Lamotrigine – Mechanism of Action, Efficacy, Side Effects and Clinical Pearls

MECHANISM OF ACTION OF LAMOTRIGINE

Lamotrigine has multiple mechanisms of action, which give this drug its diverse anti-seizure properties as well as its novel thymoleptic and psychotropic properties.

Research shows that lamotrigine’s clinical profile is the result of distinct and overlapping mechanisms that contribute to each of its pharmacological actions. [Ketter T et al., 2003]

Central to its anti-seizure activity is its action on neuronal ion channels, particularly sodium channels and chloride channels.

Proconvulsant activity is linked to Na+ influx through voltage-gated Na+ channels, which in turn leads to glutamate excitotoxicity.

1. Inhibiting Glutamate Excitotoxicity

Lamotrigine blocks voltage-gated Na+ channels inhibiting glutamate excitotoxicity.

Administration of lamotrigine is purported to have anti-glutamatergic effects as well as putative anti-kindling effects.

Kindling is described as the clinical development of bipolar disorder from reactive and triggered symptoms to a more frequent, severe and spontaneously occurring form.

2. Enhance Release of GABA

Lamotrigine enhances the release of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that attenuates neuronal electrical activity associated with paroxysms.

EFFICACY OF LAMOTRIGINE

• Lamotrigine increases the time between the relapse of mood episodes and is most beneficial in delaying the onset of new depressive episodes.
• Lamotrigine is approved for the management of bipolar I disorder due to its stabilising effect on depressive symptoms and treatment of acute depressive episodes in Bipolar I disorder. [Calabrese J et al., 1999]
• Lamotrigine’s is part of first-line treatment for acute depressive episodes in bipolar I disorder.[RANZCP Guidelines for Bipolar Disorder]

• Lamotrigine has good evidence as prophylaxis of depressive episodes as part of Bipolar I disorder. [Goodwin G et al., 2004]
• Lamotrigine is a safe and effective option as an add on to ongoing lithium treatment in acute bipolar depression. [LamLit study group]
• In Bipolar I disorder, Lamotrigine will usually require a combination with an antimanic long-term agent. [RANZCP Guidelines for Bipolar Disorder]

• Lamotrigine does not have evidence for the treatment of acute mania.
• Lamotrigine also seems to have good efficacy for Bipolar II depression.
• Lamotrigine may be considered as long-term monotherapy in Bipolar II disorder. [RANZCP Guidelines for Bipolar Disorder]

DOSING OF LAMOTRIGINE

From PI.

Monotherapy:

• Week 1-2: 25 mg OD
• Week 2-4: 50 mg once a day (or in two divided doses)
• Week 5: 100mg/day (or in two divided doses)
• Target dose: 200 mg /day (once a day or in two divided doses)
• 400 mg/day dose may be required by some patients to achieve a suitable response in the management of bipolar disorder.

Concomitant therapy with Valproate or other glucuronidation inhibitors:

• Week 1-2: 25 mg every alternate day
• Week 2-4: 25 mg /day
• Week 5: 50 mg /day (or in two divided doses)
• Target dose: 100-200 mg/day

Concomitant therapy with inducers of lamotrigine glucuronidation (e.g Carbamazepine) in patients NOT taking inhibitors such as valproate.

• Week 1-2: 50 mg /day
• Week 2-4: 100 mg /day ( in two divided doses)
• Week 5: 200mg /day (in two divided doses)
• Week 6: 300 mg /day (in two divided doses)
• Week 7: 400 mg/day (in two divided doses) (if required)

Starting lamotrigine in patients already taking hormonal contraceptives

• No change

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking enzyme inducers of lamotrigine glucuronidation:

• The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking enzyme inducers of lamotrigine glucuronidation:

• The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50%

PHARMACOKINETICS OF LAMOTRIGINE

Absorption:

• continuously along the entire length of the gastrointestinal tract
• rapidly absorbed, reaching peak concentrations within about 3 hours postdose.
• bioavailability of the oral formulation is about 98%
• plasma protein binding is 56%.

Metabolism:

• primarily by glucuronidation

Half-Life:

• Both the immediate-release and extended-release formulations have half-lives of approximately 24–30 hours, but the enteric-coated extended-release form is absorbed more slowly.

SIDE EFFECTS OF LAMOTRIGINE

Common:

• dizziness
• visual disturbances
• ataxia
• nausea or vomiting
• non serious rash – can present as morbilliform, erythema multiforme, or urticaria. (They can, however, represent the initial stages of serious rashes)

Serious Side effects

• Serious rash (Stevens-Johnson syndrome), toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are more common in pediatric populations compared with adult patients (0.3% in adults and 1% in children).
• Rash has also been reported as part of a hypersensitivity syndrome, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis. (Symptoms may present in the absence of rash)

The patient presented with wide spread rash 4 weeks after initiation of Lamotrigine. Lamotrigine was discontinued and the rash subsided completely. No associated symptoms were present

The greatest risk of rash occurs within the first 6 weeks of treatment risk factors include

• Rapid titration
• Exceeding maximum dosage
• Co-administration with valproate
• Possible Han Chinese ethnicity [Zeng T et al., 2014]
• Poor quality control of certain lamotrigine brands [Parker G., 2018]
• Possible bioequivalence differences between generic and branded formulations [Contin M et al., 2016]

The majority of rashes that occur as a result of lamotrigine use are mild.

Management of Lamotrigine induced rash

• Refer for medical evaluation within 24 hours with possible referral to dermatology.
• Discontinue Lamotrigine immediately (unless it is clear that rash is non-related)

Alert

• On April 25, 2018, the FDA released a safety alert that lamotrigine use carries a risk of the immune system disorder hemophagocytic lymphohistiocytosis (HLH). [FDA]
• HLH is an aggressive and life-threatening syndrome of excessive immune activation leading to systemic inflammation. It is associated with high mortality rates if not recognized early and treated.
• Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin and liver function and coagulation abnormalities.
• Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment.

Lamotrigine Induced Rash – Assessment and Management by Dr. Sanil Rege

DRUG INTERACTIONS

• Carbamazepine, phenytoin, or phenobarbital decrease plasma levels of Lamotrigine decrease by half.
• When it is used with Valproate Na, the Valproate levels are reduced by about 25%, and the lamotrigine levels double (This can increase the risk of side effects).  Valproate inhibits glucuronidation of Lamotrigine.
• When initiating lamotrigine with valproate start at half the usual dose of Lamotrigine. (see previous)
• Hormonal contraceptives can increase the clearance of Lamotrigine (See dosing earlier)
• Lamotrigine and the Oral Contraceptive Pill – Are Dose Adjustments Needed?

LAMOTRIGINE SAFETY IN PREGNANCY

The safety of lamotrigine in pregnancy is covered in a previous article. There were specific concerns about the risk of cleft palate.

A systematic review Estimated the overall risk of any major congenital malformation with LTG monotherapy at 2%−3%. [Besag et al, 2021]

In summary, there is no increased risk of orofacial cleft or clubfoot if the mother was administered lamotrigine during the first trimester. [Dolk H et al., 2016]

CONCLUSION

Lamotrigine is an evidence-based mood stabiliser in the treatment of bipolar disorder. It has particular efficacy for acute bipolar depression and the prophylaxis of depressive episodes.

It is well tolerated and is not associated with weight gain compared to the other medications in bipolar disorder.

Serious side effects are rare however need to be closely monitored.

Lamotrigine is not on the PBS for Bipolar disorder in Australia.

The Full Product information from TGA is available here.