Lamictal®

Lamotrigine

Antiepileptic

GlaxoSmithKline

http://www.gsk.com/index.htm

Lamictal Monograph PDF download here.

 

CPS:PIS_m280800

Date of Preparation: July 9, 2001

 

 

 

Pharmacology

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, lamotrigine 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.

 

Pharmacokinetics

Adults: Lamotrigine is rapidly and completely absorbed following oral administration, reaching peak plasma concentrations 1.4 to 4.8 hours (T_max) postdosing. When administered with food, the rate of absorption is slightly reduced, but the extent remains unchanged. Following single lamotrigine 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 lamotrigine 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: 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 nonelderly 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 lamotrigine (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 lamotrigine with enzyme-inducing AEDs (phenytoin, carbamazepine, primidone or phenobarbital) decreases the mean lamotrigine t_1/2 to 13 hours. Concomitant administration of lamotrigine with valproic acid significantly increases t_1/2 and decreases the clearance of lamotrigine, whereas concomitant administration of lamotrigine with valproic acid plus enzyme-inducing AEDs can prolong t_1/2 up to approximately 27 hours. Chronic administration of acetaminophen was shown to slightly decrease the t_1/2 and increase the clearance of a single dose of lamotrigine. The key lamotrigine parameters for adult patients and healthy volunteers are summarized in  Table 1, and for pediatric patients in  Table 2.

CPS:Lamictal_t1Click here for Table 1

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:

ND=Not done.

 

CPS:Lamictal_t2Click here for Table 2

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:

EIAEDs=Enzyme Inducing Antiepileptic Drugs.

VPA=Valproic acid.

 

 

Indications

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.

 

Contraindications

In patients with known hypersensitivity to lamotrigine or to any components of the formulation.

 

Warnings

Serious rashes associated with hospitalization have occurred with the use of 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.

     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.

     Nearly all cases of rash associated with lamotrigine 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 lamotrigine, 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 lamotrigine 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 lamotrigine discontinued if an alternative etiology cannot be established.

     Prior to initiation of treatment with lamotrigine, 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.

 

Precautions

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 lamotrigine should be tapered over a period of at least 2 weeks (see Dosage).

 

Occupational Hazards

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 lamotrigine does not affect them adversely.

Skin-related Events: In adult controlled studies of adjunctive lamotrigine therapy, the incidence of rash (usually maculopapular and/or erythematous) in patients receiving lamotrigine 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 lamotrigine. Lamotrigine 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).

CPS:Lamictal_t3Click here for Table 3

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.

 

 

CPS:Lamictal_t4Click here for Table 4

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.

 

Drug Interactions

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 lamotrigine 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 lamotrigine 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 net effects of coadministration of lamotrigine with phenytoin, carbamazepine or valproic acid are summarized in  Table 5.

CPS:Lamictal_t5Click here for 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
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.

 

 

Oral Contraceptives: In a study of 12 female volunteers, lamotrigine did not affect plasma concentrations of ethinyl estradiol and levonorgestrel following administration of the oral contraceptive pill. However, as with the introduction of other chronic therapy in patients taking oral contraceptives, the patient should be asked to report any change in the menstrual bleeding pattern.

Drugs Depressing Cardiac Conduction: See Patients with Special Diseases and Conditions and Cardiac Conduction Abnormalities.

Drug/Laboratory Test Interactions

Lamotrigine has not been associated with any assay interferences in clinical laboratory tests.

 

Children

Safety and efficacy in patients below the age of 16 years, other than those with Lennox-Gastaut Syndrome, have not been established.

Geriatrics

As the pharmacokinetics in this age group do not differ significantly from a nonelderly adult population, no dosage adjustment from the recommended adult schedule is required (see also Dosage, Adverse Effects and Pharmacology).

 

Pregnancy

Studies in mice, rats and rabbits given lamotrigine orally or i.v. revealed no evidence of teratogenicity; however, maternal and secondary fetal toxicity were observed. Studies in rats and rabbits indicate that lamotrigine crosses the placenta; placental and fetal levels of lamotrigine were low and comparable to levels in maternal plasma. Because animal reproduction studies are not always predictive of human response, lamotrigine should only be used during pregnancy if the benefits of therapy outweigh the risks associated with it.

     Clinical trial data indicate that lamotrigine has no effect on blood folate concentrations in adults; however, its effects during human fetal development are unknown.

