LAMICTAL (lamotrigine) is a drug of the phenyltriazine class chemically unrelated to existing antiepileptic drugs (AEDs).

Lamotrigine is thought to act at voltage-sensitive sodium channels to stabilize neuronal membranes and inhibit the release of excitatory amino acid neurotransmitters (e.g., glutamate, aspartate) that are thought to play a role in the generation and spread of epileptic seizures.

Clinical Trials: In adult placebo controlled clinical studies, LAMICTAL has been shown to be effective in reducing seizure frequency and the number of days with seizures, when added to existing antiepileptic drug therapy in adult patients with partial seizures, with or without generalized tonic-clonic seizures, that are not satisfactorily controlled.

The effectiveness of lamotrigine adjunctive therapy has also been shown in pediatric and adult patients with Lennox-Gastaut syndrome. A significant reduction in major motor seizures, drop attacks, and tonic-clonic seizures was seen following lamotrigine treatment compared with placebo-treated patients. Improvements in cognitive skills (speech, nonverbal communication, alertness, attention, intellectual capacity), behavior, and fine coordination have been seen with lamotrigine treatment in these patients.

Studies have also been conducted using lamotrigine monotherapy in adult patients (n=443) newly diagnosed with epilepsy (partial seizures, with or without secondary generalization or primary generalized tonic clonic). Results have shown comparable efficacy (time to first seizure, seizure frequency, percentage of patients seizure-free) with fewer side effects than currently approved therapies.

Clinical trials have also demonstrated that adult patients (any seizure type) can be converted to lamotrigine monotherapy from polytherapy, with significant numbers of patients maintaining or improving seizure control. Efficacy was maintained during long-term treatment (up to 152 weeks).

A 24-week monotherapy trial was conducted in elderly newly diagnosed patients (102 patients received lamotrigine and 48 received carbamazepine). The findings indicate comparable efficacy and demonstrate that lamotrigine was well tolerated in the elderly. However, the small and unbalanced number of patients in the study precludes any firm conclusions on the relative safety of the two drugs.

Adults: LAMICTAL is rapidly and completely absorbed following oral administration, reaching peak plasma concentrations 1.4 to 4.8 hours (T_max) post-dosing. When administered with food, the rate of absorption is slightly reduced, but the extent remains unchanged. Following single LAMICTAL doses of 50 to 400 mg, peak plasma concentration (C_max=0.6 to 4.6 µg/mL) and the area under the plasma concentration-versus-time curve (AUC=29.9 to 211 h·µg/mL) increase linearly with dose. The time-to-peak concentration, elimination half-life (t_1/2) and volume of distribution (Vd/F) are independent of dose. The t_1/2 averages 33 hours after single doses and Vd/F ranges from 0.9 to 1.4 L/kg. Following repeated dosing in healthy volunteers for 14 days, the t_1/2 decreased by an average of 26% (mean steady state t_1/2 of 26.4 hours) and plasma clearance increased by an average of 33%. In a single-dose study where healthy volunteers were administered both oral and i.v. doses of lamotrigine, the absolute bioavailability of oral lamotrigine was 98%.

Lamotrigine is approximately 55% bound to human plasma proteins. This binding is unaffected by therapeutic concentrations of phenytoin, phenobarbital or valproic acid. Lamotrigine does not displace other antiepileptic drugs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.

Lamotrigine is metabolized predominantly in the liver by glucuronic acid conjugation. The major metabolite is an inactive 2-N-glucuronide conjugate that can be hydrolyzed by β-glucuronidase. Approximately 70% of an oral LAMICTAL dose is recovered in urine as this metabolite.

Pediatrics: Lamotrigine was rapidly absorbed in children, with a T_max ranging from 1 to 6 hours. The mean Vd/F of lamotrigine in children aged 5 to 11 years (1.3 to 1.4 L/kg) was similar to that seen in adults (0.9 to 1.4 L/kg) but was larger in younger children (1.8 to 2.3 L/kg). As with adults, the elimination of lamotrigine in pediatric patients was similarly affected by concomitant AEDs. While the CL/F was higher and t_1/2 was shorter in younger children than in older children, the mean CL/F was higher and mean t_1/2 was shorter in both pediatric groups than in adults. Population analysis results showed that the estimated apparent plasma clearances in patients aged 13 to 18 years were similar to those found in adult patients.

