Lamotrigine


Article Author:
Nicholas Betchel


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
Michael Labanowski


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
10/8/2019 2:09:49 PM

Indications

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

Off-Label uses include treatment of acute bipolar depression, fibromyalgia, schizophrenia and unipolar depression.

Mechanism of Action

The mechanism of action for lamotrigine is not entirely understood. It is a triazine, and it has been shown that lamotrigine selectively binds sodium channels, stabilizing presynaptic neuronal membranes and inhibiting glutamate release. Lamotrigine has not been proven to have significant effects on other neurotransmitters such as serotonin, norepinephrine or dopamine. [4]It is thought 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 should be protected from light.

Lamotrigine dosing is altered 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 a period of 2 weeks, if possible. There is a possibility of withdrawals seizures when lamotrigine is discontinued, which is lowered 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, 25 mg should be given daily. At week three the dose should be increased to 50 mg daily. At week 5 increase by an additional 50 mg every week or every other week. Typical maintenance ranges from 225 mg to 375 mg to two divided doses.

If being used concurrently with valproic acid, dosing instructions are as follows. Initially, 25 mg should be given every other day. At week 3 the dose should be increased to 25 mg daily. At week 5 increase 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 it is given with valproic acid alone, or 100 mg to 400 mg in one or two divided doses if it is 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, 50 mg should be given daily. At week three the dose should be increased 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,g to 500 mg to two divided doses.

For Bipolar I: Maintenance is 200 mg to 400 mg, with 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 rash occur 2 to 8 weeks after the initiation of lamotrigine. It should also be noted 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. Pregnancy risk factor C, animal studies have shown risk for congenital malformations.

Lamotrigine is present in breast milk and is detected 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 must be considered, 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 is reported to interfere with urine drug screen and to cause false-positive readings phencyclidine.

Monitoring

The value of monitoring lamotrigine concentrations has not been established. 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. Ample time should be spent 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 be educated to monitor for signs/symptoms of aseptic meningitis.

Toxicity

In excessive lamotrigine overdoses, some reported to be as high as 16g; fatalities have been observed following complications including seizures, coma and conduction abnormalities. Immediate-release lamotrigine is rapidly absorbed, and emesis may not be 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 should also be noted 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.[9]


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Lamotrigine - Questions

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Which of the following anti-epileptic drugs will undergo a serum level reduction of up to 50% when taken along with oral contraceptives?



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Which of the following medications is most likely to extend the half-life of lamotrigine?



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Which combination of antiseizure medications most often causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)?



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A decision has been made to administer another anticonvulsant as adjunctive therapy to a patient being treated for Lennox Gastaut syndrome. Which of the following anticonvulsants is FDA approved to be used as adjunctive therapy for Lennox Gastaut syndrome?



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Which is false regarding lamotrigine?



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A patient is experiencing recurrent infections and sore throat. Her blood work shows that she is neutropenic and leukopenic. Upon reviewing her medication record, you find that she is taking warfarin, lamotrigine, paroxetine, and alendronate. Which of these medications has been associated with an increased incidence of neutropenia and leukopenia?



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A patient that is being treated for partial seizures is currently on a regimen that contains phenytoin but not valproic acid. A decision has been made to add lamotrigine. What would be the appropriate lamotrigine starting dose?



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A patient presents to the hospital with a life-threatening rash. Upon reviewing his medication record you find that he is taking lamotrigine, calcium carbonate, fluoxetine, and prednisone. Which drug is most likely to have caused this patient's life-threatening rash?



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A patient presents with a 3-week history of visual disturbances and asks whether any of the drugs that he is taking may be causing them. His medications include ergocalciferol, natalizumab, lamotrigine, and levothyroxine. Which medication is most likely causing his visual disturbances?



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Which of the following medications is first-line therapy for an acute depressive episode in a patient with bipolar 1 disorder?



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Which of the following is the feared side effect of lamotrigine?



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Lamotrigine - References

References

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]
Jansen AC,Andermann E, Progressive Myoclonus Epilepsy, Lafora Type 1993;     [PubMed]
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]
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Tomson T,Battino D,Perucca E, Teratogenicity of antiepileptic drugs. Current opinion in neurology. 2019 Apr;     [PubMed]
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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]
Di Stefano G,Truini A,Cruccu G, Current and Innovative Pharmacological Options to Treat Typical and Atypical Trigeminal Neuralgia. Drugs. 2018 Sep;     [PubMed]
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]

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