Lamotrigine

Lamotrigine

Lamotrigine has the most satisfactory side-effect and safety profile of any of the new mood stabilizing antiepileptic drugs (1). Present experience indicates it can be very effective in people with bipolar disorder suffering from depression (2,3) .

Side effects sometimes seen are: dizziness, headache, blurred vision, impaired coordination, sleepiness or insomnia, nausea and rash. The relative severity of side effects is less than with most other anti-epileptic drugs or psychotropic drugs.

The recommended dose escalation for mono-therapy for Bipolar Disorder in the UK product information texts is: Weeks 1 - 2 dose 25 mg daily Weeks 3 - 4 = 50 mg daily Week 5 =100 mg daily Week 6 = 200 mg daily (NB there is no advice relating to Bipolar Disorder in the Australian PI). Different regimes may be appropriate in particular circumstances.

The significant, but rare, problem is that ~ 5 / 10,000 people get ‘Stevens-Johnson syndrome’ (SJS) a severe skin rash which means they have to stop lamotrigine immediately, see below. For this reason any rash that appears with lamotrigine may be treated with precautionary action because it does not seem possible to predict which ones progress to the serious SJS. It seems that rashes affecting mucous membranes (eyes, mouth, nose) are particularly risky. However since it is not accurately predictable all rashes are included in many precautionary notices. Mild rashes occur in about 1 / 20 and are probably more frequent with higher starting doses. Rashes are quite common in people who are not on any drugs. A large study review (4) found rates of rash of 8.3% in those on lamotrigine, and 6.4% in those on placebo: very little different. That suggests many rashes seemingly associated with lamotrigine are just chance; that is probably why many people do not get another rash when they try it again.

Ideally, do not to start lamotrigine within two weeks of having had any rash, viral infection or vaccination. For the first three months, as far as possible, try to avoid other new medicines, new foods and do not change any of your cosmetics, soaps, deodorants etc, or any other chemicals that will come into contact with your skin (detergents, household cleaners etc). Avoid strong sunlight as much as reasonably possible (5) .

If you get a rash that is accompanied by eye, mouth or bladder discomfort let your doctor know immediately and have it assessed before taking any more lamotrigine, because there is a chance that could be the beginning of a severe skin reaction (the risk of this happening is between 1-10 cases per 10,000 (6)).

The most recent data shows many of these cases can tolerate lamotrigine by stopping it, and then restarting at a lower dose (5,7,8). The dose, and timing, for trying it after you have had a lamotrigine-induced rash is: 12.5 - 25 mg per day for two weeks, then double the dose every two weeks until the effective dose is reached. This maybe as little as 100 milligrams per day, but is often higher. A dose of 200 mg per day is typical, and higher doses are needed in some people (note the ‘recommended’ dose is often stated to be 50 – 200 mg). If lamotrigine is being taken with sodium valproate (Brand name ‘Epilim’, ‘Valpro’ and others) a lower dose (i.e. 12.5 mg or less) may be used, and if it is being taken with ‘Tegretol’ (carbamazepine), higher doses are used.

The following drugs probably lower lamotrigine levels: carbamazepine, ethinylestradiol, fluoxetine and lithium (but not, it appears, other antidepressants or anti-psychotics), phenytoin, phenobarbital, and topiramate .

Lamotrigine levels are variably reduced during pregnancy (10).

Lamotrigine is not associated with weight gain (11).

It seems probable that the risk of fetal malformations (teratogenicity) is low (12,13).

There is some relationship of blood levels to efficacy, side effects and toxicity (14). More than 90% of people can tolerate levels of up to 5.0 microg/mL, 85% tolerate up to 10 microg/mL and 75% up to 20 microg/mL. Increasing efficacy (judged by seizure freedom for a 6-month period) occurred up to levels of >20 microg/mL. Hirsch suggests ‘an initial target range of 1.5 to 10 microg/mL though higher levels, up to >20 microg/mL, are often tolerated and can lead to additional efficacy in refractory patients’. It is probable Bipolar Disorder blood levels are similar. The PI states that the side effects of ‘dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting, were dose related’.

The recommended dose escalation for mono-therapy in the UK PI is: Weeks 1 - 2 dose 25 mg daily Weeks 3 - 4 = 50 mg daily Week 5 =100 mg daily Week 6 = 200 mg daily

It is moderately safe in over-dose (1). The most common effects of overdose were: drowsiness/lethargy (20%), vomiting (10%), nausea, ataxia (5%), dizziness/vertigo and tachycardia (all ~ 5.%).

References

Because the Australian PI does not cover Bipolar Disorder (due to a strange and irksome quirk in the bureaucracy and regulatory procedures) I append in full those issued in the UK, unabridged.

“Bipolar Disorder: The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).

In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day (n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day.

Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.”

Listed side effects in PI are:--

“Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in this leaflet. If you develop any side effects or symptoms you are concerned about or need more information, call your doctor.”

1. Lofton, A.L. and W. Klein-Schwartz, Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother, 2004. 38(11): p. 1811-5.

2. Bowden, C.L., A different depression: clinical distinctions between bipolar and unipolar depression. J Affect Disord, 2005. 84(2-3): p. 117-25.

3. Calabrese, J.R., et al., New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder. Eur Psychiatry, 2005. 20(2): p. 92-5.

4. Calabrese, J.R., et al., Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry, 2002. 63(11): p. 1012-9.

5. Ketter, T.A., et al., Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash. J Clin Psychiatry, 2005. 66(5): p. 642-5.

6. Mockenhaupt, M., et al., Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology, 2005. 64(7): p. 1134-8.

7. Codrea Tigaran, S., P. Sidenius, and M. Dam, Lamotrigine-induced rash--worth a rechallenge. Acta Neurol Scand, 2005. 111(3): p. 191-4.

8. Kanner, A.M., Lamotrigine-induced Rash: Can We Stop Worrying? Epilepsy Curr, 2005. 5(5): p. 190-1.

9. Reimers, A., et al., Drug interactions between lamotrigine and psychoactive drugs: evidence from a therapeutic drug monitoring service. J Clin Psychopharmacol, 2005. 25(4): p. 342-8.

10. Petrenaite, V., A. Sabers, and J. Hansen-Schwartz, Individual changes in lamotrigine plasma concentrations during pregnancy. Epilepsy Res, 2005. 65(3): p. 185-8.

11. Ness-Abramof, R. and C.M. Apovian, Drug-induced weight gain. Drugs Today (Barc), 2005. 41(8): p. 547-55.

12. Cunnington, M. and P. Tennis, Lamotrigine and the risk of malformations in pregnancy. Neurology, 2005. 64(6): p. 955-60.

13. Morrow, J.I., et al., Malformation risks of anti-epileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry, 2005.

14. Hirsch, L.J., et al., Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy. Neurology, 2004. 63(6): p. 1022-6.