LAMOTRIGINE- lamotrigine_tablet, film coated, extended release
Function and Efficacy
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known. One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor-Mediated Activity Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC 50 Folate Metabolism In vitro [see Use in Specific Populations (8. 1) Cardiac Electrophysiology Effect of Lamotrigine: In vitro Effect of Lamotrigine Metabolite: in vitro [see Clinical Pharmacology (12. 3) In comparison with immediate-release lamotrigine, the plasma lamotrigine levels following administration of lamotrigine extended-release are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks and lower peak-to-trough fluctuation, as described in detail below. Absorption Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food. In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of lamotrigine extended-release given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (T max max The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED (see Table 6). A mean reduction in the lamotrigine C max max Table 6. Steady-State Bioavailability of Lamotrigine Extended-Release Relative to Immediate-Release Lamotrigine at Equivalent Daily Doses (Ratio of Extended-Release to Immediate-Release 90% CI) Concomitant Antiepileptic Drug AUC (0-24ss) C max C min Enzyme-inducing antiepileptic a 0. 09) Valproate 0. 10) Antiepileptic drugs other than a 1. 25) a Dose Proportionality In healthy volunteers not receiving any other medications and given lamotrigine extended-release once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 mg to 200 mg. At doses between 25 mg and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1. 6-fold increase in systemic exposure. Distribution Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers. Protein Binding Data from in vitro Metabolism Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14 Enzyme Induction The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated. Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t ½ [see Drug Interactions (7) Elimination The elimination half-life and apparent clearance of lamotrigine following oral administration of immediate-release lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 7. Half-life and apparent oral clearance vary depending on concomitant AEDs. Since the half-life of lamotrigine following administration of single-doses of immediate-release lamotrigine is comparable with that observed following administration of lamotrigine extended-release, similar changes in the half-life of lamotrigine would be expected for lamotrigine extended-release. Mean Pharmacokinetic Parameters a Adult Study Population Number of t ½ CL/F: Healthy volunteers taking no Single-dose lamotrigine 179 32. 44 Multiple-dose lamotrigine 36 25. 58 Healthy volunteers taking Single-dose lamotrigine 6 48. 30 Multiple-dose lamotrigine 18 70. 18 Subjects with epilepsy taking Single-dose lamotrigine 4 58. 28 Subjects with epilepsy taking b Single-dose lamotrigine 25 27. 53 Subjects with epilepsy taking b Single-dose lamotrigine 24 14. 10 Multiple-dose lamotrigine 17 12. 21 a max b [see Drug Interactions (7) Drug Interactions The apparent clearance of lamotrigine is affected by the co-administration of certain medications [see Warnings and Precautions (5. 13 Drug Interactions (7) The net effects of drug interactions with lamotrigine, based on drug interaction studies using immediate-release lamotrigine, are summarized in Tables 5 and 8, followed by details of the drug interaction studies below. Summary of Drug Interactions with Lamotrigine Drug Drug Plasma a Lamotrigine Plasma b Oral contraceptives (e. , c left-right arrow d down arrow Aripiprazole Not assessed left-right arrow e Atazanavir/ritonavir left-right arrow f down arrow Bupropion Not assessed left-right arrow Carbamazepine left-right arrow down arrow Carbamazepine epoxide g ? Felbamate Not assessed left-right arrow Gabapentin Not assessed left-right arrow Lacosamide Not assessed left-right arrow Levetiracetam left-right arrow left-right arrow Lithium left-right arrow Not assessed Lopinavir/ritonavir left-right arrow e down arrow Olanzapine left-right arrow left-right arrow e Oxcarbazepine left-right arrow left-right arrow 10-Monohydroxy oxcarbazepine h left-right arrow Perampanel Not assessed left-right arrow e Phenobarbital/primidone left-right arrow down arrow Phenytoin left-right arrow down arrow Pregabalin left-right arrow left-right arrow Rifampin Not assessed down arrow Risperidone left-right arrow Not assessed 9-Hydroxyrisperidone i left-right arrow Topiramate left-right arrow j left-right arrow Valproate down arrow up arrow Valproate + phenytoin and/or Not assessed left-right arrow Zonisamide Not assessed left-right arrow a b c d e f g h i j left-right arrow = No significant effect. ? = Conflicting data. Estrogen-Containing Oral Contraceptives In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in C max Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions (7) In the same study, co-administration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and C max The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials. 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. , break-through bleeding). Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see Dosage and Administration (2. 1) Other Hormonal Contraceptives or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. 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. Therefore, adjustments to the dosage of lamotrigine extended-release in the presence of progestogens alone will likely not be needed. Aripiprazole In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the lamotrigine AUC and C max Atazanavir/Ritonavir In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and C max Bupropion The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by co-administration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before lamotrigine. Carbamazepine Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine [see Adverse Reactions (6. 