Lamictal

Chronic administration of acetaminophen was shown to slightly decrease the t½ and increase the clearance of a single dose of lamotrigine. Oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine (see Precautions, Drug Interactions). Co-administration of olanzapine did not have a clinically relevant effect on LAMICTAL pharmacokinetics (see Precautions, Drug Interactions).

Oxcarbazepine did not affect the apparent clearance of lamotrigine (see Precautions, Drug Interactions).

Effect of Oral Contraceptives on LAMICTAL: In a study in 16 female volunteers, an oral contraceptive preparation containing 30 µg ethinylestradiol and 150 µg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in C_max of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week) for women not also taking a drug that increases the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine levels will be greater if the dose of LAMICTAL is increased in the few days before or during the pill-free week.

Dosage adjustments may be necessary for women receiving oral contraceptive preparations (see Dosage, Women and Oral Contraceptives).

One placebo-controlled trial that compared ECGs at baseline and during treatment demonstrated a mild prolongation of the PR interval associated with LAMICTAL administration. The prolongation was statistically significant but clinically insignificant. Patients with significant cardiovascular disease or electrocardiographic abnormalities were, however, systematically excluded from clinical trials. Thus, LAMICTAL should be used with caution in patients with cardiac conduction abnormalities, and in patients taking concomitant medications which depress AV conduction.

Dependence Liability: No evidence of abuse potential has been associated with LAMICTAL, nor is there evidence of psychological or physical dependence in humans.

Laboratory Tests: The relationship between clinical efficacy and plasma concentrations has not been clearly established. Based on the possible pharmacokinetic interactions between LAMICTAL and other drugs including AEDs, monitoring of the plasma levels of LAMICTAL and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and other drugs and whether or not dosage adjustments are necessary.

Safety and efficacy in patients below the age of 16 years, other than those with Lennox-Gastaut Syndrome, have not been established.

Studies in mice, rats and rabbits given lamotrigine orally or i.v. revealed no evidence of teratogenicity; however, maternal and secondary fetal toxicity were observed. Studies in rats and rabbits indicate that lamotrigine crosses the placenta; placental and fetal levels of lamotrigine were low and comparable to levels in maternal plasma.

Clinical trial data indicate that lamotrigine has no effect on blood folate concentrations in adults; however, its effects during human fetal development are unknown.

Postmarketing data from six prospective pregnancy registries have documented outcomes in approximately 4000 women exposed to lamotrigine monotherapy during the first trimester of pregnancy. Two registries have reported an increase in the risk of isolated oral cleft (isolated) malformations with exposure to lamotrigine in the first trimester, over both the study reference population and reported background rates from the literature.

The North American Anti-Epileptic Drug Registry reported rates of: 7.3/1000 for lamotrigine exposures in the registry with n=684 vs 0.70/1000 for the reference population and 0.50-2.16/1000 for the background rates.

The Swedish Medical Birth Register reported rates of 9.9/1000 for lamotrigine exposures in the registry with n=403 vs 2.0/1000 for the registry reference population and 0.50-2.16/1000 for the background rates. In the remaining registries with approximately 3000 women, 4 cases of isolated oral cleft malformation were found (1.3/1000 vs 0.50-2.16/1000 for the background rates).

EUROCAT: The European Network of Congenital Anomaly and Twin Registries (EUROCAT) is a network of 40 registries across 20 European countries. The results of a case control design using the EUROCAT dataset demonstrated that the risk of development of oral clefts in the newborn infants was similar to other defects following exposure to lamotrigine in the first trimester. Within the EUROCAT network, rates of exposure to lamotrigine in the first trimester of pregnancy were similar among 4571 non chromosomal, isolated oral cleft cases and 80 052 non chromosomal, non oral cleft defect controls.

The data on use of lamotrigine in polytherapy combinations are insufficient to assess whether the risk of malformation associated with other agents is affected by concomitant lamotrigine use.

As with other medicines, LAMICTAL should only be used during pregnancy if the expected benefits outweigh the potential risks.

Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine levels during pregnancy. Appropriate clinical management of pregnant women during lamotrigine therapy should be ensured.

To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, in the Lamotrigine Drug Pregnancy Registry by calling 1-800-336-2176 (toll free).

Labour and Delivery: The effect of LAMICTAL on labour and delivery in humans is unknown.