Geriatrics (≥65 years): Results of a population pharmacokinetic analysis, based on individual trials in which both adult (n=138) and elderly (n=13) patients with epilepsy were enrolled, indicated that the clearance of lamotrigine in elderly patients did not change to a clinically relevant extent. After single doses, apparent clearance was lower in the elderly by 12% (31 mL/min at age 70 vs 35 mL/min at age 20). After 48 weeks of treatment, the difference in clearance was 10% (37 mL/min at age 70 vs 41 mL/min at age 20). In addition, the pharmacokinetics of lamotrigine were studied in 12 healthy elderly volunteers who each received a single oral dose of 150 mg. The mean clearance in the elderly (0.39 mL/min) lies within the range of mean clearance values (0.31 to 0.65 mL/min) obtained in 9 studies with non-elderly adults after single doses of 30 to 450 mg (see also Dosage and Adverse Effects).

Renal Impairment: The pharmacokinetics of a single oral dose of LAMICTAL (100 mg) were evaluated in 12 individuals with chronic renal failure (with mean creatinine clearance of 13 mL/min) who were not receiving other antiepileptic drugs. In this study, the elimination half-life of unchanged lamotrigine was prolonged (by an average of 63%) relative to individuals with normal renal function (see Precautions, Renal Failure and Dosage).

Hemodialysis: In 6 hemodialysis patients, the elimination half-life of unchanged lamotrigine was doubled off dialysis, and reduced by 50% on dialysis, relative to individuals with normal renal function.

Hepatic Impairment: A single-dose pharmacokinetic study was performed in 24 subjects with hepatic impairment (n=12 mild/Grade A; n=5 moderate/Grade B and n=7 severe/Grade C) vs 12 healthy controls. For the moderate and severe subgroups, the mean values for AUC and plasma half-life were increased approximately 2-fold and 3-fold respectively over control values, with clearance decreased proportionately. For the mild group, while mean values were not statistically different from those of controls, a subgroup of 1 to 4 subjects (dependent on pharmacokinetic parameter examined) showed abnormal individual values which were in the range of the moderately impaired subjects (see also Dosage and Precautions).

Gilbert's Syndrome: Gilbert's syndrome (idiopathic unconjugated hyperbilirubinemia) does not appear to affect the pharmacokinetic profile of lamotrigine.

Concomitant Antiepileptic Drugs: In patients with epilepsy, concomitant administration of LAMICTAL with enzyme-inducing AEDs (phenytoin, carbamazepine, primidone or phenobarbital) decreases the mean lamotrigine t_1/2 to 13 hours. Concomitant administration of LAMICTAL with valproic acid significantly increases t_1/2 and decreases the clearance of lamotrigine, whereas concomitant administration of LAMICTAL with valproic acid plus enzyme-inducing AEDs can prolong t_1/2 up to approximately 27 hours. The key lamotrigine parameters for adult patients and healthy volunteers are summarized in Table 1, and for pediatric patients in Table 2.

Table 1: LAMICTAL

Mean Pharmacokinetic Parameters in Adult Patients with Epilepsy or Healthy Volunteers