     To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, in the Lamotrigine Drug Pregnancy Registry by calling 1-800-336-2176 (toll free).

Labor and Delivery: The effect of lamotrigine on labor and delivery in humans is unknown.

 

Lactation

There is limited information on the use of lamotrigine in lactation. Preliminary data indicate that lamotrigine passes into human milk in concentrations usually of the order 40 to 60% of the serum concentration. In a small number of infants known to have been breast-fed, the serum concentrations of lamotrigine reached levels at which pharmacological effects may occur. Because of the potential for adverse reactions from lamotrigine in nursing infants, breast-feeding while taking this medication is not recommended.

Patients with Special Diseases and Conditions: Clinical experience with lamotrigine in patients with concomitant illness is limited. Caution is advised when using lamotrigine in patients with diseases or conditions that could affect the metabolism or elimination of the drug.

Renal Failure: A study in individuals with chronic renal failure (not receiving other AEDs) indicated that the elimination half-life of unchanged lamotrigine is prolonged relative to individuals with normal renal function (see Pharmacology). Use of lamotrigine in patients with severe renal impairment should proceed with caution.

Impaired Liver Function: Results from a single-dose pharmacokinetic study indicate that the apparent clearance of lamotrigine decreased in subjects with Grades A, B or C hepatic impairment. A reduced dosage should be used for all hepatically impaired patients, and lamotrigine should be administered with caution particularly in those patients with severe hepatic impairment (see also Dosage and Pharmacology).

Cardiac Conduction Abnormalities: One placebo-controlled trial that compared ECGs at baseline and during treatment demonstrated a mild prolongation of the PR interval associated with lamotrigine administration. The prolongation was statistically significant but clinically insignificant. Patients with significant cardiovascular disease or electrocardiographic abnormalities were, however, systematically excluded from clinical trials. Thus, lamotrigine should be used with caution in patients with cardiac conduction abnormalities, and in patients taking concomitant medications which depress AV conduction.

Dependence Liability: No evidence of abuse potential has been associated with lamotrigine, nor is there evidence of psychological or physical dependence in humans.

Laboratory Tests: The use of lamotrigine does not require routine monitoring of any clinical laboratory parameters or plasma levels of concomitant AEDs.

 

Adverse Effects

Rarely, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported. Although the majority recover following drug withdrawal, some patients experience irreversible scarring and there have been rare cases of associated death (see Warnings).

     Adverse experiences in patients receiving lamotrigine were generally mild, occurred within the first 2 weeks of therapy, and resolved without discontinuation of the drug.

Commonly Observed: The most commonly observed adverse experiences associated with the use of adjunctive therapy with lamotrigine (incidence of at least 10%) were dizziness, headache, diplopia, somnolence, ataxia, nausea and asthenia.

     Dizziness, diplopia, ataxia and blurred vision were dose-related and occurred more commonly in patients receiving carbamazepine in combination with lamotrigine than in patients receiving other enzyme-inducing AEDs with lamotrigine. Reduction of the daily dose and/or alteration of the timing of doses of concomitant antiepileptic drugs and/or lamotrigine may reduce or eliminate these symptoms. Clinical data suggest a higher incidence of rash in patients who are receiving concomitant valproic acid, or non-inducing AEDs (see Warnings and Precautions, Skin-related Events,  Table 3).

Adverse Events Associated with Discontinuation of Treatment: Across all adult add-on studies, the most common adverse experiences associated with discontinuation of lamotrigine were rash, dizziness, headache, ataxia, nausea, diplopia, somnolence, seizure exacerbation, asthenia and blurred vision. In controlled clinical trials, 6.9% of the 711 patients receiving lamotrigine discontinued therapy due to an adverse experience, versus 2.9% of the 419 patients receiving placebo. Of 3501 patients and volunteers who received lamotrigine in premarketing clinical studies, 358 (10.2%) discontinued therapy due to an adverse experience.

Serious Adverse Events Associated with Discontinuation of Treatment: Discontinuation due to an adverse experience classified as serious occurred in 2.3% of adult patients and volunteers who received lamotrigine in the premarketing studies. Rash accounted for almost half of the discontinuations due to serious adverse experiences. More rapid initial titration dosing of lamotrigine, and concomitant use of valproic acid were associated with higher incidences of rash-related withdrawal in clinical studies (see Warnings and Precautions, Skin-related Events,  Table 4).

