Lamotrigine

LAMOTRIGINE- lamotrigine tablet
McKesson Packaging Services Business Unit of McKesson Corporation

Rx only Revised: 09/08

SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF LAMOTRIGINE. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN PEDIATRIC PATIENTS (AGE < 16 YEARS) RECEIVING LAMOTRIGINE AS ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER 1,000) IN ADULT PATIENTS RECEIVING LAMOTRIGINE AS INITIAL MONOTHERAPY AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMOTRIGINE AS ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF 1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMOTRIGINE, THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE.

OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH ASSOCIATED WITH LAMOTRIGINE. THERE ARE SUGGESTIONS, YET TO BE PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1) CO-ADMINISTRATION OF LAMOTRIGINE WITH VALPROATE (INCLUDES VALPROIC ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED INITIAL DOSE OF LAMOTRIGINE, OR (3) EXCEEDING THE RECOMMENDED DOSE ESCALATION FOR LAMOTRIGINE. HOWEVER, CASES HAVE BEEN REPORTED IN THE ABSENCE OF THESE FACTORS.

NEARLY ALL CASES OF LIFE-THREATENING RASHES 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 HERALDED 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 SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMOTRIGINE SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

DESCRIPTION

Lamotrigine, an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as -triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is slightly soluble in methanol. The structural formula is:

Lamotrigine Structural Formula

Lamotrigine tablets are supplied for oral administration as 25 mg, 100 mg, 150 mg, and 200 mg tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: hydroxypropyl cellulose; L- hydroxypropyl cellulose; magnesium stearate; mannitol; powdered cellulose; talc; and ferric oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state.The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate). The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.

Pharmacological Properties:

Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50 > 100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic ɑ1 , ɑ2 , and Β; dopamine D1 and D2; ɣ-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin (IC50 > 200 µM) when tested in rat synaptosomes and/or human platelets in vitro.

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:

Lamotrigine did not inhibit N-methyl daspartate (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.

Folate Metabolism:

In vitro, lamotrigine was shown to be an inhibitor of 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 PRECAUTIONS: Pregnancy). 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 was found to accumulate in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to 〈-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 Drug Disposition). 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).

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