	LAMICTAL Administered	Healthy Young Volunteers		Patients with Epilepsy
		LAMICTAL	LAMICTAL+ Valproic Acidb	LAMICTAL+ Enzyme- Inducing AEDs	LAMICTAL+ Valproic Acid	LAMICTAL+ Valproic Acid +Enzyme-Inducing AEDs
Tmax (h)	Single Dose	2.2 (0.25–12.0)a	1.8 (1.0–4.0)	2.3 (0.5–5.0)	4.8 (1.8–8.4)	3.8 (1.0–10.0)
	Multiple Dose	1.7 (0.5–4.0)	1.9 (0.5–3.5)	2.0 (0.75–5.93)	ND	ND
t1/2 (h)	Single Dose	32.8 (14.0–103.0)	48.3 (31.5–88.6)	14.4 (6.4–30.4)	58.8 (30.5–88.8)	27.2 (11.2–51.6)
	Multiple Dose	25.4 (11.6–61.6)	70.3 (41.9–113.5)	12.6 (7.5–23.1)	ND	ND
Plasma Clearance (mL/min/kg)	Single Dose	0.44 (0.12–1.10)	0.30 (0.14–0.42)	1.10 (0.51–2.22)	0.28 (0.16–0.40)	0.53 (0.27–1.04)
	Multiple Dose	0.58 (0.24–1.15)	0.18 (0.12–0.33)	1.21 (0.66–1.82)	ND	ND

^a. Range of individual values across studies.
^b. Valproic acid administered chronically (Multiple Dose Study) or for 2 days (Single Dose Study).

Legend:


Table 2: LAMICTAL

Mean Pharmacokinetic Parameters in Pediatric Patients with Epilepsy

Pediatric Study Population	Number of Subjects	Tmax (h)	t1/2 (h)	CL/F (mL/min/kg)
Ages 10 months to 5.3 years
Patients taking EIAEDs	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 drug-metabolizing enzymes	7	5.2 (2.9–6.1)	19.0 (12.9–27.1)	1.2 (0.75–2.42)
Patients taking VPA only	8	2.9 (1.0–6.0)	44.9 (29.5–52.5)	0.47 (0.23–0.77)
Ages 5 to 11 years
Patients taking EIAEDs	7	1.6 (1.0–3.0)	7.0 (3.8–9.8)	2.54 (1.35–5.58)
Patients taking EIAEDs plus VPA	8	3.3 (1.0–6.4)	19.1 (7.0–31.2)	0.89 (0.39–1.93)
Patients taking VPA onlyb	3	4.5 (3.0–6.0)	55.4 (24.3–73.7)	0.31 (0.20–0.54)
Ages 13 to 18 years
Patients taking EIAEDs	11	a	a	1.3
Patients taking EIAEDs plus VPA	8	a	a	0.5
Patients taking VPA only	4	a	a	0.3

^a. Parameter not estimated.
^b. Two subjects were included in the calculation for mean t_max.

Legend:

Oxcarbazepine did not affect the apparent clearance of lamotrigine (see Precautions, Drug Interactions).

LAMICTAL (lamotrigine) is indicated: as adjunctive therapy for the management of adult patients with epilepsy who are not satisfactorily controlled by conventional therapy; for use as monotherapy in adults following withdrawal of concomitant antiepileptic drugs; as adjunctive therapy for the management of the seizures associated with Lennox-Gastaut syndrome in pediatric and adult patients.

LAMICTAL (lamotrigine) is contraindicated in patients with known hypersensitivity to lamotrigine or to any components of the formulation.

Serious rashes associated with hospitalization have occurred with the use of LAMICTAL (lamotrigine). The incidence of these rashes in clinical trials was 1% (1/100) in pediatric patients (age <16 years) and 0.3% (3/1000) in adults. The incidence of serious rash reported as Stevens-Johnson syndrome (SJS) in clinical trials was 0.5% (1/200) in pediatric patients and 0.1% (1/1000) in adults. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or death associated with rash have been reported, but their numbers are too few to permit a precise estimate of the rate.

Serious Rash Associated with Rapid Titration: A higher incidence of serious dermatologic events (see Precautions, Skin-related Events, Table 3 and Table 4; see also Dosage) has been associated with more rapid initial titration (exceeding the recommended initial dose or exceeding the recommended dose escalation), and use of concomitant valproic acid.

Rash Associated with a History of Rash to Other Antiepileptic Drugs: In two studies (n=767 and n=988), the frequency of rash with lamotrigine treatment was approximately 3-4 times higher in patients with a history of allergy or rash to other anti-epileptics, compared to those without such history.