Adult Controlled Add-on Clinical Studies:  Table 6 enumerates adverse experiences that occurred with an incidence of 2% or greater among refractory patients with epilepsy treated with lamotrigine.

Other Events Observed During Clinical Studies: During clinical testing, multiple doses of lamotrigine were administered to 3501 patients and volunteers. The conditions and duration of exposure to lamotrigine during these clinical studies varied greatly. Studies included monotherapy and pediatric trials. A substantial proportion of the exposure was gained in open, uncontrolled clinical studies. Adverse experiences associated with exposure to lamotrigine were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of adverse experiences into a smaller number of standardized event categories.

     Since the adverse experiences reported occurred during treatment with lamotrigine in combination with other antiepileptic drugs, they were not necessarily caused by lamotrigine.

     The following adverse events have been reported on one or more occasions by at least 1% of patients and volunteers exposed to lamotrigine: anorexia, weight gain, amnesia, concentration disturbance, confusion, emotional lability, nervousness, nystagmus, paresthesia, thinking abnormality and vertigo. (All types of events are included except those already listed in  Table 6.)

Adult Monotherapy Clinical Studies: Withdrawals due to adverse events were reported in 42 (9.5%) of newly diagnosed patients treated with lamotrigine monotherapy. The most common adverse experiences associated with discontinuation of lamotrigine were rash (6.1%), asthenia (1.1%), headache (1.1%), nausea (0.7%) and vomiting (0.7%).

Elderly Monotherapy Clinical Studies: A study with elderly newly diagnosed epilepsy patients yielded rates of adverse events which were generally similar to those reported in adults (see  Table 6). The rate of withdrawal due to adverse events was 21.6%, with rash (3%), nausea (3%) and coordination abnormalities (3%) representing the most common events associated with withdrawal, followed by somnolence (2%), depression (2%), accidental injury (2%) and malaise (2%) (see also Dosage and Pharmacology).

Adjunctive Therapy in Lennox-Gastaut Syndrome: In 169 adult and pediatric patients with Lennox-Gastaut syndrome, 3.8% of patients on lamotrigine and 7.8% of patients on placebo discontinued treatment due to adverse experiences. The most commonly reported adverse experiences that led to discontinuation were rash for patients treated with lamotrigine and deterioration of seizure control for patients treated with placebo. Fever and infection occurred at least 10% more frequently in patients ≤ 12 years of age than in patients >12 years of age on lamotrigine. Rash occurred at least 10% more frequently in female patients than male patients on lamotrigine.  Table 7 lists adverse events that occurred in at least 1% of 79 adult and pediatric patients who received lamotrigine up to 15 mg/kg/day or a maximum of 400 mg/day.

CPS:Lamictal_t6Click here for Table 6

Table 6: Lamictal

Percentage of Treatment-emergent Adverse Experiences in Adult Placebo or Comparator-controlled Clinical Studies^a

 

