Lamotrigine

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 and inhibits voltage-gated sodium channels, stabilizing presynaptic neuronal membranes and inhibiting presynaptic glutamate and aspartate release. Researchers have not demonstrated that lamotrigine has significant effects on other neurotransmitters such as serotonin, norepinephrine, or dopamine.[8] 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, potentially contributing 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. It is available in formulations of 25 mg, 100 mg, 150 mg, and 200 mg tablets in tablet form. A chewable, dispersible tablet form is available in 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 need protection from light.

It also is available in 5-weeks starter "convenience packs" with different color coding: the blue pack contains 35 tablets of 25 mg, the green pack contains 84 tablets of 25 mg and 14 tablets of 100 mg, and the orange pack contains 42 tablets of 25 mg and 7 tablets of 100 mg. 

Lamotrigine dosing requires alteration if given concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, 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 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 used concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, 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.

Renal and Hepatic Dosing:

In cases of renal impairment, the immediate-release formulation dose should be reduced by 25% if CrCl is between 10 and 50. If Creatinine clearance is below 10, the maximum dosing is 100 mg every other day. For hemodialysis patients, dosing is 100 mg for a single dose after each dialysis with no supplement. For patients on peritoneal dialysis, dosing is 100 mg every other day. For the extended-release formulation, clinicians are advised to reduce the usual dose in instances of significant renal impairment.

For hepatic impairment, dosing should reduce the dose by 25% in severe impairment; if the patient has severe impairment with ascites, the dose reduction is 50%.

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. Patient education should include continuous monitoring of the rash for improvement after discontinuing the medication.[9][10]

Other serious adverse effects include multi-organ sensitivity, hemophagocytic lymphohistiocytosis, blood dyscrasias, suicidal behavior/ideations, aseptic meningitis, status epilepticus, and sudden unexplained death in epilepsy.[11][12]

Side Effects

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

Contraindications

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

Evaluating gender, age, and contraceptive use is essential when considering starting lamotrigine. While some studies in humans have not shown an increased risk for congenital malformations during lamotrigine therapy during pregnancy, animal studies have demonstrated that an increased risk exists. The drug is pregnancy risk factor C; animal studies have shown the risk for congenital malformations. Clinicians should recommend their pregnant female patients to enroll in the North American Antiepileptic Drug Pregnancy Registry.[13]

• Lamotrigine is present in breast milk and is detectable in the blood of breastfed infants. Symptoms of lamotrigine in infants include poor feeding, drowsiness, rash, and apnea. These symptoms can improve with the discontinuation of lamotrigine. If the benefits outweigh the risks in treating epilepsy during lactation/breastfeeding, clinicians should consider monitoring infant lamotrigine levels.
• 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 screening and can cause false-positive readings of phencyclidine.

Monitoring

The value of monitoring lamotrigine concentrations remains unestablished to date. Due to the pharmacokinetics between lamotrigine and other drugs and their effect on lamotrigine concentration, clinical judgment must be exercised during concomitant use if there are concerns regarding lamotrigine levels. Dofetilide can have a severe interaction with lamotrigine, and the combination is strongly discouraged. Other drugs with potential serious interactions include valproic acid, rifampin, estrogen-containing contraceptives, and estrogen replacement therapy medications, as well as certain barbiturates.

Labs should include pertinent serum levels of concurrent anticonvulsants, 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 monitor for changes in suicidality, including suicidal thoughts and increased desire to commit suicide. Finally, patients should receive counsel on how to watch for signs/symptoms of aseptic meningitis.

Toxicity

With excessive lamotrigine overdoses, some reportedly 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. As of this writing, there is no known specific antidote for lamotrigine toxicity.[14]

Enhancing Healthcare Team Outcomes

Lamotrigine is best prescribed, administered, dispensed, and managed by an interprofessional healthcare team. This team includes all clinicians (physicians, specialists, and mid-level practitioners (i.e., PAs and NPs)), nursing staff, and pharmacists. The drug is often prescribed by the primary care provider/nurse practitioner, internist, neurologist, and pain specialist to treat 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. Patient education should instruct the patient to continuously monitor for the outbreak for improvement after discontinuing the medication.[15] Pharmacists need to monitor the patient's medication record, alert the prescriber to possible drug-drug interactions, verify appropriate dosing, and offer patient counsel about their medication. Nursing can serve as an additional patient counseling resource and coordinate activities between the various clinicians and other specialties involved in patient care.

All interprofessional team members need to engage in open communication and patient data sharing so that everyone on the team is operating from the same accurate, up-to-date information. This interprofessional team approach will help yield optimal patient outcomes and reduce the potential for adverse events. [Level 5]