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Lamotrigine


Lamotrigine

Article Author:
Nicholas Betchel
Article Author:
Kamron Fariba
Article Editor:
Abdolreza Saadabadi
Updated:
10/6/2020 3:22:02 PM
For CME on this topic:
Lamotrigine CME
PubMed Link:
Lamotrigine

Indications

Lamotrigine can be used to treat the following: partial seizures, primary generalized tonic-clonic seizures, bipolar depression, bipolar disorder type I maintenance), and Lennox-Gastaut syndrome.[1][2][3]

Off-Label uses include treatment of rapid-cycling bipolar depression, basilar migraine, panic disorder, and binge eating disorder.

Mechanism of Action

The mechanism of action for lamotrigine is not entirely understood. It is a triazine, and research has shown that lamotrigine selectively binds sodium channels, stabilizing presynaptic neuronal membranes and inhibiting glutamate release. Researchers have not demonstrated that lamotrigine to have significant effects on other neurotransmitters such as serotonin, norepinephrine, or dopamine.[4] There is a theory that lamotrigine may interact with voltage-activated calcium-gated channels, contributing to its broad range of activity. In vitro studies have also shown that lamotrigine inhibited dihydrofolate reductase, which may contribute to concerns for its teratogenicity. Lamotrigine follows first-order kinetics with a half-life of 29 hours.

Administration

Lamotrigine is available as tablets, chewable tablets, and orally disintegrating tablets. In a tablet form, it is available in formulations of as 25 mg, 100 mg, 150 mg, and 200 mg tablets. In a chewable, dispersible tablet form, it is available in formulations of 2 mg, 5 mg, and 25 mg dispersible tablets. The orally disintegrating tablets are available in formulations of 25 mg, 50 mg, 100 mg, and 200 mg. All formulations should be stored at room temperature and needs protection from light.

Lamotrigine dosing requires alteration if it is given concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, and atazanavir, ritonavir and valproic acid.

If it is necessary to discontinue lamotrigine, it should be done in a step-wise fashion over two weeks, if possible. There is a possibility of withdrawal seizures when discontinuing lamotrigine, which lessens if the drug is tapered rather than stopped quickly.

For seizures:

If not being used concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, atazanavir, ritonavir, and valproic acid, dosing instructions are as follows. Initially, dosing is 25 mg given daily. At week three, the dose should increase to 50 mg daily. At week five, increase by an additional 50 mg each week or every other week. The typical maintenance ranges from 225 mg to 375 mg in two divided doses.

If being used concurrently with valproic acid, dosing instructions are as follows. Initially, dosing is 25 mg given every other day. At week three, the dose should increase to 25 mg daily. At week 5, increase the dose by an additional 25 mg to 50 mg every week or every other week. Typical maintenance varies from 100 mg to 200 mg daily in one or two divided doses if given with valproic acid alone, or 100 mg to 400 mg in one or two divided doses if given with other medications that induce glucuronidation.

If being used concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, and atazanavir, or ritonavir, dosing instructions are as follows. Initially, the dose is 50 mg given daily. At week three, the dose should increase to 100 mg daily in 2 divided doses. At week five, increase by an additional 100 mg every week or every other week. Typical maintenance ranges from 300 mg to 500 mg to two divided doses.

For Bipolar I:

Maintenance is from 200 mg to 400 mg, with additional consideration given to medication given concurrently with lamotrigine.

Adverse Effects

United States Boxed Warning: Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of this medication. Rash severity varies but includes a risk for Stevens-Johnson syndrome. The incidence of Stevens-Johnson syndrome in the pediatric population is 0.3% to 0.8% and 0.03% to 0.08% in adult populations. The number of cases associated with toxic epidermal necrolysis is too low to report an estimated incidence. Nearly all cases of a rash occur 2 to 8 weeks after the initiation of lamotrigine. It should also bear mentioning that the discontinuation of lamotrigine may not prevent a rash from becoming life-threatening, and patient education should include continuous monitoring of the rash for improvement after the discontinuation of the medication.[5][6]

Other adverse effects include multi-organ sensitivity, blood dyscrasias, suicidal behavior/ideations, aseptic meningitis, status epilepticus, and sudden unexplained death in epilepsy.[7][8]

Side effects include:

  • Nausea, vomiting
  • Chest pain, back pain
  • Xerostomia
  • Edema
  • Dysmenorrhea
  • Weight changes
  • Constipation
  • Abdominal pain
  • Pain, weakness
  • Insomnia, drowsiness
  • Dizziness, ataxia, diplopia.
  • Headache

Contraindications

Hypersensitivity to lamotrigine or its ingredients is the primary contraindication for the administration of lamotrigine.

Evaluating gender, age, and contraceptive use are essential for the consideration of starting lamotrigine. While some studies in humans have not shown an increased risk for congenital malformations during lamotrigine therapy during pregnancy, animal studies have shown there is an increased risk. The drug is pregnancy risk factor C; animal studies have shown the risk for congenital malformations.