Total number of Patients	Adults (Adjunctive Therapy)b		Elderly (Monotherapy)c
	Lamictal (and other AEDs) (n=711)	Placebo (and other AEDs) (n=419)	Lamictal  (n=102)
Body System/Adverse Experienced
Body as a Whole
Headache	29.1	19.1	8.8
Accidental Injury	9.1	8.6	8.8
Asthenia	8.6	8.8	4.9
Flu Syndrome	7.0	5.5	4.9
Pain	6.2	2.9	5.9
Back Pain	5.8	6.2	3.9
Fever	5.5	3.6	0.9
Abdominal Pain	5.2	3.6	3.9
Infection	4.4	4.1	5.9
Neck Pain	2.4	1.2	0
Malaise	2.3	1.9	4.9
Seizure Exacerbation	2.3	0.5	n/a
Cardiovascular
Chest Pain	n/a	n/a	2.9
Syncope	n/a	n/a	2.9
Cerebrovascular Accident	n/a	n/a	3.9
Digestive
Nausea	18.6	9.5	8.8
Vomiting	9.4	4.3	8.8
Diarrhea	6.3	4.1	6.9
Dyspepsia	5.3	2.1	5.9
Constipation	4.1	3.1	8.9
Tooth Disorder	3.2	1.7	0
Musculoskeletal
Myalgia	2.8	3.1	0.9
Arthralgia	2.0	0.2	2.9
Nervous
Dizziness	38.4	13.4	9.8
Ataxia	21.7	5.5	0
Somnolence	14.2	6.9	11.8
Incoordination	6.0	2.1	12.7
Insomnia	5.6	1.9	3.9
Tremor	4.4	1.4	0.9
Depression	4.2	2.6	4.9
Anxiety	3.8	2.6	0.9
Convulsion	3.2	1.2	1.9
Irritability	3.0	1.9	0
Speech Disorder	2.5	0.2	0.9
Memory Decreased	2.4	1.9	n/a
Memory Decreased (Memory Rating Question)	n/a	n/a	19.6
Respiratory
Rhinitis	13.6	9.3	0.9
Pharyngitis	9.8	8.8	1.9
Cough Increased	7.5	5.7	2.9
Respiratory Disorder	5.3	5.5	0.9
Asthma	n/a	n/a	3.0
Skin and Appendages
Rash	10.0	5.0	8.8
Pruritus	3.1	1.7	5.9
Herpes Zoster	n/a	n/a	3.0
Eczema	n/a	n/a	2.0
Ulcer Skin	n/a	n/a	2.0
Special Senses
Diplopia	27.6	6.7	0
Blurred Vision	15.5	4.5	0
Vision Abnormality	3.4	1.0	0
Urogenital
Female Patients	(n=365)	(n=207)	(n=47)
Dysmenorrhea	6.6	6.3	n/a
Menstrual Disorder	5.2	5.8	n/a
Vaginitis	4.1	0.5	0

 

 ^a Patients from the studies summarized in the first 2 columns were receiving 1 to 3 concomitant enzyme-inducing antiepileptic drugs in addition to Lamictal or placebo. Patients from the single study summarized in the last column were compared to n=48 patients receiving carbamazepine. Patients may have reported multiple adverse experiences during the study or at discontinuation. Thus, patients may be included in more than one category.

 ^b Studies 05, 06, 16 (US) &16, 21, 35 & 37 (UK).

 ^c Study 105-124-C93.

 ^d All Adverse Experiences reported by at least 2% of patients treated with either Lamictal add-on or monotherapy are included.

 

 

CPS:Lamictal_t7Click here for Table 7

Table 7: Lamictal

Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Add-on Trial in Adult and Pediatric Patients With Lennox Gastaut Syndrome^a

 

Body System/Adverse Experience	Percent of Patients Receiving Lamictal  (n=79)	Percent of Patients Receiving Placebo  (n=90)
Body as a Whole
Infection	13	8
Accidental Injury	9	7
Flu Syndrome	5	0
Asthenia	3	1
Abdominal Pain	3	0
Back Pain	1	0
Edema of the Face	1	0
Lab test Abnormal	1	0
Pain	1	0
Cardiovascular
Hemorrhage	3	0
Digestive
Vomiting	9	7
Constipation	5	2
Diarrhea	4	2
Nausea	4	1
Anorexia	3	1
Stomatitis Aphtha	1	0
Tooth Disorder	1	0
Endocrine
Cushing's Syndrome	1	0
Hypothyroidism	1	0
Hemic and Lymphatic
Lymphadenopathy (enlarged cervical nodes)	1	0
Nervous System
Ataxia	4	1
Convulsions	4	1
Tremor	3	0
Agitation	1	0
Coordination	1	0
Dizziness	1	0
Emotional Lability	1	0
Nervousness	1	0
Vertigo	1	0
Respiratory
Pharyngitis	14	10
Bronchitis	9	7
Pneumonia	3	0
Dyspnea	1	0
Skin
Rash	9	7
Eczema	4	0
Nail Disorder	1	0
Special Senses
Blepharitis	1	0
Conjunctivitis	1	0
Keratitis	1	0
Ear Pain	1	0
Eye Pain	1	0
Urogenital
Urinary Tract Infection	3	0
Balanitis	2	0
Penis Disorder	2	0

 

 ^a The most frequently reported adverse reactions in children ≤ 12 years of age in both treatment groups were pharyngitis, fever and infection.

 

 

 

 

Postmarketing and Other Experience: In addition to the adverse experiences reported during clinical testing of lamotrigine, the following adverse experiences have been reported in patients receiving lamotrigine marketed in other countries and from worldwide “compassionate plea” patients. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

 

Blood and Lymphatic

There have been reports of hematological abnormalities which may or may not be associated with hypersensitivity syndrome. These have included disseminated intravascular coagulation, hemolytic anemia, neutropenia, leukopenia, pancytopenia, anemia, thrombocytopenia, red cell aplasia, and very rarely agranulocytosis and aplastic anemia.

