Lamotrigine

Lamotrigine, marketed in the US as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage. For epilepsy, it is used to treat partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Like many other anticonvulsant medications, Lamotrigine also seems to act as an effective mood stabilizer, and in fact has been the only U.S. Food and Drug Administration (FDA)-approved drug for this purpose since lithium, a drug approved almost 30 years earlier. It is approved for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants (due to lamotrigine's being a phenyltriazine), lamotrigine has many possible side-effects. Lamotrigine is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs, but it could have additional actions inasmuch as it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and carbamazepine and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel blocking antiepileptic drugs are not. In addition, lamotrigine shares few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels), which further emphasizes its unique properties. Lamotrigine is inactivated by hepatic glucuronidation.

Epilepsy and seizures
Lamotrigine is approved in the US for the treatment of partial seizures. Lamotrigine is one of a small number of FDA-approved therapies for seizures associated with Lennox-Gastaut syndrome, a severe form of epilepsy. Typically developing before four years of age, LGS is associated with developmental delays. There is no cure, treatment is often complicated, and complete recovery is rare. Symptoms include the atonic seizure (also known as a "drop attack"), during which brief loss of muscle tone and consciousness cause abrupt falls. Lamotrigine significantly reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks. 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.

Bipolar disorder
While traditional anticonvulsant drugs are predominantly antimanics, the best evidence for lamotrigine’s effectiveness is in the prophylaxis of bipolar depression. As a consequence, it is approved in the US for maintenance treatment of Bipolar I disorder. The drug seems ineffective in the maintenance of rapid cycling bipolar disorder. According to studies in 2007, Lamotrigine may treat bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling.

The evidence for lamotrigine’s effectiveness in treating a preexisting mood episode is weaker. It has not demonstrated efficacy in the treatment of acute mania and there is controversy regarding the drug’s effectiveness in treating acute bipolar depression. The 2002 American Psychiatric Association (APA) guidelines recommend lamotrigine as a first-line treatment for acute depression in Bipolar II disorder. In light of the guidelines being more than five years old, the APA’s website notes that the guidelines “can no longer be assumed to be current." A paper written in 2008 by Nasser et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines and concludes that lamotrigine has “very limited, if any, efficacy in the treatment of acute bipolar depression.” A 2008 paper by Calabrese et al. examined much of the same data and found that in four out of five placebo controlled studies, lamotrigine was ineffective in treating acute bipolar depression. However, in a meta-analysis of the studies conducted in 2008, Calabrese found that patients who suffered from severe depression (as opposed to mild to moderate) did benefit in the use of lamotrigine vs. a placebo.

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 correlation 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 and post-traumatic stress disorder. Lamotrigine has been studied as an adjunctive therapy for treatment of refractory unipolar depression.

Mechanism of action
Lamotrigine is a member of the sodium channel blocking class of antiepileptic drugs. Early studies of lamotrigine's mechanism of action examined its effects on the release of endogenous amino acids from rat cerebral cortex slices in vitro. As is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine inhibited the release of glutamate and aspartate evoked by the sodium-channel activator veratrine and was less effective in the inhibition of acetylcholine or GABA release. At high concentrations, it had no effect on spontaneous or potassium evoked amino acid release. These studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. Several electrophysiological studies have investigated the effects of lamotrigine on voltage-dependent sodium channels. For example, lamotrigine blocked sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner at concentrations therapeutic in the treatment of human seizures. In cultured hippocampal neurons, lamotrigine reduced sodium currents in a voltage-dependent manner, and at depolarized potentials showed a small frequency-dependent inhibition. These and a variety of other results indicate that the antiepileptic effect of lamotrigine, like that of phenytoin and carbamazepine, is at least in part due to use- and voltage-dependent modulation of fast voltage-dependent sodium currents. However, lamotrigine has a broader clinical spectrum of activity than phenytoin and carbamazepine and is recognized to be protective against generalized absence epilepsy and other generalized epilepsy syndromes, including primary generalized tonic–clonic seizures, juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome. The basis for the broader spectrum of activity of lamotrigine is unknown, but could relate to actions of the drug on voltage-activated calcium channels. Lamotrigine blocks T-type calcium channels weakly, if at all. However, it does inhibit native and recombinant high-voltage–activated calcium channels (N- and P/Q/R-types) at therapeutic concentrations. Whether this activity on calcium channels accounts for lamotrigine's broader clinical spectrum of activity in comparison with phenytoin and carbamazepine remains to be determined.

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 carbamazepine, phenytoin and other hepatic enzyme inducing medications may shorten half-life. Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.

Dosage
Lamotrigine must be dose titrated carefully. Different doctors will proscribe different titration policies based on their experience and the specific condition of the patient. For this reason the titration information must be viewed purely as an example -and never to be adopted directly. Any proposal to take Lamotrogine must be discussed with a suitably qualified doctor, and their prescriptions followed -and any warning signs -such as a rash- responded to immediately.

The normal starting dose is 25 mg a day week 1-2, which may be increased 50 mg a day a week 2-3, 100 mg week 5 and 200 mg week 6. If the patient also takes valproate the dosage should be halved; if taken with carbamazepine the dosage needs to be doubled since they both interfere with lamotrigine's metabolism.

The normal maintenance dose for bipolar depression is 200 mg, but some patients may require up to 600 mg a day. Some patients who cannot tolerate 200 mg have to take a lower dose. In clinical trials doses up to 400 mg for bipolar disorder and 500 mg but it's common that higher doses are prescribed.

Too high starting doses and fast dose increase increases the risk of developing serious rashes and in worst case Stevens-Johnson syndrome Pediatric patients have a higher risk of developing rashes and bad skin reactions. .