1) The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%. Esomeprazole In a study of 30 subjects, co-administration of lamotrigine extended-release with esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in T max Felbamate In a trial in 21 healthy volunteers, co-administration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine. Folate Inhibitors Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism. Gabapentin Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine. Lacosamide 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. Levetiracetam Potential drug 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. Lithium The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by co-administration of lamotrigine (100 mg/day) for 6 days. Lopinavir/Ritonavir The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the AUC, C max Olanzapine The AUC and C max max In the same trial, the AUC and C max Oxcarbazepine The AUC and C max In the same trial, the AUC and C max Perampanel In a pooled analysis of data from 3 placebo-controlled clinical trials investigating adjunctive perampanel in patients with partial-onset and primary generalized tonic-clonic seizures, the highest perampanel dose evaluated (12 mg/day) increased lamotrigine clearance by <10%. An effect of this magnitude is not considered to be clinically relevant. Phenobarbital, Primidone The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%. Phenytoin Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%. Pregabalin 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. Rifampin 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%). Risperidone In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-OH risperidone. Following the co-administration of risperidone 2 mg with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone. Topiramate Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations. Valproate When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials. The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased. Zonisamide In a study in 18 patients with epilepsy, co-administration 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. Known Inducers or Inhibitors of Glucuronidation Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of lamotrigine extended-release may require adjustment based on clinical response. Other In vitro 50 [see Drug Interactions (7) Results of in vitro Results of in vitro Specific Populations Patients with Renal Impairment: [see Dosage and Administration (2. 1) Patients with Impairment [see Dosage and Administration (2. 1) Geriatric Patients: Male and Female Patients Racial or Ethnic Groups Pediatric Patients:.
Label
Other Information
OVERDOSAGE
Overdoses involving quantities up to 15 g have been reported for immediate-release lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma and intraventricular conduction delay. There are no specific antidotes for lamotrigine. 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; usual precautions should be taken to protect the airway. 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 by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of lamotrigine extended-release.
NONCLINICAL TOXICOLOGY
No evidence of carcinogenicity was seen in mice or rats following oral administration of lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body surface area (mg/m 2 Lamotrigine was negative in in vitro tk in vitro in vivo No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m 2
CLINICAL STUDIES
The effectiveness of lamotrigine extended-release as adjunctive therapy in subjects with PGTC seizures was established in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled trial in 143 patients aged 13 years and older (n = 70 on lamotrigine extended-release, n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with lamotrigine extended-release or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 200 to 500 mg/day of lamotrigine extended-release based on concomitant AEDs (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels and 500 mg for enzyme-inducing AEDs). The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with lamotrigine extended-release and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i. a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i. an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with lamotrigine extended-release compared with the placebo group. For example, 70% of patients randomized to lamotrigine extended-release experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as >= -100%. Proportion of Patients by Responder Rate for Lamotrigine Extended-Release and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study) Figure 1 The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures. The effectiveness of lamotrigine extended-release as adjunctive therapy in partial-onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation and Ukraine. Patients with at least 8 partial-onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with lamotrigine extended-release (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of lamotrigine extended-release based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2. 3 for lamotrigine extended-release and 2. 1 for placebo. The primary endpoint was the median percent change from baseline in partial-onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial-onset seizures were 47% in patients treated with lamotrigine extended-release and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial-onset seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial-onset seizure frequency was consistently higher for the group treated with lamotrigine extended-release compared with the placebo group. For example, 44% of patients randomized to lamotrigine extended-release experienced a 50% or greater reduction in partial-onset seizure frequency compared with 21% of patients randomized to placebo. Proportion of Patients by Responder Rate for Lamotrigine Extended-Release and Placebo Group (Partial-Onset Seizure Study) Figure 2 The effectiveness of lamotrigine extended-release as monotherapy for partial-onset seizures was established in a historical control trial in 223 adults with partial-onset seizures. The historical control methodology is described in a publication by French, et al. [see References (15) In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures during an 8-week baseline period with at least 1 seizure occurring during each of 2 consecutive 4-week periods while receiving valproate or a nonen dashenzyme-inducing AED. Lamotrigine extended-release was added to either valproate or a non-enzyme-inducing AED over a 6- to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with lamotrigine extended-release for 12 weeks. The escape criteria were 1 or more of the following: (1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure type compared with baseline (4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted. The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40. 2% at 300 mg/day and 44. 5% at 250 mg/day) were below the threshold of 65. 3% derived from the historical control data. Although the study population was not fully comparable with the historical control population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.
REFERENCES
French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia