Indicated for:

Epilepsy:

• Adjunctive Therapy: Indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older:

• partial-onset seizures
• primary generalized tonic-clonic (PGTC) seizures
• generalized seizures of Lennox-Gastaut syndrome

• Monotherapy: Indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).

Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

Bipolar Disorder:

• Indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. 

Treatment of acute manic or mixed episodes is not recommended. Effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.

Patients taking LAMICTAL for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL should be based on therapeutic response.

LAMICTAL can cause serious rashes requiring hospitalization and discontinuation of treatment. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate.

Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by LAMICTAL. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) co-administration of LAMICTAL with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation for LAMICTAL. However, cases have occurred in the absence of these factors.

Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash.

Although benign rashes are also caused by LAMICTAL, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, LAMICTAL 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.

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications.

Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with LAMICTAL. Some have been fatal or life-threatening.

The risk of non-serious rash may be increased when the recommended initial dose and/or the rate of dose escalation for LAMICTAL is exceeded and in patients with a history of allergy or rash to other AEDs.

No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites.

Reduced maintenance doses may be effective for patients with significant renal impairment.

Isolated liver failure without rash or involvement of other organs has also been reported with LAMICTAL.

In vitro testing showed that LAMICTAL exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. Based on these in vitro findings, LAMICTAL could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease). Any expected or observed benefit of LAMICTAL in an individual patient with clinically  important structural or functional heart disease must be carefully weighed against the risks for serious arrhythmias and/or death for that patient. Concomitant use of other sodium channel blockers may further increase the risk of proarrhythmia.

There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS). These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking LAMICTAL for various indications. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities. In cases of HLH reported with LAMICTAL, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.

AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Therapy with LAMICTAL 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.

Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications.

As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL.

If a decision is made to discontinue therapy with LAMICTAL, a stepwise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal.

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.

During the pre-marketing development of LAMICTAL, sudden and unexplained deaths were recorded among a cohort of patients with epilepsy.

Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen- containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation.

Drugs that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine.

Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of LAMICTAL will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. If adverse reactions attributable to LAMICTAL consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. 

Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of LAMICTAL will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise.

For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of LAMICTAL should be necessary.

It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.

In patients already taking maintenance doses of LAMICTAL and not taking glucuronidation inducers, the dose of LAMICTAL may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued.

Because valproate reduces the clearance of lamotrigine, the dosage of LAMICTAL in the presence of valproate is less than half of that required in its absence.

The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.

The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.

Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

Addition of rifampin decreases lamotrigine AUC approximately 40%. 

Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.

Co-administration of LAMICTAL with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical method should be used to confirm a positive result.

There are no adequate and well-controlled studies in pregnant women. Animal studies: increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities. Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans.

Lamotrigine is present in milk from lactating women taking LAMICTAL.

Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but is not reduced after delivery to the pre-pregnancy dosage. Glucuronidation is required for drug clearance. Glucuronidation capacity is immature in the infant and this may also contribute to the level of lamotrigine exposure.

GoToSource

• Monotherapy for epilepsy in patients under the age of 16. GoToSource

• Use in patients under 2 years of age for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome and PGTC seizures. GoToSource

• Unipolar depression. GoToSource

• Schizoaffective disorder. GoToSource

• Borderline personality disorder. GoToSource

• Bipolar II disorder. GoToSource

• Hemiplegic migraine. GoToSource

• Neuropathic pain. GoToSource

• Trigeminal neuralgia. GoToSource

• SUNCT syndrome, cluster headaches, glossopharyngeal neuralgia, allodynia, neuralgia after nerve section, postherpetic neuralgia, HIV-associated neuropathy, spinal cord injury pain and neuralgia after nerve section. GoToSource

• Depersonalization disorder. GoToSource

• Myotonia. GoToSource

• Delirium tremens. GoToSource

• Ketamine use disorder. GoToSource

• Startle-induced seizures. GoToSource

• Panic disorder. GoToSource

• Pathological skin picking. GoToSource

• Aggression in female borderline patients. GoToSource

• Post-traumatic stress disorder. GoToSource

Stevens-johnson syndrome and toxic epidermal necrolysis (severe skin reaction). GoToSource

Multi-organ failure. GoToSource

Lymphadenopathy (enlargement of lymph nodes). GoToSource

Eosinophilia and systemic symptoms (severe drug reaction). GoToSource

Liver failure. GoToSource

Aseptic meningitis (inflammation of membrane covering brain and spinal cord). GoToSource

Sudden unexplained death in epilepsy. GoToSource

Hemophagocytic lymphohistiocytosis (immune system produces too many activated immune cells). GoToSource

Blood dyscrasias (blood disorder). GoToSource

Withdrawal seizures. GoToSource

Syndrome of inappropriate antidiuretic hormone secretion (body makes too much antidiuretic hormone). GoToSource

Tinnitus (noise or ringing in ears), phonophobia (fear of loud noises), sensorineural hearing loss, dizziness, ataxia (lack of muscle coordination), disequilibrium (loss of equilibrium or stability), nystagmus (rapid and repetitive eye movement) and delayed conduction within the cochlea, auditory nerve and brainstem auditory pathways and central and/or peripheral vestibular dysfunctions. GoToSource

Anticonvulsant hypersensitivity syndrome (potentially fatal drug reaction). GoToSource

Immunoglobulin A (IgA) deficiency (lack or low level of a protein that fights infection). GoToSource

Hyponatremia (low blood sodium level). GoToSource

Pneumonitis (inflammation of lung tissue). GoToSource

Lymphadenopathy (enlargement of lymph nodes). GoToSource

Disabling tremor. GoToSource

Anger and aggression. GoToSource

Exacerbation of atherosclerosis. GoToSource

Brugada type 1 pattern (abnormal heart rhythm). GoToSource

Generalized myoclonus (involuntary muscle jerk) and spasticity. GoToSource

Tachypnea (rapid breathing), tachycardia (rapid heart rate), hypertension (high blood pressure), QTc prolongation and altered mental status. GoToSource

Visual and auditory hallucinations. GoToSource

Alopecia (hair loss). GoToSource

Oral hairy leukoplakia (white or gray lesions in mouth). GoToSource

Myocarditis (inflammation of heart muscle). GoToSource

Dyspepsia (indigestion), insomnia and drug-induced lupus. GoToSource

Neuroleptic malignant syndrome (life-threatening drug reaction). GoToSource

Downbeat nystagmus (eyes drift upward). GoToSource

Seizure aggravation. GoToSource

Suicidal thoughts and behavior. GoToSource

Lawsuits filed for aseptic meningitis, stevens-johnson syndrome, toxic epidermal necrolysis, birth defects and suicide.