In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine. At least 14 out of 22 healthy adult volunteers reported diarrhea and 5 out of 22 subjects reported rash following the addition of lopinavir/ ritonavir (400 mg/100 mg b.i.d.) to lamotrigine (up to 200 mg b.i.d.), compared to 1 out of 24 reporting diarrhea or rash, when lamotrigine was administered alone (up to 100 mg b.i.d.). Diarrhea is a common adverse event reported for lopinavir/ritonavir. The titration of lamotrigine in this study was rapid, which is a known risk factor for the development of a rash. The rashes necessitated the discontinuation of the medications. One subject also discontinued the medications due to elevated AST and ALT levels. Caution is advised for the co-administration of lopinavir/ritonavir with lamotrigine. In patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for concomitant enzyme-inducing AEDs (without VPA) should be used (see Dosage and Administration, Table 9).

Clinical experience with LAMICTAL in patients with concomitant illness is limited. Caution is advised when using LAMICTAL in patients with diseases or conditions that could affect the metabolism or elimination of the drug.

Renal Failure: A study in individuals with chronic renal failure (not receiving other AEDs) indicated that the elimination half-life of unchanged lamotrigine is prolonged relative to individuals with normal renal function (see Pharmacology). Use of LAMICTAL in patients with severe renal impairment should proceed with caution.

Hepatic Impairment: Results from a single-dose pharmacokinetic study indicate that the apparent clearance of lamotrigine decreased in subjects with Grades A, B or C hepatic impairment. A reduced dosage should be used for all hepatically impaired patients, and lamotrigine should be administered with caution particularly in those patients with severe hepatic impairment (see also Dosage and Pharmacology).

Increased incidence of rash-related withdrawal was seen when initial doses were higher and titration more rapid than recommended under Dosage.

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL for any reason, 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 LAMICTAL for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of LAMICTAL is affected by other concomitant medications (see Pharmacology, Pharmacokinetics and Dosage).

LAMICTAL has not been associated with any assay interferences in clinical laboratory tests.

As the pharmacokinetics in this age group do not differ significantly from a non-elderly adult population, no dosage adjustment from the recommended adult schedule is required (see also Dosage, Adverse Effects and Pharmacology).

There is limited information on the use of LAMICTAL in lactation. Preliminary data indicate that lamotrigine passes into human milk in concentrations usually of the order 40 to 60% of the serum concentration. In a small number of infants known to have been breast-fed, the serum concentrations of lamotrigine reached levels at which pharmacological effects may occur. Because of the potential for adverse reactions from LAMICTAL in nursing infants, breast-feeding while taking this medication is not recommended.

See Patients with Special Diseases and Conditions and Cardiac Conduction Abnormalities.

Co-administration of LAMICTAL: (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of an oral contraceptive preparation containing 30 µg ethinylestradiol and 150 µg levonorgestrel. There was a mean decrease in the AUC and C_max of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.

The effects of doses of LAMICTAL other than 300 mg/day have not been studied.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).

Patients with uncontrolled epilepsy should not drive or handle potentially dangerous machinery. During clinical trials, common adverse effects included dizziness, ataxia, drowsiness, diplopia and blurred vision. Patients should be advised to refrain from activities requiring mental alertness or physical coordination until they are sure that LAMICTAL does not affect them adversely.

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 a history, than those without.

Following the co-administration of 2 mg risperidone with lamotrigine (up to 400 mg daily), 12 out of the 14 healthy adult volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and 0 out of 20 when lamotrigine was administered alone.

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, although the effect may be similar to oral contraceptive preparations. Therefore, as for oral contraceptives, dosage adjustments may be necessary (see Dosage, Women and Oral Contraceptives).

In a study in 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%). For patients taking rifampin with LAMICTAL, follow the titration schedule for concomitant enzyme-inducing AEDs (without VPA) (see Dosage, Table 9).

The AUC and C_max of lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n=16) compared to healthy male volunteers receiving LAMICTAL alone (n=12). This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.

Each white to off-white, elongated and biconvex tablet, engraved “GS CL2” on one side and “5” on the other (initiation dose only), contains: lamotrigine 5 mg. Nonmedicinal ingredients: aluminum magnesium silicate, blackcurrant flavor, calcium carbonate, hydroxypropylcellulose, magnesium stearate, povidone, saccharin sodium and sodium starch glycolate. Blisters of 28. Store at controlled room temperature (15 to 30°C) in a dry place and protect from light.

Each peach, scored, shield-shaped tablet, engraved with “LAMICTAL” and “100”, contains: lamotrigine 100 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, povidone, sunset yellow FCF lake and sodium starch glycolate. Bottles of 100. Store at controlled room temperature (15 to 30°C) in a dry place and protect from light.

Each cream, scored, shield-shaped tablet, engraved with “LAMICTAL” and “150”, contains: lamotrigine 150 mg. Nonmedicinal ingredients: cellulose, ferric oxide (yellow), lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 60. Store at controlled room temperature (15 to 30°C) in a dry place and protect from light.

