Lamitrin®: composition and pharmaceutical form
One tablet contains 25 mg, 50 mg or 100 mg of lamotrigine. One dispersible tablet, marked with the letter S, contains 2 mg, 5 mg, 25 mg, 100 mg or 250 mg. That range of strengths is not about convenience: treatment always begins with very small doses and is raised over weeks.
Ordinary tablets are swallowed whole, without chewing or biting them. The S tablets can be swallowed after chewing or whole with water, or dissolved: add a little water — at least enough to cover the whole tablet — and drink the resulting suspension.
How Lamitrin® works
Lamotrigine is a voltage-dependent blocker of sodium channels, and through that it suppresses the high-frequency repetitive firing of neuronal action potentials. The medicine inhibits the excessive release of glutamate — the amino acid that plays a key role in the generation of epileptic seizures — and thereby blocks the formation of glutamate-evoked action potentials.
Lamotrigine is absorbed rapidly and completely from the digestive tract without significant first-pass metabolism; the maximum serum concentration occurs after about 2.5 hours and plasma protein binding is around 55%. Metabolism is handled by UDP-glucuronosyltransferases, and the medicine induces its own metabolism slightly, in proportion to the dose. Elimination proceeds mainly through conversion into glucuronide derivatives, which are then excreted in the urine: less than 10% of the medicine is excreted unchanged in urine and 2% in the faeces. There is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptics, and interactions with medicines metabolised by cytochrome P-450 are unlikely.
Indications
The first field of use is epilepsy. In adults and adolescents aged 13 and over this means combination treatment or monotherapy of partial and generalised seizures, including tonic-clonic ones, as well as seizures associated with Lennox-Gastaut syndrome: here the medicine is used within combination treatment, though it may also be the first antiepileptic introduced into the treatment of that syndrome.
The remaining indications differ by age and by the nature of the disorder.
- in children and adolescents aged 2 to 12 the medicine is added to other antiepileptics for partial and generalised seizures, tonic-clonic ones included, and also for seizures associated with Lennox-Gastaut syndrome;
- in children and adolescents aged 2 to 12, monotherapy of typical absence seizures;
- in adults from 18 years, prevention of depressive episodes in patients with bipolar affective disorder type I in whom depressive episodes predominate; the medicine is not indicated for the acute treatment of manic or depressive episodes.
Method of use and dosage
All of lamotrigine's dosing is governed by a single consideration: the risk of severe rash, which is linked to high starting doses and to escalation that is too fast. The recommended doses — both the starting dose and those during escalation — must therefore not be exceeded. The regimen depends on what the patient takes at the same time: valproate inhibits the glucuronidation of lamotrigine and nearly doubles its half-life, while phenytoin, carbamazepine, phenobarbital, primidone, rifampicin and lopinavir with ritonavir speed it up.