Lamotrigine is present in breast milk and is detectable in the blood of breast-fed infants. Symptoms of lamotrigine in infants include poor feeding, drowsiness, rash, and apnea. These symptoms can improve with the discontinuation of lamotrigine.

Consideration for other drugs' effects on glucuronidation merit consideration, as glucuronic acid conjugation primarily metabolizes lamotrigine.

Drugs that induce lamotrigine glucuronidation include carbamazepine, phenytoin, phenobarbital, rifampin, lopinavir/ritonavir, atazanavir/ritonavir, and primidone.

Valproic acid inhibits lamotrigine glucouronidation.

Concurrent use with central nervous system (CNS) depressants may increase the potency of CNS depression.

Lamotrigine reportedly interferes with urine drug screen and to cause false-positive readings phencyclidine.

Monitoring

The value of monitoring lamotrigine concentrations remains unestablished to date. Due to pharmacokinetics between lamotrigine and other drugs and their effect on lamotrigine concentration, clinical judgment must be exercised during concomitant use if there are concerns in regards to lamotrigine levels.

Labs should include pertinent serum levels of concurrent anticonvulsants, as well as liver function testing, and renal function assessments. Clinical team staff should spend ample time educating patients on monitoring themselves for hypersensitivity, particularly rashes or other skin changes occurring near or on the mucosa. Patient education should also include discussing how to monitor for changes in seizures and their frequency and duration. Patients should also be informed to monitor for changes in suicidality, including suicidal thoughts and increased desire to commit suicide. Finally, patients should learn how to watch for signs/symptoms of aseptic meningitis.

Toxicity

In excessive lamotrigine overdoses, some reported to be as high as 16 g; fatalities have occurred following complications, including seizures, coma, and conduction abnormalities. Immediate-release lamotrigine is rapidly absorbed, and inducing emesis may not be the appropriate intervention indicated in this instance. However, hospitalization and supportive care are indicated, as well as the usual precautions to protect the airway. There is no known specific antidote for lamotrigine toxicity.

Enhancing Healthcare Team Outcomes

Lamotrigine is often prescribed by the primary care provider, nurse practitioner, internist, neurologist, and the pain specialist for the treatment of several other disorders besides seizures. However, all prescribers should be aware of the United States Boxed Warning, which states that lamotrigine can cause serious rashes requiring hospitalization and discontinuation of this medication. Rash severity varies but includes a risk for Stevens-Johnson syndrome. It also bears mentioning that the discontinuation of lamotrigine may not prevent a rash from becoming life-threatening, and patient education should consist of continuous monitoring of the outbreak for improvement after the discontinuation of the medication.[9]


References

[1] Bendtsen L,Zakrzewska JM,Abbott J,Braschinsky M,Di Stefano G,Donnet A,Eide PK,Leal PRL,Maarbjerg S,May A,Nurmikko T,Obermann M,Jensen TS,Cruccu G, EAN guideline on trigeminal neuralgia. European journal of neurology. 2019 Mar 12;     [PubMed PMID: 30860637]
[2] Jansen AC,Andermann E, Progressive Myoclonus Epilepsy, Lafora Type 1993;     [PubMed PMID: 20301563]
[3] Brigo F,Igwe SC,Lattanzi S, Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. The Cochrane database of systematic reviews. 2019 Feb 8;     [PubMed PMID: 30734919]
[4] Verrotti A,Striano P,Iapadre G,Zagaroli L,Bonanni P,Coppola G,Elia M,Mecarelli O,Franzoni E,Liso P,Vigevano F,Curatolo P, The pharmacological management of Lennox-Gastaut syndrome and critical literature review. Seizure. 2018 Dec;     [PubMed PMID: 30391662]
[5] Tomson T,Battino D,Perucca E, Teratogenicity of antiepileptic drugs. Current opinion in neurology. 2019 Apr;     [PubMed PMID: 30664067]
[6] Hou S,Huh B,Kim HK,Kim KH,Abdi S, Treatment of Chemotherapy-Induced Peripheral Neuropathy: Systematic Review and Recommendations. Pain physician. 2018 Nov;     [PubMed PMID: 30508986]
[7] Kanner AM,Ashman E,Gloss D,Harden C,Bourgeois B,Bautista JF,Abou-Khalil B,Burakgazi-Dalkilic E,Park EL,Stern J,Hirtz D,Nespeca M,Gidal B,Faught E,French J, Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Epilepsy currents. 2018 Jul-Aug;     [PubMed PMID: 30254528]
[8] Di Stefano G,Truini A,Cruccu G, Current and Innovative Pharmacological Options to Treat Typical and Atypical Trigeminal Neuralgia. Drugs. 2018 Sep;     [PubMed PMID: 30178160]
[9] Demir M,Akarsu EO,Dede HÖ,Bebek N,Yıldız SÖ,Baykan B,Akkan AG, Investigation of the roles of new antiepileptic drugs' and serum BDNF levels in efficacy and safety monitoring and quality of life: a clinical research. Current clinical pharmacology. 2019 Mar 12;     [PubMed PMID: 30864528]