Lamotrigine

Lamictal is the brand name used in the United States, Canada, the UK, Australia, and other countries for lamotrigine.

Lamictal was approved by the FDA in 1994 for the treatment of partial seizures and secondarily generalized seizures in adults, and in 1998 as an add-on treatment for generalized seizures associated with Lennox-Gastaut syndrome. More recently, Lamictal was approved as monotherapy.

Lamictal
Tablet
Lamictal 25mg

25-mg (white, scored, shield-shaped)
Tablets marked "LAMICTAL" and "25"

Lamictal 100mg

100-mg (peach-colored, scored, shield-shaped)
Tablets marked "LAMICTAL" and "100"

Lamictal 150mg

150-mg (cream-colored, scored, shield-shaped)
Tablets marked "LAMICTAL" and "150"

Lamictal 200mg

200-mg (blue, scored, shield-shaped)
Tablets marked "LAMICTAL" and "200"

Tablet
Lamictal Chewable 2mg

2-mg (white to off-white, round)

Chewable Dispersible Tablets marked with "LTG 2"

Lamictal Chewable 5mg

5-mg (white to off-white, caplet-shaped)
Chewable Dispersible Tablets marked with "GX CL2"

Lamictal Chewable 25mg

25-mg (white, rounded-square-shaped)
Chewable Dispersible Tablets marked with "GX CL5"

Indications

The U.S. Food and Drug Administration (FDA) has approved lamotrigine as adjunctive therapy for both adults and children aged 2 years and older for

  • simple and complex partial seizures
  • generalized seizures of Lennox-Gastaut syndrome (LGS)
  • primary generalized tonic-clonic seizures

It is also FDA-approved as monotherapy in adults for the treatment of simple and complex partial seizures after conversion from valproate or a single enzyme-inducing antiepileptic drug (carbamazepine, phenytoin, primidone, or phenobarbital).

Forms

Lamictal is sold in the United States by GlaxoSmithKline. These descriptions apply to the U.S. versions:

How to take and store Lamotrigine?

Lamictal can be taken with food or without food, but advise your patients to be consistent from day to day.

Regular Lamictal tablets should be swallowed whole because chewing them may leave a bitter taste.

Lamictal "Chewable Dispersible Tablets" can be swallowed whole, chewed, or mixed in water or diluted fruit juice and swallowed immediately.

All Lamictal tablets should be stored at room temperature, away from heat, light and moisture. Remind patients also to keep them safe from children.

Missed Doses

In general, tell patients that if they forget a dose, they should take it as soon as they remember. If it is almost time for the next dose, they should delay that dose for a few hours, instead of taking two doses very close together.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm.

Mechanisms of actions of Lamotrigine

The mechanism of action of Lamictal is related to inactivation of voltage-dependent sodium channels. However, this would not account for its apparent action against absence and myoclonic seizures.

Lamictal may selectively influence neurons that synthesize glutamate and aspartate, since it diminishes the release of these excitatory neurotransmitters through its effect on sodium channels.

Clinical Pharmacology of Lamotrigine

Absorption
Lamictal is quickly and totally absorbed when given orally, and plasma concentrations have an apparent linear relationship to dose.

Distribution and metabolism
The drug is approximately 55% bound to plasma proteins. The liver metabolizes Lamictal to inactive glucuronide conjugates that are excreted in the urine.

The half-life of Lamictal taken alone is about 25 hours, but it rises to 70 hours in patients also taking valproate. In patients also taking hepatic enzyme–inducing AEDs, the half-life of Lamictal drops to 14 hours.

Steady state
Steady state is reached after 3 to 15 days, depending on whether Lamictal is taken with enzyme-inducing AEDs, valproate, or neither.

Efficacy of Lamotrigine

Randomized, controlled studies add-on studies of Lamictal in patients with refractory partial seizures found that Lamictal reduces seizure frequency by at least half in 16% to 20% more patients than add-on placebo (Messenheimer et al. 1994). Side effects were more troublesome than with the placebo, but they were generally minor and often went away without stopping the medication.

Lamictal is also used to treat absence, myoclonic, and tonic-clonic seizures. It is effective against some seizure types in patients with Lennox-Gastaut syndrome and other forms of symptomatic generalized epilepsy. In one study using Lamictal as add-on therapy for patients with Lennox-Gastaut syndrome, 23% more patients who took Lamictal (compared to a placebo) had the number of their tonic-clonic seizures cut at least in half (Motte et al. 1997). Nearly half of the patients who took the Lamictal had less than a 25% decrease in these seizures, however.