| Regimen | Doses by week |
| Epilepsy, monotherapy, from 13 years | weeks 1–2: 25 mg a day; weeks 3–4: 50 mg; maintenance 100–200 mg a day, with steps of no more than 50–100 mg every 1–2 weeks; some patients needed 500 mg a day |
| Epilepsy, with valproate | weeks 1–2: 12.5 mg a day, that is 25 mg every other day; weeks 3–4: 25 mg a day; maintenance 100–200 mg a day, with steps of no more than 25–50 mg every 1–2 weeks |
| Epilepsy, without valproate but with glucuronidation inducers | weeks 1–2: 50 mg a day; weeks 3–4: 100 mg a day in two divided doses; maintenance 200–400 mg a day in two divided doses, with steps of no more than 100 mg; some patients needed 700 mg a day |
| Epilepsy, without valproate and without inducers | weeks 1–2: 25 mg a day; weeks 3–4: 50 mg a day; maintenance 100–200 mg a day, with steps of no more than 50–100 mg |
| Bipolar disorder, monotherapy or without valproate and without inducers | weeks 1–2: 25 mg; weeks 3–4: 50 mg; week 5: 100 mg; target dose at week 6: 200 mg a day; trials used 100–400 mg |
| Bipolar disorder, with valproate | weeks 1–2: 12.5 mg; weeks 3–4: 25 mg; week 5: 50 mg; target dose at week 6: 100 mg a day, up to a maximum of 200 mg depending on clinical response |
| Bipolar disorder, with glucuronidation inducers | weeks 1–2: 50 mg; weeks 3–4: 100 mg; week 5: 200 mg; target dose at week 6: 300 mg a day and, if needed, 400 mg at week 7, in two divided doses |
In children aged 2 to 12 doses are calculated per kilogram of body weight: in monotherapy of absence seizures, weeks 1–2 at 0.3 mg/kg a day, weeks 3–4 at 0.6 mg/kg, maintenance 1–10 mg/kg; with valproate, 0.15 and 0.3 mg/kg with maintenance of 1–5 mg/kg and a maximum of 200 mg a day; with inducers, 0.6 and 1.2 mg/kg with maintenance of 5–15 mg/kg and a maximum of 400 mg a day. The child's weight is monitored and the dose recalculated if it changes, and children aged 2 to 6 more often need doses from the upper part of the range. In moderate hepatic impairment of Child-Pugh grade B doses are reduced by about 50%, and in severe grade C by 75%; in renal impairment caution is needed, and over the age of 65 no adjustment is required. If the calculated dose does not correspond to a whole number of tablets, the dose matching the smaller number is given.
Contraindications
Hypersensitivity to the components of the preparation. Not to be used in children under 2 years.
Alongside this short list stands an important rule for restarting therapy. If the patient stopped taking the medicine for any reason, the need for gradual escalation is reassessed: the longer the break, the more carefully the increase is approached, and if more than five half-lives have passed since the last dose, the escalation schedule is worked through again from the start. Restarting treatment in patients who previously stopped it because of a rash is not recommended — except where the potential benefit clearly outweighs the risk.
Special warnings and precautions
Abrupt withdrawal of the medicine may cause epileptic seizures to return, so it is withdrawn gradually, over at least 2 weeks. Caution is needed in patients with end-stage renal failure: accumulation of the glucuronide metabolite is to be expected in them.
- severe epileptic seizures, including status epilepticus, may lead to breakdown of striated muscle, multi-organ failure and disseminated intravascular coagulation, sometimes with a fatal outcome;
- a rash may be one element of a hypersensitivity syndrome that includes fever, lymphadenopathy, facial oedema and abnormalities in blood counts and liver function; its early signs — fever and lymphadenopathy — may appear without any obvious skin rash;
- when concomitant antiepileptics are withdrawn or new medicines are added to a lamotrigine regimen, the possible effect of that on lamotrigine pharmacokinetics is taken into account;
- in bipolar disorder, clinical trials showed no increase in the frequency, severity or number of adverse reactions after abrupt withdrawal of the medicine.
Hormonal contraceptives deserve separate attention. In women on maintenance doses of lamotrigine without glucuronidation inducers, starting a contraceptive usually requires raising the dose by 50–100 mg a day each week, and stopping it requires lowering the dose, often by half, by 50–100 mg a week over 3 weeks and by no more than 25% of the weekly dose. With a regimen that includes a week of inactive preparation, the lamotrigine concentration is checked in the third week of active tablets, that is on days 15 to 21 of the cycle. If contraception is started against a background of inducers, adjustment may not be needed, and contraception without a week's break is worth considering as the first choice.
Interaction with other medicines
Every significant lamotrigine interaction comes down to the speed of its glucuronidation, and that is precisely why they determine the dosing schedule rather than merely calling for monitoring.
