Brands, Medical Use, Clinical Data
Drug Category
- Antimanic Agents
- Antidepressants
- Anticonvulsants
- Analgesics
- Calcium Channel Blockers
- Excitatory Amino Acid Antagonists
Dosage Forms
Brands / Synonyms
Lamictal; Lamictal Cd; Lamotrigina [Spanish]; Lamotrigine; Lamotriginum [Latin]
Indications
For the adjunctive treatment of partial seizures in epilepsy and generalized seizures of Lennox-Gastaut syndrome; For the maintenance treatment of Bipolar I Disorder
Pharmacology
Lamotrigine, an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Lamotrigine is also used in the treatment of depression and bipolar disorder. Lamotrigine is thought to exert its anticonvulsant effect by stabilizing presynaptic neuronal membranes. Lamotrigine inhibits sodium currents by selectively binding to the inactivated state of the sodium channel and subsequently suppresses the release of the excilatory amino acid, glutamate.
Mechanism of Action
One proposed mechanism of action of Lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. in vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
Absorption
98%
Toxicity
LD50=250 (mg/kg) (in rat, mice); LD50>640 orally (mg/kg) (in rat, mice) (Sawyer); Decreased level of consciousness, coma, delayed heartbeat, increased seizures, lack of coordination, rolling eyeballs
Biotrnasformation / Drug Metabolism
Hepatic
Contraindications
LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its
ingredients.
Drug Interactions
Effects of Lamotrigine on the Pharmacokinetics of Other Drugs:.
LAMICTAL Added to Carbamazepine: LAMICTAL has no appreciable effect on steady-state
carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia,
ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in patients receiving other EIAEDs
with LAMICTAL. 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 were seen to increase.
LAMICTAL Added to Valproate: When LAMICTAL was administered to 18 healthy volunteers receiving
valproate in a pharmacokinetic study, the trough steady-state valproate concentrations in plasma decreased by an
average of 25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing therapy did not
cause a change in plasma valproate concentrations in either adult or pediatric patients in controlled clinical
trials.
LAMICTAL Added to Lithium: The pharmacokinetics of lithium were not altered in healthy
subjects (n = 20) by co-administration of 100 mg/day lamotrigine for 6 days.
LAMICTAL Added to Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin
plasma concentrations in patients with epilepsy.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs
eliminated predominantly by CYP2D6.
Effects of Other Drugs on the Pharmacokinetics of Lamotrigine: .
Valproate Added to LAMICTAL: The addition of valproate increases lamotrigine steady-state
concentrations in normal volunteers by slightly more than 2-fold.
Enzyme-Inducing Antiepileptic Drugs (e.g., carbamazepine, phenytoin, phenobarbital, primidone)
Added to LAMICTAL: The addition of EIAEDs decreases lamotrigine steady-state concentrations by approximately
40%.
Bupropion Added to LAMICTAL: The pharmacokinetics of a 100-mg single dose of lamotrigine in 12
healthy volunteers were not changed by co-administration of bupropion at 300 mg/day starting 11 days before the
lamotrigine dose.
Other Psychotropic Drugs Added to LAMICTAL: Results of in vitro experiments suggest that
clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam,
clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.
Interactions With Folate Inhibitors: Lamotrigine is an inhibitor of dihydrofolate reductase.
Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
Interactions With Oral Contraceptives: In women taking lamotrigine, there have been reports of
decreased lamotrigine concentrations following introduction of oral contraceptives and reports of increased
lamotrigine concentrations following withdrawal of oral contraceptives. Dosage adjustments may be necessary to
maintain clinical response when starting or stopping oral contraceptives during lamotrigine therapy.
The net effects of drug interactions with LAMICTAL are summarized in Table 3.
Table 3. Summary of Drug Interactions With LAMICTAL
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Drug
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Drug Plasma Concentration With Adjunctive LAMICTAL*
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Lamotrigine Plasma Concentration With Adjunctive Drugs
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Phenytoin (PHT)
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«
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¯
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Carbamazepine (CBZ)
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«
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¯
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CBZ epoxide
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?
|
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Valproate
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¯
|
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Valproate + PHT and/or CBZ
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Not assessed
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«
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Lithium
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«
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Not assessed
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Bupropion
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Not assessed
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«
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*From adjunctive clinical trials and volunteer studies.
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Net effects were estimated by comparing the mean clearance values obtained in adjunctive
clinical trials and volunteers studies.
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Not administered, but an active metabolite of carbamazepine.
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« = No significant effect.
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? = Conflicting data.
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Drug/Laboratory Test Interactions: None known.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity was seen
in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated
doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for rats, doses that are equivalent to 90
mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4
mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended
human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL
have been recorded.
Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2
gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in
vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of
structural or numerical chromosomal abnormalities.
No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4
times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a
mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was found
in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of
organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual
human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced
fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology
studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and
rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the
incidence of intrauterine death without signs of teratogenicity was increased.
A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day
21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period
for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44
postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent
0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively.
Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed
prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual
human maintenance dose on a mg/m2 basis.
When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose
(on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death
were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged
(22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest
number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between
day 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A
no-observed-effect level (NOEL) could not be determined for this study.
Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine decreases fetal
folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are
no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Non-Teratogenic Effects: As with other antiepileptic drugs, physiological changes during
pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased
lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage
adjustments may be necessary to maintain clinical response.
Pregnancy Exposure Registry: 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, and can obtain information by calling the Lamotrigine Pregnancy Registry at
(800) 336-2176 (toll-free). Patients can enroll themselves in the North American Antiepileptic Drug Pregnancy
Registry by calling (888) 233-2334 (toll-free).
Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.
Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk.
Because the effects on the infant exposed to LAMICTAL by this route are unknown, breast-feeding while taking LAMICTAL
is not recommended.
Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures in patients
above 2 years of age and for the generalized seizures of Lennox-Gastaut syndrome. Safety and effectiveness for other
uses in patients with epilepsy below the age of 16 years have not been established .
Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been
established.
Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. 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.
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