Valproic Acid with Lamotrigine Interaction Details

Brand Names Associated with Valproic Acid

Brand Names Associated with Lamotrigine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 08, 2023

Interaction Effect

Increased lamoTRIgine exposure and increased risk of severe, potentially life-threatening rash

Interaction Summary

Concomitant use of lamoTRIgine (metabolized predominantly by glucuronic acid conjugation) with valproate, which is known to inhibit glucuronidation, has resulted in a 2-fold increase in plasma concentrations of lamoTRIgine. Dose decreases of lamoTRIgine may be necessary to prevent toxicity, especially in patients receiving adjunctive antiepileptics, in patients with bipolar disorder, and in pediatric patients. The dosage of lamoTRIgine in the presence of valproate is less than half of that required in its absence. Dosage of lamoTRIgine may need to be subsequently increased when valproate is discontinued. LamoTRIgine dose should be adjusted as clinically indicated. If coadministered, monitor closely for the development of rash. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamoTRIgine and valproate administration .

Severity

Major

Onset

Unspecified

Evidence

Established

How To Manage Interaction

Concomitant use of lamoTRIgine (metabolized predominantly by glucuronic acid conjugation) with valproate, which is known to inhibit glucuronidation, has resulted in a 2-fold increase in plasma concentrations of lamoTRIgine. Dose decreases of lamoTRIgine may be necessary to prevent toxicity, especially in patients receiving adjunctive antiepileptics, in patients with bipolar disorder, and in pediatric patients. The dosage of lamoTRIgine in the presence of valproate is less than half of that required in its absence. Dosage of lamoTRIgine may need to be subsequently increased when valproate is discontinued. LamoTRIgine dose should be adjusted as clinically indicated. If coadministered, monitor closely for the development of rash. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamoTRIgine and valproate administration .

Mechanism Of Interaction

Inhibition of lamoTRIgine glucuronidation and decreased lamoTRIgine clearance

Literature Reports

A) In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamoTRIgine increased from 26 to 70 hours with valproate coadministration (a 165% increase) .

B) There is evidence that the inclusion of valproate in a multidrug regimen with lamoTRIgine increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate .

C) There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered lamoTRIgine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered lamoTRIgine in the absence of valproate were hospitalized .

D) A 23-year-old woman presented to the emergency room with generalized rash, redness and swelling on her eyelids and lips, fever, weakness, blisters, and a sore throat 3 weeks after lamoTRIgine was added to her anti-epilepsy regimen. Her initial regimen consisted of carbamazepine 400 mg twice a day. Valproic acid 500 mg twice daily was added 2 months and lamoTRIgine 50 mg twice daily was added 3 weeks prior to current presentation. The patient had an elevated erythrocyte sedimentation rate and C-reactive protein. However, serum carbamazepine and valproic acid levels were within therapeutic range. Serum lamoTRIgine concentrations were not measured. She was diagnosed with lamoTRIgine-induced Stevens-Johnson syndrome (SJS), with a Naranjo Adverse Drug Reactions Probability Scale score of 6 (probably drug induced). LamoTRIgine was discontinued and treatment was initiated for the SJS. She was discharged on day 18 on oral carbamazepine 400 mg twice daily and oral valproic acid 1500 mg/day. At the one month follow-up, she displayed significant improvement in oromucosal and skin lesions, with areas of hyperpigmentation. The patient's increased risk of developing SJS may have potentially been a result of either the combination of lamoTRIgine and valproic acid leading to decreased metabolism of lamoTRIgine, or due to initiation of lamoTRIgine at a dose higher than the manufacturer's recommended starting dose of 25 mg per day .

E) Fever, rash, multiorgan dysfunction, and disseminated intravascular coagulation were reported in two children treated with valproic acid and lamoTRIgine. Both children were receiving valproic acid for treatment of seizures. LamoTRIgine was added because of poor control. Symptoms developed within nine days of starting lamoTRIgine, but did not abate after lamoTRIgine was discontinued .