- antiepileptics that activate hepatic microsomal enzymes — phenytoin, carbamazepine, phenobarbital and primidone — speed up the metabolism of lamotrigine;
- valproate competes with lamotrigine for the liver's metabolising enzymes, slows its metabolism and nearly doubles its half-life;
- there are reports of dizziness, ataxia, double vision, disturbances of visual acuity and nausea in patients previously taking carbamazepine to whom lamotrigine was added;
- adding lamotrigine to existing therapy with atazanavir and ritonavir or lopinavir and ritonavir does not require changing the escalation schedule, but in patients on maintenance doses without glucuronidation inducers the dose may need raising when those medicines are added and lowering when they are withdrawn — plasma lamotrigine concentrations are checked before the change and for 2 weeks after it.
The practical consequence is simple: any change to concomitant therapy in a patient on lamotrigine is a reason to recalculate the dose rather than continue the previous one. That applies both to adding a medicine and to withdrawing one: the escalation schedule and the maintenance dose differ several-fold depending on what is taken alongside.
Pregnancy and breastfeeding
The medicine belongs to category C. It may be used in pregnancy and during lactation only where the benefit to the mother outweighs the potential threat to the fetus.
In practice that means the decision rests with the doctor, weighing seizure control against the risks: in epilepsy, uncontrolled seizures are themselves dangerous both for the mother and for the fetus. Treatment is therefore not stopped on one's own initiative, and a planned pregnancy is discussed with the doctor in advance — all the more so because the lamotrigine dose is tied to concomitant therapy and to the use of hormonal contraceptives.
Adverse reactions
The most common were headache, fatigue, rash, nausea, dizziness, drowsiness and insomnia. When lamotrigine was used in combination treatment, double and blurred vision, conjunctivitis, dizziness, drowsiness, headache, a feeling of tiredness, gastrointestinal disturbances — vomiting and diarrhoea — and also irritability and aggression, agitation, confusion and hallucinations were observed.
- very rare: a lupus-like syndrome and cases of severe rash presenting a potential threat to life, including Stevens-Johnson syndrome and toxic epidermal necrolysis, that is Lyell's syndrome;
- the hypersensitivity syndrome with rash varies in the severity of its clinical changes and may sometimes lead to disseminated intravascular coagulation and multi-organ failure;
- haematological changes: neutropenia, leukopenia, anaemia, thrombocytopenia, pancytopenia and, in very rare cases, aplastic anaemia and agranulocytosis;
- movement disorders: tics, unsteady gait, ataxia, nystagmus, tremor; in rare cases a rise in laboratory measures of liver function is possible.
The story of extrapyramidal disturbances deserves separate mention. In some cases the medicine may worsen parkinsonian symptoms in patients with previously diagnosed Parkinson's disease and, in very rare cases, produce extrapyramidal symptoms, including choreoathetoid ones, in patients without any concomitant extrapyramidal disorder.
Overdose
The symptoms of overdose are nystagmus, ataxia, disturbance of consciousness and coma. Treatment is symptomatic: lamotrigine has no specific antidote.
The section is short, but it has a practical continuation. Far more often than a single overdose, another situation arises: the patient speeds up the dose escalation on their own initiative, wanting the effect sooner. It is precisely that — exceeding the starting dose and raising it too quickly — that carries the risk of severe rash, so the week-by-week schedule must not be departed from.
How to get a prescription for Lamitrin® online
The medicine is prescription-only, and the conversation with the doctor is shaped by two questions: which indication lamotrigine is being prescribed for — epilepsy or prevention of depressive episodes in bipolar disorder type I — and what the patient takes alongside it. The second is no formality: the entire escalation schedule follows from it, and the starting doses differ fourfold between variants.
It is therefore worth preparing a full list of medicines for the consultation — especially valproate, carbamazepine, phenytoin, phenobarbital, primidone, rifampicin and combinations with ritonavir — and, for women, details of hormonal contraception and its regimen. Liver and kidney disease with test results, past reactions to antiepileptics and above all any rash on lamotrigine, Parkinson's disease, and pregnancy or plans for it are reported separately. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