Nearly all cases of rash associated with LAMICTAL have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk signalled by the first appearance of a rash.

Although benign rashes also occur with LAMICTAL, it is not possible to predict reliably which rashes will prove to be life-threatening. Accordingly, all patients who develop rash should be promptly evaluated and LAMICTAL withdrawn immediately, unless the rash is clearly not drug-related.

Hypersensitivity Reactions: Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial edema and abnormalities of the blood and liver (see Adverse Effects). The syndrome shows a wide spectrum of clinical severity and may rarely lead to disseminated intravascular coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present, the patient should be evaluated immediately and LAMICTAL discontinued if an alternative etiology cannot be established.

Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Patients taking LAMICTAL should be advised not to start or stop their oral contraceptives without consulting their physician. Significant adjustments in the maintenance dose of LAMICTAL may be required in some patients (see Precautions, Drug Interactions, Oral Contraceptives and Dosage, Women and Oral Contraceptives).

Drug Discontinuation: Abrupt discontinuation of any antiepileptic drug (AED) in a responsive patient with epilepsy may provoke rebound seizures. In general, withdrawal of an AED should be gradual, to minimize this risk. Unless safety concerns (i.e., rash) require a more rapid withdrawal, the dose of LAMICTAL (lamotrigine) should be tapered over a period of at least 2 weeks (see Dosage).

Patients with uncontrolled epilepsy should not drive or handle potentially dangerous machinery. During clinical trials, common adverse effects included dizziness, ataxia, drowsiness, diplopia and blurred vision. Patients should be advised to refrain from activities requiring mental alertness or physical coordination until they are sure that LAMICTAL does not affect them adversely.

In adult controlled studies of adjunctive lamotrigine therapy, the incidence of rash (usually maculopapular and/or erythematous) in patients receiving LAMICTAL was 10%, compared with 5% in placebo patients. The rash usually occurred within the first 6 weeks of therapy and resolved during continued administration of LAMICTAL. LAMICTAL was discontinued because of rash in 1.1% of adult patients in controlled studies and 3.8% of all patients in all studies. The rate of rash-related withdrawal in clinical studies was higher with more rapid initial titration dosing, and in patients receiving concomitant valproic acid (VPA), particularly in the absence of enzyme-inducing AEDs (see Table 3 and Table 4; see also Warnings and Dosage).

Table 3: LAMICTAL

Effect of Concomitant AEDs on Rash Associated with LAMICTAL in All Adult Controlled and Uncontrolled Clinical Trials Regardless of Dosing Escalation Scheme

AED Group	Total Patient Number	All Rashes	Withdrawal Due to Rash	Hospitalization in Association with Rash
Enzyme-inducing AEDsa	1788	9.2%	1.8%	0.1%
Enzyme-inducing AEDsa+VPA	318	8.8%	3.5%	0.9%
VPA±Non-enzyme-inducing AEDsb	159	20.8%	11.9%	2.5%
Non-enzyme-inducing AEDsb	27	18.5%	0.0%	0.0%

^a. Enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin and primidone.
^b. Non-enzyme-inducing AEDs include clonazepam, clobazam, ethosuximide, methsuximide, vigabatrin and gabapentin.



Table 4: LAMICTAL

Effect of the Initial Daily Dose^a of LAMICTAL in the Presence of Concomitant AEDs on the Incidence of Rash Leading to Withdrawal of Treatment in Adult Add-on Clinical Trials

AED Group	Enzyme-inducing AEDsb		Enzyme-inducing AEDsb+VPA		VPA±Non-enzyme-inducing AEDsc
LAMICTAL Average Daily Dose (mg)	Total Patient Number	Percentage of Patients Withdrawn	Total Patient Number	Percentage of Patients Withdrawn	Total Patient Number	Percentage of Patients Withdrawn
12.5	9	0.0	10	0.0	51	7.8
25	3	0.0	7	0.0	58	12.1
50	182	1.1	111	0.9	35	5.7
100	993	1.4	179	4.5	15	40.0
≥125	601	2.8	11	18.2	0	0.0

^a. Average daily dose in week 1.
^b. Enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin and primidone.
^c. Non-enzyme-inducing AEDs include clonazepam, clobazam, ethosuximide, methsuximide, vigabatrin and gabapentin.

