Lamictal ®

Lamotrigine

(pronounced /ləˈmɪktÉ™l/) by GlaxoSmithKline) is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. 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 acts as an effective mood stabilizer, and in fact has been the only 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 being a Phenyltriazine), lamotrigine has relatively few side-effects and does not require blood monitoring in monotherapy. The exact way lamotrigine works is unknown. Some think that it is a sodium channel blocker, though it is interesting to note that lamotrigine shares very few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, (e.g. Oxcarbazepine), which may suggest that lamotrigine has a different mechanism of action^{[citation needed]}. The drug information provided at the time of prescription notes that “it is thought to work by restoring the balance of certain natural substances (neurotransmitters) in the brain.”^[1] Lamotrigine is inactivated by hepatic glucuronidation.

U.S. Food and Drug Administration approval history

• December 1994 – Lamotrigine was approved for the treatment of partial seizures.^[2]
• 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.^[3]
• 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)).

Therapeutic uses

Epilepsy and seizures

Lamotrigine is approved in the US for the treatment of partial seizures.^[2] 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.^[4] 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.^[5]

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.^[3] While traditional anticonvulsant drugs are predominantly antimanics, lamotrigine is most effective in the treatment and prophylaxis of bipolar depression. Lamotrigine treats bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling. It has not demonstrated efficacy in the treatment of acute mania.^[6] 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.^{[citation needed]}

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.^{[citation needed]}

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.^{[citation needed]}

Other uses

Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain. ^[7][8][9] 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.^[10]

Mechanism of action

One proposed mechanism of action for lamotrigine involves an effect on sodium channels,^[11] 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).^[12]

[edit] Pharmacokinetics

The pharmacokinetics of lamotrigine are quite complicated, with highly varying half-life and blood plasma levels. Lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with Sodium Valproate in particular is an indication for blood monitoring.

Side effects

Lamotrigine prescribing information has a black box warning about life threatening skin reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.^[12] 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 Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. It is estimated that 5 to 10 % of patients will develop a rash, but that only one in a thousand patients will develop a serious rash. It is thought that one in 50,000 exposed patients may die from a rash.

Common side effects include headaches, dizziness and insomnia. Other side effects may include acne and skin irritation, vivid dreams or nightmares, night sweats, body aches and cramps, muscle aches, dry mouth, mouth ulcers, damage to tooth enamel, fatigue, memory and cognitive problems, irritability, weight changes, hair loss, changes in libido, frequent urination, nausea, appetite changes and other side effects. In very 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.

Effects in women

In clinical trials women were more likely than men to have side effects^{[citation needed]}. 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^[13]. Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Similarily, 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^[12]. 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^[14]. However, these increases were not in conjunction with increased progesterone, indicating that oral contraceptives maintained suppression of ovulation^[14].

Use during pregnancy is recommended only if benefits outweigh potential risks. It was also reported on CNN in September 2006 that taking Lamictal during the first trimester of pregnancy can lead to a cleft palate in babies.^{[citation needed]} Lamotrigine is found in breast milk; breastfeeding is not recommended during treatment.

Lamotrigine can inhibit sleep. It is best taken in the morning.^{[citation needed]}

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.^[15]

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.^[16]

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.