Each white, scored, shield-shaped tablet, engraved with “LAMICTAL” and “25”, contains: lamotrigine 25 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 100. Store at controlled room temperature (15 to 30°C) in a dry place and protect from light.

Each white, round tablet, engraved “LTG” over “2”, contains: lamotrigine 2 mg. Nonmedicinal ingredients: aluminum magnesium silicate, blackcurrant flavor, calcium carbonate, hydroxypropylcellulose, magnesium stearate, povidone, saccharin sodium and sodium starch glycolate. Bottles of 30. Store at controlled room temperature (15 to 30°C) in a dry place and protect from light.

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 lamotrigine.

The incidence of suicidal ideation and behaviour was evaluated in a pooled analysis of placebo-controlled clinical trials with lamotrigine involving a total of 6467 patients from a number of indications, including studies in epilepsy and bipolar disorder.

In the subset of bipolar disorder trials, the rate of events was numerically, but not statistically significantly, greater for lamotrigine (29/1212 [2.4%]) compared with placebo (19/1054 [1.8%]). In a pooled analysis of psychiatric indications, events were more common in the first month of treatment, in patients taking lamotrigine. Behavioural events were more common in males.

In the subset of epilepsy trials, there were no statistically significant differences in the rate of events between lamotrigine and placebo; the number of events of suicidal ideation and behaviour was too low (6/1073 [0.6%] on lamotrigine and 2/805 [0.3%] on placebo) to allow a meaningful comparison of these rates.

Patients taking LAMICTAL should be advised not to start or stop their oral contraceptives without consulting their physician. Significant adjustments in the maintenance dose of LAMICTAL may be required in some patients (see Precautions, Drug Interactions, Oral Contraceptives and Dosage, Women and Oral Contraceptives).

There have been reports of hematological abnormalities which may or may not be associated with hypersensitivity syndrome. These have included disseminated intravascular coagulation, hemolytic anemia, neutropenia, leukopenia, pancytopenia, anemia, thrombocytopenia, red cell aplasia, and very rarely agranulocytosis and aplastic anemia.

There have been reported cases of lymphadenopathy in the absence of hypersensitivity reactions, in patients with or without previous history, and taking LAMICTAL alone or in combination with other medications (including other AEDs). Discontinuation of LAMICTAL or, in some cases, dose reduction resolved the reaction.

hallucinations. Exacerbation of parkinsonian symptoms in patients with pre-existing Parkinson's disease and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition. Movement disorders such as tics and unsteadiness have also been reported.

There have been very rare reports of aseptic meningitis in patients taking LAMICTAL alone or in combination with other AEDs. In some cases, discontinuation of LAMICTAL resolved this reaction.

apnea.

esophagitis.

Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

Postmarketing and Other Experience: In addition to the adverse experiences reported during clinical testing of LAMICTAL, the following adverse experiences have been reported in patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

pancreatitis. Elevations of liver function tests and rare reports of hepatic dysfunction, including hepatic failure, have been reported. Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.

lupus-like reaction, vasculitis.

hypersensitivity reaction, multiorgan failure, progressive immunosuppression.

Adults: Acute ingestion of doses in excess of 20 times the maximum therapeutic dose has been reported. In general, overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma.

However, there has been one fatality reported, a 22 year-old female who intentionally ingested 15 g of LAMICTAL. The patient experienced acute clonic seizures and heart failure, then became asystolic and was resuscitated, but she died 2 days later.

Children: Among patients ≤16 years of age, the two highest known single doses of LAMICTAL have been 3000 mg by a 14 year-old female and approximately 1000 mg by a 4 year-old male. The 14 year-old female was taking marketed LAMICTAL; after the dose, she lost consciousness and was admitted to the hospital for supportive therapy, where she recovered fully (time to recovery not reported). The 4 year-old male was drowsy and agitated when found, and his condition worsened to coma level II after hospitalization. He was given supportive therapy and his condition improved rapidly, with full recovery in 3 days.

There are no specific antidotes for LAMICTAL. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced or gastric lavage should be performed. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed during 4 hours of hemodialysis.

Do not exceed the recommended initial dose and subsequent dose escalations of LAMICTAL. More rapid initial titration has been associated with an increased incidence of serious dermatological reactions (see Warnings), as has concomitant use of valproic acid, particularly in the absence of enzyme-inducing AEDs (see Warnings and Precautions). Patients with a history of rash or allergy to other AEDs are more at risk for LAMICTAL-associated rash than those without such history (see Warnings and Precautions).