 

Gastrointestinal

esophagitis.

Hepatobiliary Tract and Pancreas

pancreatitis. Elevations of liver function tests and rare reports of hepatic dysfunction, including hepatic failure, have been reported. Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.

 

Immunologic

lupus-like reaction, vasculitis.

 

Lower Respiratory

apnea.

 

Musculoskeletal

Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

 

Neurology

hallucinations. Exacerbation of parkinsonian symptoms in patients with pre-existing Parkinson's disease and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition. Movement disorders such as tics and unsteadiness have also been reported.

Non-site Specific

hypersensitivity reaction, multiorgan failure, progressive immunosuppression.

 

Overdose

 

 

Symptoms

Adults: Acute ingestion of doses in excess of 20 times the maximum therapeutic dose has been reported. In general, overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma.

     However, there has been one fatality reported, a 22 year-old female who intentionally ingested 15 g of lamotrigine. The patient experienced acute clonic seizures and heart failure, then became asystolic and was resuscitated, but she died 2 days later.

Children: Among patients ≤ 16 years of age, the two highest known single doses of lamotrigine have been 3000 mg by a 14 year-old female and approximately 1000 mg by a 4 year-old male. The 14 year-old female was taking marketed lamotrigine; after the dose, she lost consciousness and was admitted to the hospital for supportive therapy, where she recovered fully (time to recovery not reported). The 4 year-old male was drowsy and agitated when found, and his condition worsened to coma level II after hospitalization. He was given supportive therapy and his condition improved rapidly, with full recovery in 3 days.

 

 

Treatment

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 or gastric lavage should be performed. 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 during 4 hours of hemodialysis.

 

Dosage

General

Lamotrigine is intended for oral administration and may be taken with or without food. Lamotrigine should be added to the patient's current antiepileptic therapy.

     Valproic acid more than doubles the elimination half-life of lamotrigine and reduces the plasma clearance by 50%; conversely, hepatic enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, and primidone reduce the elimination half-life of lamotrigine by 50% and double the plasma clearance (see Pharmacology). These clinically important interactions require dosage schedules of lamotrigine as summarized in  Table 8 through  Table 11.

     Lamotrigine does not alter plasma concentrations of concomitantly administered enzyme-inducing AEDs, and therefore, they do not usually require dose adjustment to maintain therapeutic plasma concentrations. For patients receiving lamotrigine in combination with other AEDs, an evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed. If there is a need to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns (i.e., rash) require a more rapid withdrawal (see Warnings and Precautions).

     The relationship of plasma concentration to clinical response has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response. In controlled clinical studies, doses of lamotrigine that were efficacious generally produced steady-state trough plasma lamotrigine concentrations of 1 to 4 µg/mL in patients receiving one or more concomitant AEDs. Doses of lamotrigine producing this plasma concentration range were well tolerated. As with any antiepileptic drug, the oral dose of lamotrigine should be adjusted to the needs of the individual patient, taking into consideration the concomitant AED therapy the patient is receiving.

Adults and Children Over 12 Years of Age

Do not exceed the recommended initial dose and subsequent dose escalations of lamotrigine. More rapid initial titration has been associated with an increased incidence of serious dermatological reactions (see Warnings). For patients taking AEDs whose pharmacokinetic interactions with lamotrigine are currently unknown, follow the titration schedule for concomitant VPA and non-enzyme-inducing AEDs.

CPS:Lamictal_t8Click here for Table 8

Table 8: Lamictal

Lamictal added to VPA with Enzyme-Inducing AEDs^a  in Patients over 12 years of age

 

		For Informationb
	Patients Taking Valproic Acid Only or VPA and non-Enzyme-Inducing AEDs
Weeks 1 + 2	25 mg once a day	25 mg every other day
Weeks 3 + 4	25 mg twice a day	25 mg once a day
Usual Maintenance	To achieve maintenance, doses may be increased by 25–50 mg every 1 to 2 weeks. Usual dose is between 50–100 mg twice a day	To achieve maintenance, doses may be increased by 25–50 mg every 1 to 2 weeks. Usual dose is between 50–100 mg twice a day

 

 ^a Enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin, and primidone.