Studies have also looked at the effectiveness of Lamictal used alone. In one study (Brodie et al. 1995), patients with newly diagnosed epilepsy were treated with either Lamictal or carbamazepine (Tegretol, Carbatrol). A similar study (Steiner et al. 1999) compared Lamictal to phenytoin (Dilantin, Phenytek). The patients in these studies had partial seizures with or without secondary generalization, or they had primary generalized tonic-clonic seizures. In each study, the effect on the frequency of each seizure type was almost the same for both medications, but the patients taking Lamictal had fewer problems with side effects.

Common side effects of Lamotrigine

Dose-related side effects
The common dose-related side effects of Lamictal are neurotoxic and include:

  • insomnia
  • drowsiness
  • dizziness
  • headache
  • somnolence
  • diplopia
  • ataxia

Increased alertness may be experienced as a side effect that is beneficial to the patient. Neurotoxic side effects are more likely if Lamictal is taken at the same time as carbamazepine or oxcarbazepine. This effect can be reduced by staggering the doses by 1-2 hours.

Lamictal has no known long-term side effects.

Idiosyncratic reactions
The primary systemic side effects of Lamictal are rash and nausea. A benign rash may develop in up to 10% of patients during the initial one to two months of therapy.

Serious Side effects of Lamotrigine

Rash: In some patients, rash progresses to a systemic illness with fever, arthralgia, myalgia, lymphadenopathy, eosinophilia, and malaise. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis occur rarely. Based upon clinical trials and post-marketing reports, the risk of severe dermatologic reaction is 0.3% in adults and approximately 1% in children 16 years and younger.

The risk factors for severe dermatologic reactions with Lamictal include:

  • younger age (children more than adults)
  • co-medication with valproate
  • a rapid rate of Lamictal titration
  • high Lamictal starting dose

Any rash should be evaluated promptly. It is generally recommended that Lamictal be discontinued at the first sign of rash, unless the rash is clearly not drug-related.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Other Uses of Lamotrigine

Lamictal is approved as maintenance therapy for bipolar disorder. It is used off-label for neuropathic pain and trigeminal neuralgia.

Lamotrigine Contraindications

Patients who are allergic to lamotrigine should not take Lamictal.

Caution should be exercised when prescribing Lamictal for patients who have liver disease and for those taking valproate, because of the increased risk of serious rash.

Lamotrigine Interactions with other medications

Serum concentrations of Lamictal are not influenced by interactions with non-AEDs, but are markedly increased by an interaction with valproate, which inhibits glucuronidation, the main metabolic pathway of Lamictal. Consequently, the half-life of Lamictal varies according to concomitant therapy. If the patient is taking hepatic enzyme–inducing AEDs, the half-life is 14 hours, whereas if the patient is taking valproate (e.g., Depakote), the half-life is approximately 70 hours. As a result, if valproate is added to Lamictal, the Lamictal dose will probably need to be reduced.

Another consequence of this interaction is that if hepatic enzyme–inducing drugs are withdrawn, the serum concentration of Lamictal will rise. Withdrawing valproate, on the other hand, will lower the Lamictal concentration. Similarly, if oral contraceptives are stopped for 7 days each month, Lamictal levels will increase during that week. Lamictal levels will fall when the oral contraceptive is restarted.

Lamotrigine does not alter the hepatic metabolism of other drugs, including other AEDs.

AED Interaction Sheets: 
Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

Lamotrigine effects on Children

The FDA has approved Lamictal for use as adjunctive therapy for partial seizures in children as young as 2 years. It is also approved as adjunctive therapy for generalized seizures in children with Lennox-Gastaut syndrome.

A main concern with Lamictal and its use for children is the interaction with valproate, because of the increased risk of severe rash. Lamictal should always be introduced gradually to prevent toxicity and the development of a rash. Other than rash, the most common side effects include dizziness, sleepiness, double vision, and sometimes upset stomach.

