Lamotrigine

Is lamotrigine safe?

For most people with epilepsy or bipolar disorder it is one of the better tolerated long-term options, provided the dose is built up exactly as prescribed. Lamotrigine, sold as Lamictal, is not addictive and has unusually strong pregnancy safety data for an epilepsy drug. It was filled about 12.6 million times in the US in 2024.

The main worry is a rare, potentially fatal skin reaction, which is why it carries a boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary and why the starting schedule is so slow. We score it 64: below gabapentin (66) and above quetiapine (55) and lithium (51), the other common bipolar options.

The rash warning and why the dose starts low

The US label puts the rate of serious rash needing hospital care and stopping the drug at about 0.08% to 0.3% in adults and 0.3% to 0.8% in children aged 2 to 17. These include Stevens-Johnson syndrome and toxic epidermal necrolysis, in which the skin and mouth lining blister and peel. In a cohort of 1,983 children with epilepsy there was one rash-related death, and rare deaths have been reported in adults.

The label names four things that raise the risk:

• taking valproate at the same time
• starting above the recommended dose
• increasing faster than the recommended schedule
• carrying the HLA-B*1502 gene variant (found mainly in people of Han Chinese and Thai origin), which roughly doubles or triples the risk; the boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary, updated in October 2025, now names it

Nearly all life-threatening rashes begin 2 to 8 weeks after starting, though some have appeared after 6 months. Because it is not possible to tell early which rash will turn serious, the label says to stop lamotrigine at the first sign of a rash unless it is clearly due to something else. Ring your prescriber that day.

For adults with bipolar disorder who take neither valproate nor enzyme-inducing drugs, the US label schedule is:

With valproate everything is halved, starting at 25 mg every other day. If you stop for longer than about five half-lives (a few days), the label says to restart from the beginning of the schedule.

Valproate, the pill and other interactions

Lamotrigine is broken down by glucuronidation, and drugs that speed or slow that process shift its levels a lot:

• Valproate (Depakote, Epilim) slightly more than doubles lamotrigine levels and raises the rash rate. In epilepsy trials, 1% of people on both were hospitalised with rash, against 0.16% without valproate.
• Oestrogen-containing pills cut lamotrigine levels by about half; during the pill-free week levels can nearly double, causing dizziness, unsteadiness or double vision. See combined oral contraceptives.
• Carbamazepine, phenytoin, phenobarbital, rifampin and some HIV medicines lower lamotrigine levels, so higher doses are needed.
• Dofetilide is not recommended with lamotrigine, and other sodium channel blockers may add to the heart rhythm risk.

Starting or stopping any of these needs a dose review.

Heart rhythm in people with heart disease

Laboratory studies found that lamotrigine blocks heart sodium channels in the same way as class IB antiarrhythmic drugs, at normal blood levels. On 31 March 2021 the FDA warned that this could slow conduction and trigger serious arrhythmias or sudden death in people with significant heart disease: heart failure, valve disease, congenital heart disease, conduction problems, Brugada syndrome or significant coronary disease. Combining it with other sodium channel blockers may add to the risk. In a study of healthy volunteers, normal doses did not slow conduction, so the warning is aimed at people with heart disease.

Other serious risks

Rarer warnings on the label include haemophagocytic lymphohistiocytosis (HLH), an overactive immune response that can be fatal; multi-organ allergic reactions (DRESS); low blood counts; aseptic meningitis; and a small rise in suicidal thoughts shared by all antiseizure drugs. Common side effects in epilepsy trials were dizziness, headache, double vision, unsteadiness, nausea and blurred vision; in bipolar trials, nausea, insomnia and sleepiness. Name confusion with other medicines has led to dispensing errors, so check your tablets.

In overdose, the label reports cases of up to 15 g, some fatal, with seizures, coma and conduction delay on the heart trace. Anyone who takes too much needs hospital assessment: in the US call Poison Help on 1-800-222-1222, in the UK 111, or 999 if someone is drowsy or fitting.

Pregnancy

A 2021 MHRA review concluded that lamotrigine and levetiracetam are the safer of the antiepileptic drugs reviewed in pregnancy. Studies covering more than 12,000 pregnancies on lamotrigine alone showed no increased risk of major birth defects at maintenance doses. The US label cites registry rates of 2.0% to 2.9%, close to the general population, with one registry finding a small rise in cleft lip or palate. Lamotrigine levels can fall during pregnancy and recover after delivery, so doses need monitoring. Anyone planning a pregnancy should see their specialist first, and the MHRA advises 5 mg of folic acid a day before conception.

Who should be careful

Talk to your doctor or pharmacist before starting lamotrigine, or before changing other medicines, if you take valproate, carbamazepine, phenytoin or a hormonal contraceptive, have had a rash with another antiseizure drug, have heart disease, or are pregnant or planning to be. Do not stop it suddenly; with epilepsy, abrupt withdrawal can cause seizures.

How we scored it

Track record (92) and dependence (85) are strong. Serious side effects (55) and regulatory warnings (40) reflect the boxed rash warning, the 2021 heart rhythm warning and rare immune reactions. Interactions (55) reflect the large dose effects of valproate, oestrogen and enzyme-inducing drugs, while the overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (65) reflects fatal cases at very high doses.