 ^b Column reflects dosage recommendations in the United Kingdom and is provided for information.

 

 

CPS:Lamictal_t9Click here for Table 9

Table 9: Lamictal

Lamictal Added to Enzyme-Inducing AEDs^a  (without VPA) in Patients Over 12 Years of Age

 

Weeks 1 + 2	50 mg once a day
Weeks 3 + 4	50 mg twice a day
Usual Maintenance	To achieve maintenance, doses may be increased by 100 mg every 1 to 2 weeks. Usual dose is between 150–250 mg twice a day

 

 ^a Enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin, and primidone.

 

 

     There have been no controlled studies to establish the effectiveness or optimal dosing regimen of add-on lamotrigine therapy in patients receiving only non-enzyme-inducing AEDs or valproic acid. However, available data from open clinical trials indicate that the addition of lamotrigine under these conditions is associated with a higher incidence of serious rash or rash-related withdrawal, even at an initial titration dose of 12.5 mg daily (see Precautions, Skin-related Events,  Table 3 and  Table 4; see also Warnings). The potential medical benefits of addition of lamotrigine under these conditions must be weighed against the increased risk of serious rash. If use of lamotrigine under these conditions is considered clinically indicated, titration should proceed with extreme caution, especially during the first 6 weeks of treatment.

Withdrawal of Concomitant AEDs in Adults: Concomitant AEDs may be decreased over a 5-week period, by approximately 20% of the original dose every week. However, a slower taper may be used if clinically indicated. During this period, the dose of lamotrigine administered will be dependent upon the effect of the drug being withdrawn on the pharmacokinetics of lamotrigine, together with the overall clinical response of the patient. The withdrawal of enzyme inducing AEDs (i.e., phenytoin, phenobarbital, primidone, and carbamazepine) will result in an approximate doubling of the t_1/2 of lamotrigine. Under these conditions, it may be necessary to reduce the dose of lamotrigine. In contrast, the withdrawal of enzyme-inhibiting AEDs (i.e., valproic acid) will result in a decrease in the t_1/2 of lamotrigine and may require an increase in the dose of lamotrigine.

 

Children

Do not exceed the recommended initial dose and subsequent dose escalations of lamotrigine. More rapid initial titration has been associated with an increased incidence of serious dermatological reactions (see Warnings). Safety and efficacy in patients below the age of 16 years, other than those with Lennox-Gastaut Syndrome, have not been established.

     The starting doses and dose escalations listed below are different than those used in clinical trials; however, the maintenance doses are the same as those used in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of concern that the risk of serious rash may be greater with higher initial doses and more rapid dose escalation. Consequently, it may take several weeks to months to achieve an individualized maintenance dose.

     The smallest available strength of Lamictal Chewable/Dispersible Tablets is 2 mg. Only whole tablets should be administered (scoreline on the 5 mg tablet is not intended for tablet splitting). Recommended doses have been determined based on the individual, tablet strengths which most closely approximates, but does not exceed, the target dose calculated on the basis of patient weight. In patients on concomitant VPA, Lamictal should not be administered if the calculated daily dose is less than 1 mg (e.g., patients weighing less than 9 kg). If the initial calculated daily dose of Lamictal is 1 to 2 mg or 2.5 to 5 mg, then 2 or 5 mg respectively of Lamictal should be taken on alternate days for the first 2 weeks.

CPS:Lamictal_t10Click here for Table 10

Table 10: Lamictal

Pediatric Dosing with Lamictal for Patients Receiving Valproic Acid with or without Enzyme-inducing AEDs^a

 

Weight Range	Weeks 1 + 2 0.15 mg/kg once a day	Weeks 3 + 4 0.3 mg/kg once a day	Weeks 5 and onwards to Usual Maintenance Doseb  To achieve maintenance, doses may be increased by 0.3 mg/kg every 1–2 weeks, to a maximum of 200 mg/day. Usual dose is between 1–5 mg/kg once a dayc
<9 kg	Do not take Lamictal since there is insufficient experience in children weighing less than 9 kg.
9–13 kg	2 mg every other day	2 mg/day	Increase dose by no more than 2 mg/day every 1–2 weeks
14–16 kg	2 mg/day	4 mg/day	Increase dose by no more than 4 mg/day every 1–2 weeks
17–33 kg	5 mg every other day	5 mg/day	Increase dose by no more than 5 mg/day every 1–2 weeks
34–49 kg	5 mg/day	10 mg/day	Increase dose by no more than 10 mg/day every 1–2 weeks
≥ 50 kgd	5 mg/day	15 mg/day	Increase dose by no more than 15 mg/day every 1–2 weeks

 

 ^a Enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin, and primidone.

