Lamictal (Lamotrigine) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action:    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. The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of LAMICTAL, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

LAMICTAL also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of this animal model to specific types of human epilepsy is unclear.

The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.

Pharmacological Properties:    Although the relevance for human use is unknown, the following data characterize the performance of LAMICTAL in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT₃ receptor (IC₅₀= 18 µM). It does not exhibit high affinity binding (IC₅₀>100 µM) to the following neurotransmitter receptors: adenosine A₁ and A₂; adrenergic (alpha)₁, (alpha)₂, and (beta); dopamine D₁ and D₂; (gamma)-aminobutyric acid (GABA) A and B; histamine H₁; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT₂. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC₅₀= 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC₅₀>200 µM) when tested in rat synaptosomes and/or human platelets 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 IC₅₀ for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

Folate Metabolism:    In vitro, lamotrigine was shown to be an inhibitor of dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis (see PRECAUTIONS: Pregnancy). Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Accumulation in Kidneys:    Lamotrigine was found to accumulate in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to (alpha)-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.

Melanin Binding:    Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.

Cardiovascular:    In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).

Pharmacokinetics and Drug Metabolism:    The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 1 and 2.

Absorption:    Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.

Distribution:    Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. 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 studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.

Drug Disposition:    Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of¹⁴ C-lamotrigine (15 µCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Drug Interactions:    The apparent clearance of lamotrigine is affected by the coadministration of certain medications. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking these AEDs.

Rifampin also increases the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the elimination half-life of lamotrigine), whether given with or without carbamazepine, phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half the dose used in patients not receiving valproate, even in the presence of drugs that increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions).

Oxcarbazepine and levetiracetam do not affect the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

In vitro inhibition experiments indicated that the formation of the primary metabolite of lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not inhibit the metabolism of drugs eliminated predominantly by CYP2D6.

LAMICTAL has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug Interactions).

The pharmacokinetics of LAMICTAL were not changed by co-administration of bupropion (see PRECAUTIONS: Drug Interactions).

Co-administration of olanzapine did not have a clinically relevant effect on LAMICTAL pharmacokinetics (see PRECAUTIONS: Drug Interactions).

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_1/2 and a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

Dose Proportionality:    In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.

Elimination:   (see Table 1).

Special Populations: Patients With Renal Insufficiency: Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session.

Hepatic Disease:    The pharmacokinetics of lamotrigine following a single 100-mg dose of LAMICTAL were evaluated in 24 subjects with moderate to severe hepatic dysfunction and compared with 12 subjects without hepatic impairment. The median apparent clearance of lamotrigine was 0.31, 0.24, or 0.10 mL/kg/min in patients with Grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34 mL/kg/min in the healthy controls. Median half-life of lamotrigine was 36, 60, or 110 hours in patients with Grade A, B, or C hepatic impairment, respectively, versus 32 hours in healthy controls.

Age: Pediatric Patients:    The pharmacokinetics of LAMICTAL following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged 10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received concomitant therapy with other AEDs and 12 patients received LAMICTAL as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.

Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.

Elderly:    The pharmacokinetics of lamotrigine following a single 150-mg dose of LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).

Gender:    The clearance of lamotrigine is not affected by gender. However, during dose escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.

Race:    The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

CLINICAL STUDIES

Epilepsy:    The results of controlled clinical trials established the efficacy of LAMICTAL as monotherapy in adults with partial onset seizures already receiving treatment with carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug (AED), as adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult patients.

Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone, as the Single AED:    The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.

Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.

The percentage of patients who met escape criteria was 42% (32/76) in the LAMICTAL group and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (p = 0.0012) in favor of LAMICTAL. No differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of LAMICTAL to an adequate dose of valproate.

Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures:    The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.

One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-mg/day group compared to the placebo group, but not in the 300-mg/day group.

A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on LAMICTAL compared to placebo (p<0.001).

The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on LAMICTAL compared to placebo (p<0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.

Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures:    The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate (maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference that was statistically significant (p<0.01).

Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut Syndrome:    The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose, 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a difference that was statistically significant (p<0.05). Drop attacks were significantly reduced by LAMICTAL (34%) compared to placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).

Bipolar Disorder:    The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).

In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day (n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day.

Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.