F) A 54-year-old male presented to the hospital with a five-day history of facial swelling, intermittent fever, anorexia, ataxia, and pruritic rash on the chest, upper extremities, neck, and back. He had been taking allopurinol 100 mg daily and captopril 50 mg daily for four years prior to admission. Because of a glioblastoma multiforme brain tumor, valproic acid and lamoTRIgine therapy was begun and the doses were titrated to valproic acid 500 mg three times daily and lamoTRIgine 50 mg twice daily approximately four weeks prior to his hospital admission. By hospital day 7, the patient was experiencing extensive sloughing of his skin along his back, face, and trunk, accounting for more than 60% of his total body surface area. He continued to deteriorate and was withdrawn from life support on hospital day 12. His death was attributed to toxic epidermal necrolysis probably due to lamoTRIgine therapy and possibly enhanced by valproic acid .

G) A study including 28 patients with intractable epilepsy was conducted to determine whether the dose of steady-state serum concentrations (Css) of valproic acid were inversely related to lamoTRIgine clearance. Valproic acid was initiated at 500 mg/day for 3 days and increased to 750 mg/day on day 4, depending on tolerance and response. The valproic acid dose was increased 125 to 250 mg every 3 weeks, until patients became seizure-free or developed adverse events. Upon initiation of valproic acid, the dose of lamoTRIgine was decreased by 50%, so as to maintain lamoTRIgine Css at comparable levels to those reached during monotherapy. A 50% reduction in lamoTRIgine clearance was reported in these patients. The dose of lamoTRIgine needs to be decreased by 50% at the start of valproic acid therapy to maintain comparable lamoTRIgine Css. However, additional increases in valproic acid dose would not require further reductions of lamoTRIgine to maintain stable lamoTRIgine Css. Seizure-free periods were significantly longer during treatment with both lamoTRIgine and valproic acid than during lamoTRIgine monotherapy, an indication that therapeutic synergism exists between lamoTRIgine and valproic acid .

H) A study involving eight patients with epilepsy found a significant increase in lamoTRIgine area under the concentration-time curve (AUC) and longer half-life with concomitant valproic acid administration. Dosages of valproic acid of up to 1,000 mg/day resulted in mean increases in lamoTRIgine AUC of more than 2.5-fold. Even low doses of valproic acid (200 mg/day) resulted in significant increases in lamoTRIgine AUC (mean 84%). Significant increases in plasma lamoTRIgine concentrations by inhibiting lamoTRIgine metabolism and increased half-life has been achieved with the use of low to moderate doses of valproic acid .

I) LamoTRIgine decreased valproic acid steady-state concentrations by 25% in 18 healthy volunteers over a 3-week period, and then stabilized. Adding lamoTRIgine to the existing therapy did not cause a change in plasma valproate concentrations in adult or pediatric patients in controlled clinical trials. The addition of valproate increased lamoTRIgine steady-state concentrations in normal volunteers by more than 2-fold .

J) In a black box warning from the manufacturer, the incidence of severe rash may be higher in patients on co-administered valproic acid and lamoTRIgine .

K) Valproic acid interferes with the metabolic clearance of lamoTRIgine. The normal elimination half-life of lamoTRIgine is approximately 24 hours; in patients receiving concomitant valproic acid therapy, the half-life increases to approximately 40 to 60 hours. The mechanism of this interaction is thought to be competition of the two drugs for hepatic metabolism . Fever, rash, multiorgan dysfunction, disseminated intravascular coagulation, and fatal toxic necrolysis have been reported with this combination in adults and pediatric patients .

Valproic Acid Overview

• Valproic acid is used alone or with other medications to treat certain types of seizures. Valproic acid is also used to treat mania (episodes of frenzied, abnormally excited mood) in people with bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). It is also used to prevent migraine headaches but not to relieve headaches that have already begun. Valproic acid is in a class of medications called anticonvulsants. It works by increasing the amount of a certain natural substance in the brain.

Lamotrigine Overview

• Lamotrigine extended-release (long-acting) tablets are used with other medications to treat certain types of seizures in patients who have epilepsy. All types of lamotrigine tablets (tablets, orally disintegrating tablets, and chewable tablets) other than the extended-release tablets are used alone or with other medications to treat seizures in people who have epilepsy or Lennox-Gastaut syndrome (a disorder that causes seizures and often causes developmental delays). All types of lamotrigine tablets other than the extended-release tablets are also used to increase the time between episodes of depression, mania (frenzied or abnormally excited mood), and other abnormal moods in patients with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Lamotrigine has not been shown to be effective when people experience the actual episodes of depression or mania, so other medications must be used to help people recover from these episodes. Lamotrigine is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.