The consensus is that the dose titration should be taken slow in small steps. Many patients develop benign rashes when starting treatment but the patient doesn't have to stop take lamotrigine if the same dose is withheld for some time the rash usually goes away and then the dose can be increased again. If a patient has stopped taken lamotrigine for a period of more than 5 times the half life of its metabolism (approximately two-and-a-half days), the dose titration has to start over again from zero. As stopping any anti-epilepsy drug may trigger seizures, this implies that stopping taking lamotrogine is a serious action. Reducing dosage of the drug must also be performed after consultation with a suitably qualified doctor -and their prescriptions strictly followed.

Side-effects
Lamotrigine prescribing information has a black box warning about life-threatening skin reactions, including Stevens-Johnson syndrome, DRESS syndrome and toxic epidermal necrolysis. The manufacturer states that nearly all cases appear in the first 2 to 8 weeks of therapy and if medication is suddenly stopped then resumed at the normal dosage. Patients should seek medical attention for any unexpected skin rash, as its presence is an indication of a possible serious or even deadly side-effect of the drug. Not all rashes that occur while taking lamotrigine progress to SJS or TEN. Between 5 to 10% of patients will develop a rash, but only one in a thousand patients will develop a serious rash. It is thought that one in 50,000 exposed patients may die from the rash.

As of December 2010, lamotrigine carries an FDA black box warning for aseptic meningitis.

Side-effects include loss of balance or coordination, double vision, crossed eyes, blurred vision, dizziness and lack of coordination, drowsiness, insomnia, anxiety, vivid dreams or nightmares, dry mouth, mouth ulcers, memory and cognitive problems, mood changes, runny nose, cough, nausea, indigestion, abdominal pain, weight loss, missed or painful menstrual periods, and vaginitis. The side-effect profile is different for different patient populations.

Side-effects such as rash, fever, and fatigue are very serious, as they may indicate incipient Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome or aseptic meningitis.

In rare cases, lamotrigine has been known to cause the dangerous drug eruptions DRESS syndrome, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The rash is more common in children, so this medication is often reserved for adults. There is also an increased incidence of these eruptions in patients who are currently on, or recently discontinued a valproate-type anticonvulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased. The rash often appears in the first month of treatment and is even more likely to appear if dosage is started too high, but it can appear at any time and at any dosage.

Lamotrigine has been associated with a decrease in white blood cell count (leucopenia). Lamotrigine does not prolong QT/QTc in TQT studies in healthy subjects

Effects in women
In clinical trials women were more likely than men to have side-effects. This is the opposite of most other anticonvulsants and antipsychotics.

There is evidence showing interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing hormonal contraceptives. Ethinyl estradiol, the ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine. Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Likewise, 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 twofold. Another study showed a significant increase in follicle stimulating hormone (FSH) and luteinizing hormone (LH) in women taking lamotrigine with oral contraceptive compared to women taking oral contraceptives alone. However, these increases were not in conjunction with increased progesterone, indicating that oral contraceptives maintained suppression of ovulation.

Pregnancy and breastfeeding
Lamotrigine is rated Pregnancy Category Risk C. Use during pregnancy is recommended only if benefits outweigh potential risks. In September 2006, the FDA issued a warning stating that taking lamotrigine during the first trimester of pregnancy may increase the risk for cleft lip and palate malformation in newborns. Since then, review studies have found that overall rates of congenital malformations in infants exposed to lamotrigine in utero are relatively low (1-4%). This compares to a typical 3% rate in the untreated population. A prospective study on cognition in children (mean age = 4.2 years) exposed to lamotrigine in utero did not indicate any adverse effects.

Lamotrigine is found in breast milk; the manufacturer does not recommend breastfeeding during treatment. In "Medications and Mothers' Milk", a frequently updated review of scientific literature, lamotrigine is rated as L3: moderately safe.

Other types of effects
Lamotrigine binds to melanin-containing tissues such as the iris of the eye. The long-term consequences of this are unknown.

Some 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 is known to affect sleep. Studies with small numbers (10-15) of patients reported that lamotrigine increases sleep stability (increases the duration of REM sleep, decreases the number of phase shifts, and decreases the duration of slow-wave sleep), and that there was no effect on vigilance, and daytime somnolence and cognitive function. However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an 'alerting effect' resulting in intolerable insomnia, for which the treatment had to be discontinued.

Lamotrigine can induce a type of seizure known as a myoclonic jerk, which tends to happen soon after the use of the medication. 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, which is a medical emergency. It can also cause myoclonic status epilepticus.

In overdose, lamotrigine can cause uncontrolled seizures in most people.

History

 * December 1994 — Lamotrigine was approved for the treatment of partial seizures.
 * August 1998 — for use as adjunctive treatment of Lennox-Gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets.
 * December 1998 — for use as monotherapy for treatment of partial seizures in adult patients when converting from a single enzyme-inducing anti-epileptic drug (EIAED).
 * January 2003 — for use as adjunctive therapy for partial seizures in pediatric patients as young as 2 years of age.
 * June 2003 — Lamotrigine approved for maintenance treatment of Bipolar I disorder; the first since lithium.
 * January 2004 — for use as monotherapy for treatment of partial seizures in adult patients when converting from the anti-epileptic drug valproate (including valproic acid (Depakene); sodium valproate (Epilim) and divalproex sodium (Depakote)).

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, למוג'ין (Lamogine) in Israel, and 라믹탈 in South Korea and generally named as Lamitor.

International Legal Status
In Japan, Lamotrigine is classified as a narcotic and prior to entering the country a proper license must be obtained from the patient's country's Japanese embassy.