Lamotrigine 84057-84-1

U. S. Food and Drug Administration approval history

Therapeutic uses

Epilepsy and seizures

Lamotrigine is approved in the US for the treatment of partial seizures. Combination with valproate is common, but this increases the risk of lamotrigine-induced rash, and necessitates reduced dosing due to the interaction of these drugs. Lamotrigine is also used as first line therapy for childhood absence epilepsy.

Bipolar disorder

Lamotrigine is approved in the US for maintenance treatment of Bipolar I disorder. The 2002 American Psychiatric Association guidelines recommended lamotrigine as a first-line treatment for acute depression in bipolar disorder as well as a maintenance therapy. However, lamotrigine is not indicated on label for the treatment of acute bipolar symptoms. Because the dosage must be slowly increased from a sub-therapeutic level to the therapeutic level, the drug's utility in the management of acute manic symptoms is debatable; typically benzodiazepines or another anticonvulsant will be used to manage the acute mania until the lamotrigine reaches therapeutic blood concentration. At doses considered sub-therapeutic, lamotrigine is thought to have a mild anti-depressant effect, leading some to question its safety for use in bipolar disorder, as partial remediation of cyclically depressed individuals (especially teens and young adults) has an elevated corelation to suicide until remission attains therapeutically acceptable levels.

Other uses

Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain. Off-label psychiatric usage includes the treatment of depersonalization disorder, bipolar II disorders, schizoaffective disorder, borderline personality disorder, Post Traumatic Stress Disorder, and as adjunctive therapy for treatment refractory unipolar depression.

Mechanism of action

One proposed mechanism of action for lamotrigine involves an effect on sodium channels, although this remains to be established in humans. 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 (for example glutamate and aspartate).

Pharmacokinetics

The pharmacokinetics of lamotrigine follow first order kinetics, with a half-life of 13. 5 hours and volume of distribution of 1. 36l/kg. . Lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with Sodium Valproate and other enzyme inducing medications may shorten half-life. Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.

Side effects

Lamotrigine prescribing information has a black box warning about life threatening skin reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. . Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Similarly, women may experience an increase in lamotrigine side effects upon discontinuation of the pill. This may include the "pill free" week where lamotrigine serum levels have been shown to increase two-fold. However, these increases were not in conjunction with increased progesterone, indicating that oral contraceptives maintained suppression of ovulationSome patients have reported experiencing a loss of concentration, even with very small doses, while some others have actually reported an increase in alertness and concentration. GlaxoSmithKline investigated lamotrigine for the treatment of ADHD. The results were inconclusive. No detrimental effects on cognitive function were observed, however, the only statistical improvement in core ADHD symptoms was an improvement on a test, PASAT (Paced Auditory Serial Addition Test), that measures auditory processing speed and calculation ability. Lamotrigine can induce a type of seizure known as a Myoclonic Jerk. When used in the treatment of myoclonic epilepsies such as Juvenile myoclonic epilepsy, lower doses (and lower plasma levels) are usually needed, as even moderate doses of this drug can lead to induction of seizures, including tonic-clonic seizures, which can develop into Status epilepticus (a medical emergency). It can also cause Myoclonic Status Epilepticus. In overdose, Lamotrigine can cause uncontrolled seizures in most patients regardless of the reason they were prescribed the drug.

Availability

GlaxoSmithKline's trademarked brand of Lamotrigine, Lamictal, is manufactured in scored tablets (25 mg, 50 mg, 100 mg, 150 mg and 200 mg) and chewable dispersible tablets (2 mg, 5 mg and 25 mg). Five-week sample kits are also available; these include titration instructions and scored tablets (25 mg for patients taking valproate, 25 mg and 100 mg for patients not taking valproate). Lamotrigine is also available in un-scored tablet form. In 2005, Teva Pharmaceutical Industries Ltd. began selling generic Lamotrigine in the United States, but only in 5 mg and 25 mg chewable dispersible tablets. On 23 July 2008 Teva began offering the full line of generic Lamotrigine in the US. Lamotrigine is also available in generic form in the United States, the United Kingdom, Canada and Australia. It should be noted that brand name Lamictal is not available in 200 mg tablets in Canada, at all registered pharmacies (while 25, 100, and 150 mg are all offered). Starter kits are also not available in Canada. GlaxoSmithKline has also recently received FDA Approval for an extended release version of lamotrigine called Lamictal XR. Lamotrigine is marketed as Lamictin in South Africa, {{lang

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