LAMOTRIGINE Kit (Page 9 of 12)

8.5 Geriatric Use

Clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Clinical Pharmacology (12.3)] , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response [see Dosage and Administration (2.1)].

8.7 Renal Impairment

Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see Clinical Pharmacology (12.3)].

Initial doses of lamotrigine should be based on patients’ AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients [see Dosage and Administration (2.1)].

10 OVERDOSAGE

10.1 Human Overdose Experience

Overdoses involving quantities up to 15 g have been reported for 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.

10.2 Management of Overdose

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 should be kept in mind that immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. 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.

11 DESCRIPTION

Lamotrigine, USP an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as -triazine, its molecular formula is C9 H7 N5 Cl2 , and its molecular weight is 256.09. Lamotrigine, USP is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine, USP is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

Structure

Lamotrigine tablets, USP are supplied for oral administration as 25-mg (white to off white), 100-mg (white to off white) tablets. Each tablet contains the labeled amount of lamotrigine, USP and the following inactive ingredients: lactose monohydrate; magnesium stearate; microcrystalline cellulose; povidone; and sodium starch glycolate.

Meets USP Dissolution Test 3

12 CLINICAL PHARMACOLOGY

12.1 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 virto 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).

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.

12.2 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 (8.1)]. 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, patients taking concomitant medications that inhibit glucuronidation).

12.3 Pharmacokinetics

The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric subjects and healthy normal volunteers are summarized in Tables 14 and 16.

Table 14. Mean Pharmacokinetic Parametersa in Healthy Volunteers and Adult Subjects with Epilepsy

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 Tm a x . The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/subjects in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/subject values across studies.

b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [ see Drug Interactions ( 7 )].

Adult Study Population Number of Subjects Tm a x : Time of Maximum Plasma Concentration ( h ) t1 / 2 : Elimination Half - life ( h ) CL / F : Apparent Plasma Clearance ( mL / min / kg )
Healthy volunteers taking no other medications : Single-dose Lamotrigine Multiple-dose Lamotrigine 17936 2.2(0.25 to 12.0)1.7(0.5 to 4.0) 32.8(14.0 to 103.0)25.4(11.6 to 61.6) 0.44(0.12 to 1.10)0.58(0.24 to 1.15)
Healthy volunteers taking valproate : Single-dose Lamotrigine Multiple-dose Lamotrigine 618 1.8(1.0 to 4.0)1.9(0.5 to 3.5) 48.3(31.5 to 88.6)70.3(41.9 to 113.5) 0.30(0.14 to 0.42)0.18(0.12 to 0.33)
Subjects with epilepsy taking valproate only : Single-dose Lamotrigine 4 4.8(1.8 to 8.4) 58.8(30.5 to 88.8) 0.28(0.16 to 0.40)
Subjects with epilepsy taking carbamazepine , phenytoin , phenobarbital , or primidoneb plus valproate : Single-dose Lamotrigine 25 3.8(1.0 to 10.0) 27.2(11.2 to 51.6) 0.53(0.27 to 1.04)
Subjects with epilepsy taking carbamazepine , phenytoin , phenobarbital , or primidone : b Single-dose Lamotrigine Multiple-dose Lamotrigine 2417 2.3(0.5 to 5.0)2.0(0.75 to 5.93) 14.4(6.4 to 30.4)12.6(7.5 to 23.1) 1.10(0.51 to 2.22)1.21(0.66 to 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 14 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%).

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 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 other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) ].

Elimination

The elimination half-life and apparent clearance of lamotrigine following oral administration of lamotrigine to adult subjects 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, 5.12), 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

a From adjunctive clinical trials and volunteer trials.

b Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer trials.

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 Slight decrease, not expected to be clinically meaningful.

f Compared with historical controls.

g Not administered, but an active metabolite of carbamazepine.

h Not administered, but an active metabolite of oxcarbazepine.

i Not administered, but an active metabolite of risperidone.

j Slight increase, not expected to be clinically meaningful.

