"The U.S. Food and Drug Administration today approved Aptiom (eslicarbazepine acetate) as an add-on medication to treat seizures associated with epilepsy.
Epilepsy is a brain disorder caused by abnormal or excessive activity in the brain"...
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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. 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 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).
Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine 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 α1, α2, and β; dopamine D1 and D2; γ-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.
The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.
In vitro, lamotrigine inhibited 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 Use In Specific Populations]. 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 accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.
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.
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. 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).
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 14 and 16.
Table 14: Meana Pharmacokinetic Parameters in Healthy
Volunteers and Adult Patients With Epilepsy
|Adult Study Population||Number of Subjects||Tmax: Time of Maximum Plasma Concentration (hr)||t½: Elimination Half-life (hr)||Cl/F: Apparent Plasma Clearance (mL/min/kg)|
|Healthy volunteers taking no other medications:|
|Healthy volunteers taking valproate:|
|Patients with epilepsy taking valproate only:|
|Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidoneb plus valproate:|
|Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:b|
|a The majority of parameter means determined
in each study had coefficients of variation between 20% and 40% for half-life
and Cl/F and between 30% and 70% for Tmax. The overall mean values were
calculated from individual study means that were weighted based on the number
of volunteers/patients in each study. The numbers in parentheses below each
parameter mean represent the range of individual volunteer/patient values
b Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see DRUG INTERACTIONS].
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. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth or swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed with water.
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.
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.
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.
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 14C-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%).
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 t½ and a 37% increase in Cl/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS].
The elimination half-life and apparent clearance of lamotrigine following administration of LAMICTAL to adult patients with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs.
The net effects of drug interactions with LAMICTAL are summarized in Tables 13 and 15, followed by details of the drug interaction studies below.
Table 15: Summary of Drug Interactions With LAMICTAL
|Drug||Drug Plasma Concentration With Adjunctive LAMICTALa||Lamotrigine Plasma Concentration With Adjunctive Drugsb|
|Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)c||↔d||↓|
|10-monohydroxy oxcarbazepine metaboliteg||↔|
|Valproate + PHT and/or CBZ||Not assessed||↔|
|a From adjunctive clinical trials and
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer studies.
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.
d Modest decrease in levonorgestrel.
e Not administered, but an active metabolite of carbamazepine.
f Slight decrease, not expected to be clinically relevant.
g Not administered, but an active metabolite of oxcarbazepine.
h Slight increase, not expected to be clinically relevant.
↔ = 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 Cmax 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 hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.
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 that induce lamotrigine glucuronidation [see DRUG INTERACTIONS]). The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.
In the same study, coadministration of LAMICTAL (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 Cmax 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 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.g., break-through bleeding).
Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see DOSAGE AND ADMINISTRATION].
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 LAMICTAL in the presence of progestogens alone will likely not be needed.
The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before LAMICTAL.
LAMICTAL 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]. The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.
In a study of 21 healthy volunteers, coadministration 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.
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
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.
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same study, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).
In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared with those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.
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%.
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.
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%).
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
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 one study, 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.
In a study of 18 patients with epilepsy, coadministration 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 may require adjustment based on clinical response.
Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.
Patients With Renal Impairment: 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 lamotrigine. 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 with 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 [see DOSAGE AND ADMINISTRATION].
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see DOSAGE AND ADMINISTRATION].
Age: Pediatric Patients: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients 10 months to 5.9 years of age and n = 26 for patients 5 to 11 years of age). Forty-three patients received concomitant therapy with other AEDs and 12 patients received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.
Population pharmacokinetic analyses involving patients 2 to 18 years of age 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.
Table 16: Mean Pharmacokinetic Parameters in Pediatric
Patients With Epilepsy
|Pediatric Study Population||Number of Subjects||Tmax
|Ages 10 months-5.3 years|
|Patients taking carbamazepine, phenytoin, phenobarbital, or primidonea||10||3
|Patients taking AEDs with no known effect on the apparent clearance of lamotrigine||7||5.2
|Patients taking valproate only||8||2.9
|Ages 5-11 years|
|Patients taking carbamazepine, phenytoin, phenobarbital, or primidonea||7||1.6
|Patients taking carbamazepine, phenytoin, phenobarbital, or primidonea plus valproate||8||3.3
|Patients taking valproate onlyb||3||4.5
|Ages 13-18 years|
|Patients taking carbamazepine, phenytoin, phenobarbital, or primidonea||11||c||c||1.3|
|Patients taking carbamazepine, phenytoin, phenobarbital, or primidonea plus valproate||8||c||c||0.5|
|Patients taking valproate only||4||c||c||0.3|
|a Carbamazepine, phenobarbital, phenytoin, and
primidone have been shown to increase the apparent clearance of lamotrigine.
Estrogen-containing oral contraceptives and rifampin have also been shown to
increase the apparent clearance of lamotrigine [see DRUG INTERACTIONS].
b Two subjects were included in the calculation for mean Tmax.
c Parameter not estimated.
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.
Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug
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 seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.
The percentages of patients who met escape criteria were 42% (32/76) in the group receiving LAMICTAL 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 with 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 with 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 with 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 2 to 16 years of age (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/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/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 3 to 25 years of age (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/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/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 with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).
Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures
The effectiveness of LAMICTAL as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥ 2 years (n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with LAMICTAL 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 3 mg/kg/day to 12 mg/kg/day for pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant AED.
The primary efficacy endpoint was percentage change from baseline in primary generalized tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on placebo, a difference that was statistically significant (P = 0.006).
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 dose of LAMICTAL 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.
Last reviewed on RxList: 2/25/2014
This monograph has been modified to include the generic and brand name in many instances.
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