Lamotrix Special Precautions

Haemophagocytic lymphohistiocytosis (HLH): HLH has occurred in patients taking lamotrigine. HLH is a syndrome of pathological immune activation, which can be life threatening, characterised by clinical signs and symptoms such as 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. Immediately evaluate patients who develop these signs and symptoms and consider a diagnosis of HLH. Lamotrigine should be discontinued unless an alternative aetiology can be established.
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 hospitalization and discontinuation of lamotrigine have also been reported. These have included potentially life threatening rashes such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Adverse Reactions). It is not possible to predict reliably which rashes will prove to be life-threatening. Accordingly, lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.
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 SJS (1 in 1000).
In clinical trials in patients with bipolar disorder, the incidence of serious skin rashes 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 hospitalization 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 drug reaction in children that develop symptoms of rash and fever during the first 8 weeks of therapy.
Additionally 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 Dosage & Administration); concomitant use of valproate (see Dosage & Administration).
Caution is also required when treating patients with a history of allergy or rash to other antiepileptic drugs as it was found in two studies (n =767 and n=988) on the frequency of rash after treatment with lamotrigine that the rate of rash was approximately three to four times higher in patients with such history than without.
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. 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.
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 and aseptic meningitis (see Adverse Reactions). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to Disseminated Intravascular Coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g. fever and 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: Therapy with LAMOTRIX increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
Post-marketing cases of aseptic meningitis have been reported in paediatric and adult patients taking LAMOTRIX for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of LAMOTRIX. Re-exposure resulted in a rapid return of symptoms (from 30 minutes to 1 day following re-initiation of treatment) 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.
Some of the patients treated with LAMOTRIX who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analysed at the time of clinical presentation in reported cases was characterised by a mild to moderate pleocytosis, normal glucose levels and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one-third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
Suicide risk: Symptoms of depression and/or bipolar disorder may occur in patients with epilepsy, and there is evidence that patients with epilepsy and bipolar disorder have an elevated risk for suicidality. Twenty-five to 50% of patients with bipolar disorder attempt suicide at least once, and may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder, including LAMOTRIX.
Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications, including epilepsy and bipolar disorder. A meta-analysis of randomised placebo-controlled trials of AEDs (including lamotrigine) 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.
Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Clinical worsening in bipolar disorder: Patients receiving LAMOTRIX 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.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
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.
Hormonal contraceptives: Effect of hormonal contraceptives on LAMOTRIX efficacy: An ethinyloestradiol/levonorgestrel (30 mcg/150 mcg) combination has been demonstrated to increase the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see Interactions). 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. In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive medication (e.g. "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive medication. These increases will be greater when lamotrigine dose increases are made in the days before or during the week of inactive medication. For dosing instructions see "General Dosing Recommendations for LAMOTRIX in Special Patient Populations, under Dosage & Administration" Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during lamotrigine therapy and lamotrigine dosing adjustments will be needed in most cases. Effects of other hormonal contraceptive preparations or HRT on LAMOTRIX: Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of lamotrigine on hormonal contraceptive efficacy: 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 Interactions). The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy insome patients taking hormonal preparations with lamotrigine cannot be excluded. A limited number of reports have been received of unexpected pregnancies and of menstrual bleeding disorders (e.g. break through bleeding) occurring with the concomitant use of lamotrigine and hormonal contraceptives. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e., breakthrough bleeding while receiving lamotrigine in combination with these medications.
Effect of lamotrigine on organic cationic transporter 2 (OCT 2) substrates: Lamotrigine is an inhibitor of renal tubular secretion via OCT 2 proteins (see Interactions). This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Co-administration of LAMOTRIX with OCT 2 substrates with a narrow therapeutic index e.g. dofetilide is not recommended.
Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving lamotrigine. Fatalities associated with mutiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 paediatric patients who received lamotrigine in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial cause. Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after lamotrigine was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in two patients. Both paediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with lamotrigine was discontinued.
Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Dihydrofolate Reductase:Lamotrigine is a weak inhibitor of dihydrofolate reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. 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.
Renal Failure: 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.
Patients taking other preparations containing lamotrigine: LAMOTRIX tablets should not administered to patients currently being treated with other preparation containing lamotrigine without consulting a doctor.
Brugada-type ECG: A very rare association with Brugada-type ECG has been observed, although a causal relationship has not been established. Therefore, careful consideration should be given before using LAMOTRIX in patients with Brugada syndrome.
Epilepsy: As with other AEDs, abrupt withdrawal of LAMOTRIX may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of 2 weeks.
There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan dysfunction and disseminated intravascular coagulation (DIC), sometimes with fatal outcome. Similar cases have occurred in association with the use of lamotrigine.
Bipolar Disorder: Children and adolescents (less than 18 years of age): 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.
Effects on Ability to Drive and Use Machines: 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 events of neurological character such as dizzines and diplopia have been reported. Therefore, patients should see how lamotrigine therapy affects them before driving or operating machinery.
Epilepsy: as there is individual variation in response to all antiepileptic drug therapy patient should consult their physician on the specific issues of driving and epilepsy.