 ^b It may take several weeks to months to achieve an individualized maintenance dose.

 ^c Can be given as 2 divided doses.

 ^d Insufficient data are available to be able to support the mg/kg dosing in patients weighing more than 50 kg.

 

 

CPS:Lamictal_t11Click here for Table 11

Table 11: Lamictal

Pediatric Dosing with Lamictal for Patients Receiving Enzyme-inducing AEDs^{a b c}  without Valproic Acid

 

Weight Range	Weeks 1 + 2 0.3 mg/kg once a day	Weeks 3 + 4 0.6 mg/kg once a day	Weeks 5 and onwards to Usual Maintenance Doseb  To achieve maintenance, doses may be increased by 1.2 mg/kg every 1–2 weeks, to a maximum of 400 mg/day. Usual dose is between 2.5–7.5 mg/kg twice a day
<9 kg	Do not take Lamictal since there is insufficient experience in children weighing less than 9 kg.
9–12 kg	5 mg/day	10 mg/day	Increase dose by no more than 10 mg/day every 1–2 weeks
13–16 kg	5 mg/day	15 mg/day	Increase dose by no more than 15 mg/day every 1–2 weeks
17–20 kg	10 mg/day	20 mg/day	Increase dose by no more than 20 mg/day every 1–2 weeks
21–24 kg	10 mg/day	25 mg/day	Increase dose by no more than 25 mg/day every 1–2 weeks
25–29 kg	15 mg/day	30 mg/day	Increase dose by no more than 30 mg/day every 1–2 weeks
30–33 kg	15 mg/day	35 mg/day	Increase dose by no more than 35 mg/day every 1–2 weeks
34–37 kg	20 mg/day	40 mg/day	Increase dose by no more than 40 mg/day every 1–2 weeks
38–41 kg	20 mg/day	45 mg/day	Increase dose by no more than 45 mg/day every 1–2 weeks
42–45 kg	25 mg/day	50 mg/day	Increase dose by no more than 50 mg/day every 1–2 weeks
46–49 kg	25 mg/day	55 mg/day	Increase dose by no more than 55 mg/day every 1–2 weeks
50–54 kg	30 mg/day	60 mg/day	Increase dose by no more than 60 mg/day every 1-2 weeks
55–58 kg	30 mg/day	65 mg/day	Increase dose by no more than 65 mg/day every 1–2 weeks
≥ 59 kge	35 mg/day	70 mg/day	Increase dose by no more than 70 mg/day every 1–2 weeks

 

 ^a Enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin, and primidone.

 ^b Can be given as two divided doses.

 ^c Total daily dose can be divided.

 ^d It may take several weeks to months to achieve an individualized maintenance dose.

 ^e Insufficient data are available to be able to support the mg/kg dosing in patients weighing more than 59 kg.

 

 

     For patients taking AEDs whose pharmacokinetic interactions with lamotrigine are currently unknown, follow the titration schedule for concomitant VPA.

 

Geriatrics

No dosage adjustment from the recommended adult schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a nonelderly population (see also Pharmacology and Adverse Effects).

Patients with Impaired Renal Function: The elimination half-life of lamotrigine is prolonged in patients with impaired renal function (see Pharmacology). Caution should be exercised in dose selection for patients with impaired renal function.

Patients with Impaired Hepatic Function: Mild and Moderate Hepatic-impaired Patients: It is recommended that initial, escalation and maintenance doses be reduced by approximately 50% in patients with either mild or moderate (Child-Pugh Grade A or B) hepatic impairment; dosage schedules based on pharmacokinetic data are summarized in  Table 12. Maintenance doses may be adjusted according to clinical response and tolerance (see also Pharmacology and Precautions).

Severe Hepatic-impaired Patients: Caution should be exercised with severe hepatic-impaired patients with epilepsy, as there is no clinical experience with lamotrigine in this group. It is recommended that initial, escalation and maintenance doses be reduced by approximately 75% in severe (Child-Pugh Grade C) hepatic impairment; dosage schedules based on pharmacokinetic data are summarized in  Table 13. Maintenance doses may be adjusted according to clinical response and tolerance (see also Pharmacology and Precautions).