↔ = No significant effect.

? = Conflicting data.

Drug Drug Plasma Concentration with Adjunctive Lamotriginea Lamotrigine Plasma Concentration with Adjunctive Drugsb
Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)c d
Aripiprazole Not assessed e
Atazanavir/ritonavir f
Bupropion Not assessed
Carbamazepine
Carbamazepine epoxideg ?
Felbamate Not assessed
Gabapentin Not assessed
Lacosamide Not assessed
Levetiracetam
Lithium Not assessed
Lopinavir/ritonavir e
Olanzapine e
Oxcarbazepine
10-Monohydroxy oxcarbazepine metaboliteh
Perampanel Not assessed
Phenobarbital/primidone
Phenytoin
Pregabalin
Rifampin Not assessed
Risperidone Not assessed
9-Hydroxyrisperidonei
Topiramate j
Valproate
Valproate + phenytoin and/or Not assessed
carbamazepine
Zonisamide Not assessed

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 and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir 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 (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 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 Cmax were reduced by approximately 10% in patients who received aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in lamotrigine exposure is not considered clinically meaningful.

Atazanavir/Ritonavir

In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.

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 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 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 trial in 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.

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.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.

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.

Lopinavir/Ritonavir

The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the AUC, Cmax , and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant lamotrigine, compared with that in historical controls.

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 trial, 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 meaningful.

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 trial, 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.

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 coadministration 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, 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

In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations, with IC50 value of 53.8 μM [see Drug Interactions (7)].

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, sertraline, or trazodone.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.

Specific 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 (2.1)].

Patients with Hepatic Impairment: 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 subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects 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 subjects 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 (2.1)].

Pediatric patients: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy with other AEDs and 12 subjects received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.

Population pharmacokinetic analyses involving subjects 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 <30 kg compared with those weighing >30 kg. Accordingly, patients weighing <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 (2.2)]. 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 Subjects with Epilepsy

a Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to increase the apparent clearance of lamotrigine [ see Drug Interactions ( 7 )].

b Two subjects were included in the calculation for mean Tm a x .

c Parameter not estimated.

Pediatric Study Population Number of Subjects Tm a x ( h ) t1 / 2 ( h ) CL / F ( mL / min / kg )
Ages 10 months to 5 . 3 years Subjects taking carbamazepine, phenytoin, phenobarbital, or primidonea Subjects taking antiepileptic 10 3.0(1.0 to 5.9) 7.7 (5.7 to 11.4) 3.62 (2.44 to 5.28)
drugs with no known effect on the apparent clearance of lamotrigine Subjects taking 7 5.2(2.9 to 6.1) 19.0 (12.9 to 27.1) 1.2 (0.75 to 2.42)
valproate only 8 2.9(1.0 to 6.0) 44.9(29.5 to 52.5) 0.47(0.23 to 0.77)
Ages 5 to 11 years Subjects taking carbamazepine, phenytoin, phenobarbital, or primidonea 7 1.6 (1.0 to 3.0) 7.0 (3.8 to 9.8) 2.54 (1.35 to 5.58)
Subjects taking carbamazepine, phenytoin, phenobarbital, or primidonea plus valproate 8 3.3 (1.0 to 6.4) 19.1 (7.0 to 31.2) 0.89 (0.39 to 1.93)
Subjects taking valproate onlyb 3 4.5 (3.0 to 6.0) 65.8 (50.7 to 73.7) 0.24 (0.21 to 0.26)
Ages 13 to 18 years Subjects taking carbamazepine, phenytoin, phenobarbital, or primidonea 11 ___c ___c 1.3
Subjects taking valproate only 4 ___c ___c 0.3

Geriatric Patients: 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).

Male and Female Patients: The clearance of lamotrigine is not affected by gender. However, during dose escalation of lamotrigine in 1 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.

Racial or Ethnic Groups: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

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