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. 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.
Pharmacodynamics
Folate Metabolism: 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.
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 Clinical Pharmacology
(12.3)]
. 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
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. Mean
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) |
C1/F: Apparent Plasma Clearance (mL/min/kg) |
Healthy volunteers taking no other medications:
|
|
|
|
|
Single-dose Lamotrigine |
179 |
2.2 (0.25-12.0) |
32.8 (14.0-103.0) |
0.44 (0.12-1.10) |
Multiple-dose Lamotrigine |
36 |
1.7 (0.5-4.0) |
25.4 (11.6-61.6) |
0.58 (0.24-1.15) |
Healthy volunteers taking valproate:
|
|
|
|
|
Single-dose Lamotrigine |
6 |
1.8 (1.0-4.0) |
48.3 (31.5-88.6) |
0.30 (0.14-0.42) |
Multiple-dose Lamotrigine |
18 |
1.9 (0.5-3.5) |
70.3 (41.9-113.5) |
0.18 (0.12-0.33) |
Patients with epilepsy taking valproate only:
|
|
|
|
|
Single-dose Lamotrigine |
4 |
4.8 (1.8-8.4) |
58.8 (30.5-88.8) |
0.28 (0.16-0.40) |
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone
plus valproate:
|
|
|
|
|
Single-dose Lamotrigine |
25 |
3.8 (1.0-10.0) |
27.2 (11.2-51.6) |
0.53 (0.27-1.04) |
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:
|
|
|
|
|
Single-dose Lamotrigine |
24 |
2.3 (0.5-5.0) |
14.4 (6.4-30.4) |
1.10 (0.51-2.22) |
Multiple-dose Lamotrigine |
17 |
2.0 (0.75-5.93) |
12.6 (7.5-23.1) |
1.21 (0.66-1.82) |
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.
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.
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.
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 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%).
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 t½ and a 37% increase in C1/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 (7)].
Elimination: The elimination half-life and apparent clearance of Lamotrigine following administration of Lamotrigine to adult patients with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs.
Drug Interactions: The apparent clearance of Lamotrigine is affected by the coadministration of certain medications [see Warnings and Precautions (5.8, 5.13), Drug Interactions (7)].
The net effects of drug interactions with Lamotrigine are summarized in Tables 13 and 15, followed by details of the drug interaction studies below.
Table 15. Summary of Drug Interactions With Lamotrigine
Drug |
Drug Plasma Concentration With Adjunctive Lamotrigine
|
Lamotrigine Plasma Concentration With Adjunctive Drugs
|
Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)
|
↔
|
↓ |
Bupropion |
Not assessed |
↔ |
Carbamazepine (CBZ) |
↔ |
↓ |
CBZ epoxide
|
? |
|
Felbamate |
Not assessed |
↔ |
Gabapentin |
Not assessed |
↔ |
Levetiracetam |
↔ |
↔ |
Lithium |
↔ |
Not assessed |
Olanzapine |
↔ |
↔
|
Oxcarbazepine |
↔ |
↔ |
10-monohydroxy oxcarbazepine metabolite
|
↔ |
|
Phenobarbital/primidone |
↔ |
↓ |
Phenytoin (PHT) |
↔ |
↓ |
Pregabalin |
↔ |
↔ |
Rifampin |
Not assessed |
↓ |
Topiramate |
↔
|
↔ |
Valproate |
↓ |
↑ |
Valproate + PHT and/or CBZ |
Not assessed |
↔ |
Zonisamide |
Not assessed |
↔ |
↔ = 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 a mean decrease 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 (7)). The increase in Lamotrigine plasma levels will be greater if the dose of Lamotrigine 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 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 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 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.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 Lamotrigine in the presence of progestogens alone will likely not be needed.
Bupropion: The pharmacokinetics of a 100-mg single dose of Lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice a day) 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 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%.
Felbamate: 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.
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 patients who received Lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of Lamotrigine.
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 coadministration of Lamotrigine (100 mg/day) for 6 days.
Olanzapine: 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.
Oxcarbazepine: 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 Lamotrigine in healthy male volunteers compared with those receiving Lamotrigine 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.
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%).
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 one study, maximal inhibition of Lamotrigine clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not increase as the valproate dose was further increased.
Zonisamide: 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.
Other: 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.
Special Populations:
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 (hr) |
t½ (hr) |
C1/F (mL/min/kg) |
Ages 10 months-5.3 years
|
|
|
|
|
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone
|
10 |
3.0 (1.0- 5.9) |
7.7 (5.7- 11.4) |
3.62 (2.44- 5.28) |
Patients taking AEDs with no known effect on the apparent clearance of Lamotrigine |
7 |
5.2 (2.9- 6.1) |
19.0 (12.9- 27.1) |
1.2 (0.75- 2.42) |
Patients taking valproate only |
8 |
2.9 (1.0- 6.0) |
44.9 (29.5- 52.5) |
0.47 (0.23- 0.77) |
Ages 5-11 years
|
|
|
|
|
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone
|
7 |
1.6 (1.0- 3.0) |
7.0 (3.8- 9.8) |
2.54 (1.35- 5.58) |
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone plus valproate |
8 |
3.3 (1.0- 6.4) |
19.1 (7.0- 31.2) |
0.89 (0.39- 1.93) |
Patients taking valproate only
|
3 |
4.5 (3.0- 6.0) |
65.8 (50.7- 73.7) |
0.24 (0.21- 0.26) |
Ages 13-18 years
|
|
|
|
|
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone
|
11 |
|
|
1.3 |
Patients taking carbamazpine, phenytoin, phenobarbital, or primidone plus valproate |
8 |
|
|
0.5 |
Patients taking valproate only |
4 |
|
|
0.3 |
Elderly: The pharmacokinetics of Lamotrigine following a single 150-mg dose of Lamotrigine 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 Lamotrigine 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of Lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg/day for mice and 10 to 15 mg/kg/day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), Lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.
No evidence of impairment of fertility was detected in rats given oral doses of Lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg/day or 0.4 times the human dose on a mg/m2 basis. The effect of Lamotrigine on human fertility is unknown.
|