CPS:Lamictal_t12Click here for Table 12

Table 12: Lamictal

Dosing for Mild (Child-Pugh Grade A) and Moderate (Child-Pugh Grade B) Hepatic-impaired Adult Patients (Based on pharmacokinetic data from 12 mild and 5 moderate hepatic-impaired subjects given a single 100 mg dose)

 

	Weeks 1 + 2	Weeks 3 + 4c	Week 5 and onwards to Usual Maintenance Doseb
Lamictal + EI AEDSa	25 mg/day	50 mg/day	To achieve maintenance, doses may be increased by 50 mg every 1 to 2 weeks.
Lamictal + EI AEDS + VPA	10 mg/day	20 mg/day	To achieve maintenance, doses may be increased by 10–20 mg every 1 to 2 weeks.
Lamictal + VPAd  (± non-EI AEDS)	5 mg/day	10 mg/day	To achieve maintenance, doses may be increased by 10–20 mg every 1 to 2 weeks.

 

 ^a Enzyme-inducing AEDs (EI AEDS) include carbamazepine, phenobarbital, phenytoin, and primidone.

 ^b It may take several weeks to months to achieve an individualized maintenance dose.

 ^c Can be given as 2 divided doses.

 ^d Based on dosage recommendations from the United Kingdom.

 

 

CPS:Lamictal_t13Click here for Table 13

Table 13: Lamictal

Dosing for Severe (Child-Pugh Grade C) Hepatic-impaired Adult Patients (Based on pharmacokinetic data from 7 severe hepatic-impaired subjects given a single 100 mg dose)

 

	Weeks 1 + 2	Weeks 3 + 4c	Week 5 and onwards to Usual Maintenance Doseb
Lamictal + EI AEDSa	10 mg/day	20 mg/day	To achieve maintenance, doses may be increased by 20 mg every 1 to 2 weeks.
Lamictal + EI AEDS + VPA	5 mg/day	10 mg/day	To achieve maintenance, doses may be increased by 5–10 mg every 1 to 2 weeks.
Lamictal + VPAd  (± non-EI AEDS)	5 mg every other day	5 mg/day	To achieve maintenance, doses may be increased by 5–10 mg every 1 to 2 weeks.

 

 ^a Enzyme-inducing AEDs (EI AEDS) include carbamazepine, phenobarbital, phenytoin, and primidone.

 ^b It may take several weeks to months to achieve an individualized maintenance dose.

 ^c Can be given as 2 divided doses.

 ^d Based on dosage recommendations from the United Kingdom.

 

 

Administration of Lamictal Chewable/Dispersible Tablets: Lamictal Chewable/Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. The scoreline on the 5 mg tablet is not intended for tablet splitting. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing. To disperse the tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

 

Supplied

Chewable/Dispersible Tablets

2 mg

Each white, round tablet, engraved “LTG 2”, contains: lamotrigine 2 mg. Nonmedicinal ingredients: aluminum magnesium silicate, blackcurrant flavor, calcium carbonate, hydroxypropylcellulose, magnesium stearate, povidone, saccharin sodium and sodium starch glycolate. Bottles of 30.

 5 mg

Each white, scored, biconvex tablet, engraved “LAMICTAL 5”, contains: lamotrigine 5 mg. Nonmedicinal ingredients: aluminum magnesium silicate, blackcurrant flavor, calcium carbonate, hydroxypropylcellulose, magnesium stearate, povidone, saccharin sodium and sodium starch glycolate. Blisters of 28.

Tablets

25 mg

Each white, scored, shield-shaped tablet, engraved with “LAMICTAL” and “25”, contains: lamotrigine 25 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 100.

100 mg

Each peach, scored, shield-shaped tablet, engraved with “LAMICTAL” and “100”, contains: lamotrigine 100 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, povidone, sunset yellow FCF lake and sodium starch glycolate. Bottles of 100.

150 mg

Each cream, scored, shield-shaped tablet, engraved with “LAMICTAL” and “150”, contains: lamotrigine 150 mg. Nonmedicinal ingredients: cellulose, ferric oxide (yellow), lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 60.

     Store at controlled room temperature (15 to 30°C) in a dry place and protect from light.