Very common: Skin rash5†§
Uncommon: Alopecia
Rare: Stevens–Johnson Syndrome§
Very rare: Toxic epidermal necrolysis, Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)
Common: Arthralgia§
Very rare: Lupus-like reactions
Common: Tiredness†, pain§, back pain§
1 Haematological abnormalities and lymphadenopathy may or may not be associated with the hypersensitivity syndrome (see Immune system disorders2).
2 Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver. 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.
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 lamotrigine (see section 4.4).
Serious potentially life-threatening skin rashes, including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, 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:
Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms (see Immune system disorders2).
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