Although the effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, the effect may be similar to oral contraceptives (see Precautions, Drug Interactions). Therefore, similar adjustments to the dosage of LAMICTAL may be needed, based on clinical response.

Dosing for Severe (Child-Pugh Grade C) Hepatic-impaired Adult Patients (based on pharmacokinetic data from 7 severe hepatic-impaired subjects given a single 100 mg dose)

For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL may need to be to be decreased by as much as 50% of the maintenance dose with concurrent oral contraceptives, according to clinical response (see Precautions, Drug Interactions). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone or rifampin, no adjustment should be necessary.

No dosage adjustment from the recommended adult schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly population (see also Pharmacology and Adverse Effects).

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL for any reason, 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 LAMICTAL for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of LAMICTAL is affected by other concomitant medications (see Pharmacology, Pharmacokinetics).

LAMICTAL Chewable/Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. The scoreline on the 5 mg tablet is not intended for tablet splitting. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing. To disperse the tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

Starting LAMICTAL in Women Taking Oral Contraceptives: Although oral contraceptives have been shown to increase the clearance of lamotrigine (see Precautions, Drug Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL should be necessary solely based on the use of oral contraceptives. Therefore, dose escalation should follow the recommended guidelines based on whether LAMICTAL is added to valproate, whether LAMICTAL is added to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, or whether LAMICTAL is added in the absence of valproate, carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

LAMICTAL (lamotrigine) is intended for oral administration and may be taken with or without food. LAMICTAL should be added to the patient's current antiepileptic therapy.

Valproic acid more than doubles the elimination half-life of lamotrigine and reduces the plasma clearance by 50%; conversely, hepatic enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, and primidone reduce the elimination half-life of lamotrigine by 50% and double the plasma clearance (see Pharmacology). These clinically important interactions require dosage schedules of LAMICTAL as summarized in Table 8, Table 9, Table 10 and Table 11.

LAMICTAL does not alter plasma concentrations of concomitantly administered enzyme-inducing AEDs, and therefore, they do not usually require dose adjustment to maintain therapeutic plasma concentrations. For patients receiving LAMICTAL in combination with other AEDs, an evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed. If there is a need to discontinue therapy with LAMICTAL, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns (i.e., rash) require a more rapid withdrawal (see Warnings and Precautions).

The relationship of plasma concentration to clinical response has not been established for LAMICTAL. Dosing of LAMICTAL should be based on therapeutic response. In controlled clinical studies, doses of LAMICTAL that were efficacious generally produced steady-state trough plasma lamotrigine concentrations of 1 to 4 µg/mL in patients receiving one or more concomitant AEDs. Doses of LAMICTAL producing this plasma concentration range were well tolerated. As with any antiepileptic drug, the oral dose of LAMICTAL should be adjusted to the needs of the individual patient, taking into consideration the concomitant AED therapy the patient is receiving.

For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL may need to be increased, by as much as 2-fold over the recommended target maintenance dose, according to clinical response (see Precautions, Drug Interactions). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary.

The elimination half-life of lamotrigine is prolonged in patients with impaired renal function (see Pharmacology). Caution should be exercised in dose selection for patients with impaired renal function.

There have been no controlled studies to establish the effectiveness or optimal dosing regimen of add-on LAMICTAL therapy in patients receiving only non-enzyme-inducing AEDs or valproic acid. However, available data from open clinical trials indicate that the addition of LAMICTAL under these conditions is associated with a higher incidence of serious rash or rash-related withdrawal, even at an initial titration dose of 12.5 mg daily (see Precautions, Skin-related Events, Table 3 and Table 4; see also Warnings). The potential medical benefits of addition of LAMICTAL under these conditions must be weighed against the increased risk of serious rash. If use of LAMICTAL under these conditions is considered clinically indicated, titration should proceed with extreme caution, especially during the first 6 weeks of treatment.

Withdrawal of Concomitant AEDs in Adults: Concomitant AEDs may be decreased over a 5-week period, by approximately 20% of the original dose every week. However, a slower taper may be used if clinically indicated. During this period, the dose of LAMICTAL administered will be dependent upon the effect of the drug being withdrawn on the pharmacokinetics of lamotrigine, together with the overall clinical response of the patient. The withdrawal of enzyme inducing AEDs (i.e., phenytoin, phenobarbital, primidone, and carbamazepine) will result in an approximate doubling of the t_1/2 of lamotrigine. Under these conditions, it may be necessary to reduce the dose of LAMICTAL. In contrast, the withdrawal of enzyme-inhibiting AEDs (i.e., valproic acid) will result in a decrease in the t_1/2 of lamotrigine and may require an increase in the dose of LAMICTAL.