Dosage for Lamictal depends on the age of the child and whether the child is also taking valproate. For children aged 2 to 12 years who are also taking valproate, the starting dose is 0.15 mg/kg per day in one or two divided doses, and the usual maintenance dose is 1 to 5 mg/kg per day. Without valproate, children aged 2 to 12 years start at 0.6 mg/kg per day and the usual maintenance dose is 5 to 15 mg/kg per day.

For children over 12 years of age who are taking valproate, the starting dose is 25 mg every other day and the usual maintenance dose is 100 to 400 mg per day (in one or two divided doses). Children over 12 who don't take valproate usually start at 50 mg per day and work up to 300 to 500 mg per day.

Lamotrigine and Pregnancy

Emerging data from a pregnancy registry suggest an association between LAMICTAL ® (lamotrigine) and an increased risk of non-syndromic oral clefts

The U.S. Food and Drug Administration (FDA) lists Lamictal in Pregnancy Category C. This indicates that caution is advised, but the benefits of the medication may outweigh the potential risks. So far there is no indication that Lamictal causes serious birth defects, but there have been no well-controlled studies in women, and studies in animals have shown some harm to the fetus.

The risk of birth defects is higher for women who take more than one AED and for women with a family history of birth defects.

Women who are capable of becoming pregnant should take at least 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent a type of birth defect called a neural tube defect. (The best-known of these is spina bifida, in which the spinal cord is not completely enclosed.) Women at high risk, such as those with a history of this kind of defect in a previous pregnancy, should take 4000 mcg (4 mg) daily, beginning before they become pregnant. Whether folic acid is effective in preventing defects has not been proven, however, so the doctor may recommend a check-up using ultrasound during the 18th to 20th week of pregnancy.

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how their seizure medicine is handled by the body. This appears to be particularly true for Lamictal. Therefore, the doctor may recommend checking the level of Lamictal in the blood regularly during pregnancy so that the dosage can be adjusted as needed.

The risks, benefits, and options should be discussed with women taking Lamictal who are interested in breast-feeding. The baby will get some Lamictal through the milk, and its possible effects are unknown. For this reason, breast-feeding while taking Lamictal is not recommended.

Lamotrigine effects on Seniors

Older people metabolize Lamictal more slowly than younger adults and they may be more susceptible to its side effects. Therefore, lower initial doses and caution in titration are advisable.

Lamotrigine Dosing and titration

The appropriate dosages of Lamictal depend on what other AEDs, if any, the patient is taking. If Lamictal is used as monotherapy for young adults, the starting dose is 25 mg a day, increased every two weeks by 25 mg daily as needed, usually to 100-200 mg a day.

For young adults who are taking hepatic enzyme–inducing AEDs, however, Lamictal is usually started at 25 mg twice a day. Every 1-2 weeks, the amount can be increased by 50 mg per day as required (if side effects are not troublesome) to a target dose of 300-500 mg per day. The AEDs that require these higher dosages of Lamictal are:

  • carbamazepine (Tegretol, Tegretol-XR, Carbatrol)
  • phenytoin (Dilantin, Phenytek)
  • phenobarbital)
  • primidone (Mysoline)

For adults taking valproate (Depakote, Depakote ER, valproic acid), the initial dose is 12.5 to 25 mg every other day, with increases of 25 mg per day every two weeks as needed and tolerated, usually to 150-200 mg daily.

Patients over age 65 generally require a lower initial dose and lower target maintenance dose.

Measurements of serum concentrations are useful, particularly if the patient stops or starts enzyme-inducing AEDs or valproate. Therapeutic serum concentrations of lamotrigine have not been established, but generally levels of 5-15 mcg/mL are achieved.

Lamotrigine Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for Lamictal (lamotrigine) is found at:

Some of the information may differ in other countries.

To learn how to read and understand a package insert, see How to read a package insert.

Lamotrigine References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine.

Here are links to some articles relevant to this subject:

Messenheimer J, Ramsay RE, Willmore LJ, et al. Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia 1994 Jan-Feb;35(1):113-21. PMID: 8112232.

Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. Lamictal Lennox-Gastaut Study Group. N Engl J Med 1997 Dec 18;337(25):1807-12. PMID: 9400037.

Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995 Feb 25;345(8948):476-9. PMID: 7710545.

Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin. Epilepsia 1999 May;40(5):601-7. PMID: 10386529.

Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001 Nov;47(1-2):17-25. PMID: 11673017.

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