Increased incidence of rash-related withdrawal was seen when initial doses were higher and titration more rapid than recommended under Dosage.

Caution is also required when treating patients with a history of allergy or rash to other anti-epileptic drugs, as it was found in two studies (n=767 and n=988) on the frequency of rash after treatment with lamotrigine that the rate of rash was approximately three-four times higher in patients with such a history, than those without.

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL for any reason, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of LAMICTAL is affected by other concomitant medications (see Pharmacology, Pharmacokinetics and Dosage).

Antiepileptic Drugs (AEDs): Lamotrigine does not affect the plasma concentrations of concomitantly administered enzyme-inducing AEDs. Antiepileptic drugs that induce hepatic drug-metabolizing enzymes (phenytoin, carbamazepine, phenobarbital, primidone) increase the plasma clearance and reduce the elimination half-life of lamotrigine (see Pharmacology).

Valproic acid reduces the plasma clearance and prolongs the elimination half-life of lamotrigine (see Pharmacology). When LAMICTAL was administered to 18 healthy volunteers already receiving valproic acid, a modest decrease (25% on average) in the trough steady-state valproic acid plasma concentrations was observed over a 3-week period, followed by stabilization. However, the addition of LAMICTAL did not affect the plasma concentration of valproic acid in patients receiving enzyme-inducing AEDs in combination with valproic acid (see Precautions, Skin-related Events).

The AUC and C_max of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n=13) compared to healthy male volunteers receiving oxcarbazepine alone (n=13). Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with co-administration of LAMICTAL and oxcarbazepine compared to LAMICTAL alone or oxcarbazepine alone.

The net effects of co-administration of LAMICTAL with phenytoin, carbamazepine, oxcarbazepine, or valproic acid are summarized in Table 5.

Table 5: LAMICTAL

Summary of AED Interactions with LAMICTAL

AED	AED Plasma Concentration with Adjunctive Lamotriginea	Lamotrigine Plasma Concentration with Adjunctive AEDsb
Phenytoin (PHT)	No significant effect	↓ 50%
Carbamazepine (CBZ)	No significant effect	↓ 40%
CBZ epoxidec	Conflicting data
Oxcarbazepine	No significant effect	No significant effect
10-monohydroxy oxcarbazepine metabolite	No significant effect	Not evaluated
Valproic Acid (VPA)	Decreased	↑ 200%
VPA+PHT and/or CBZ	Not evaluated	No significant effect

^a. From adjunctive clinical trials and volunteer studies.
^b. Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer studies.
^c. Not administered, but an active metabolite of carbamazepine.

Effect of Oral Contraceptives on LAMICTAL: In a study in 6 female volunteers, an oral contraceptive preparation containing 30 µg ethinylestradiol and 150 µg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately two fold with a mean decrease in AUC of 52% and in C_max 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 preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week) for women not also taking a drug that increases the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine levels will be greater if the dose of LAMICTAL is increased in the few days before or during the pill-free week.

Dosage adjustments may be necessary for women receiving oral contraceptive preparations (see Dosage, Women and Oral Contraceptives).

Co-administration of LAMICTAL: (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of an oral contraceptive preparation containing 30 µg ethinylestradiol and 150 µg levonorgestrel. There was a mean decrease in the AUC and C_max 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 studied.

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).

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, although the effect may be similar to oral contraceptive preparations. Therefore, as for oral contraceptives, dosage adjustments may be necessary (see Dosage, Women and Oral Contraceptives).

The AUC and C_max of lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n=16) compared to healthy male volunteers receiving LAMICTAL alone (n=12). This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.

In a study 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%). For patients taking rifampin with LAMICTAL, follow the titration schedule for concomitant enzyme-enducing AEDs (without VPA) (see Dosage, Table 9).