Lamotrigine

Dosage for lamotrigine is highly individualized and depends strictly on whether the patient is taking concurrent medications that affect its metabolism. A "slow and low" titration (gradual increase) is mandatory to minimize the risk of serious skin rashes.

• Bipolar I Disorder Maintenance: The standard target dose is 200 mg daily. For patients not taking enzyme-inducing or inhibiting drugs, the typical titration starts at 25 mg daily for weeks 1 and 2, followed by 50 mg daily for weeks 3 and 4, then 100 mg for week 5, reaching the 200 mg maintenance dose by week 6.
• Epilepsy (Adjunctive Therapy): The target dose ranges from 100 mg to 500 mg daily, often divided into two doses. If combined with valproate, the starting dose is significantly lower (12.5 mg to 25 mg every other day).
• Epilepsy (Monotherapy): The maintenance target is typically 500 mg daily, achieved through a multi-week titration schedule.

Lamotrigine is approved for children as young as 2 years for certain types of epilepsy. Dosing is strictly weight-based (mg/kg). For example, in children taking valproate, the starting dose may be as low as 0.15 mg/kg/day. Pediatric patients must be monitored closely by a specialist, as the risk of rash is statistically higher in children than in adults.

Renal Impairment

In patients with significant renal impairment (reduced kidney function), the initial dose of lamotrigine may not need adjustment, but the maintenance dose should generally be reduced. Because lamotrigine and its metabolites are cleared by the kidneys, reduced clearance can lead to drug accumulation. Healthcare providers typically reduce the maintenance dose by 25% to 50% in cases of moderate to severe renal failure.

Hepatic Impairment

For patients with moderate hepatic impairment (Child-Pugh Grade B), doses should be reduced by approximately 25%. In severe hepatic impairment (Child-Pugh Grade C), the dose should be reduced by 50%. The liver is the primary site of glucuronidation, so impaired liver function directly increases the circulating levels of the drug.

Elderly Patients

While no specific age-based dosage adjustment is universally required, clinicians often start at the lower end of the dosing range for elderly patients. This population is more susceptible to balance issues (ataxia) and cognitive side effects, and they often have age-related declines in renal or hepatic function.

• Consistency: Take lamotrigine at the same time every day to maintain stable blood levels. It can be taken with or without food.
• Swallowing: Immediate-release and extended-release tablets must be swallowed whole. Do not crush, chew, or break them, as this can interfere with the controlled release of the medication or cause a bitter taste.
• Chewable Tablets: These can be swallowed whole, chewed, or dispersed in a small amount of water or diluted fruit juice.
• ODT Tablets: Place on the tongue and allow to dissolve; they can be swallowed with or without water.
• Storage: Store at room temperature (68°F to 77°F) in a dry place away from light and moisture.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and return to your regular schedule. Never take two doses at once to make up for a missed one. If you miss more than a few days of lamotrigine, do not restart at your previous dose. You must contact your doctor immediately, as you may need to restart the titration process from the lowest dose to avoid the risk of a serious rash.

Signs of a lamotrigine overdose may include ataxia (lack of muscle coordination), nystagmus (involuntary eye movement), increased seizures, coma, or heart rhythm abnormalities (intraventricular conduction delay). In the event of a suspected overdose, contact emergency services or a poison control center immediately. Emergency treatment usually involves supportive care and gastric lavage if the ingestion was recent.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop the medication without medical guidance, as sudden discontinuation can trigger seizures.

Most patients tolerate lamotrigine well, but common side effects can occur, particularly during the titration phase. These usually diminish as the body adjusts to the medication:

• Dizziness and Ataxia: A feeling of lightheadedness or being unsteady on your feet. This is one of the most frequently reported side effects.
• Headache: Often mild to moderate, occurring shortly after starting the medication.
• Somnolence (Drowsiness): While less sedating than other AEDs, some patients feel fatigued or sleepy.
• Nausea and Vomiting: Gastrointestinal upset is common but can often be mitigated by taking the drug with food.
• Diplopia (Double Vision): Blurred or double vision may occur, especially at higher doses.

• Insomnia: Some patients report difficulty falling or staying asleep.
• Tremor: Small, involuntary shaking movements, usually in the hands.
• Anxiety or Irritability: Mood changes that are not related to the underlying condition.
• Dry Mouth: A persistent feeling of thirst or lack of saliva.
• Weight Changes: While generally weight-neutral, some patients may experience minor fluctuations.

• Aseptic Meningitis: Inflammation of the protective membranes covering the brain and spinal cord, not caused by bacteria. Symptoms include fever, headache, stiff neck, and light sensitivity.
• Hemophagocytic Lymphohistiocytosis (HLH): A rare but life-threatening immune system reaction. Symptoms include persistent fever, rash, and enlarged liver or spleen.
• Blood Dyscrasias: Rare instances of leukopenia (low white blood cells), anemia, or thrombocytopenia (low platelets).

> Warning: Stop taking Lamotrigine and call your doctor immediately if you experience any of these.

1. 1The Lamotrigine Rash: Any rash, especially one accompanied by fever, malaise, or swelling, must be evaluated immediately. This can be a precursor to Stevens-Johnson Syndrome (SJS).
2. 2Suicidal Thoughts: Like all AEDs, lamotrigine may increase the risk of suicidal thoughts or behaviors. Monitor for worsening depression or sudden changes in mood.
3. 3Hypersensitivity Reactions (DRESS): Drug Reaction with Eosinophilia and Systemic Symptoms. This involves a rash, fever, and damage to internal organs like the liver or kidneys.
4. 4Cardiac Arrhythmias: In patients with pre-existing heart conditions, lamotrigine may cause abnormal heart rhythms.

With prolonged use, some patients may experience changes in bone mineral density, although this risk is lower with lamotrigine than with enzyme-inducing AEDs like phenytoin. Long-term cognitive effects are generally minimal, but patients should report any persistent memory or concentration issues to their provider.

Serious Skin Rashes: The FDA has issued a Black Box Warning for lamotrigine regarding serious, life-threatening rashes, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).

• The risk is higher in pediatric patients (approximately 0.8% in children vs. 0.3% in adults).
• The risk is significantly increased if the starting dose is too high or if the dose is increased too quickly.
• Co-administration with valproate (Depakote) increases the risk of these rashes because valproate inhibits lamotrigine metabolism, leading to higher blood levels.
• Nearly all cases of life-threatening rashes occur within the first 2 to 8 weeks of treatment.

Report any unusual symptoms, especially skin changes or fever, to your healthcare provider immediately.

Lamotrigine is a high-alert medication because of the potential for severe dermatological and immunological reactions. Patients must be educated on the "titration schedule"—the process of slowly increasing the dose. Skipping doses or restarting at a high dose after a break can be fatal due to the risk of Stevens-Johnson Syndrome.

FDA Black Box Warning Summary: Lamotrigine can cause serious, life-threatening rashes, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). These rashes usually require hospitalization and discontinuation of the drug. The risk is highest in children and in those taking valproate or exceeding the recommended titration schedule. While benign rashes also occur, it is impossible to predict which rashes will become life-threatening. Therefore, the drug should ordinarily be discontinued at the first sign of a rash unless the rash is clearly not drug-related.

• Allergic Reactions / Anaphylaxis: Beyond the skin, lamotrigine can cause multi-organ hypersensitivity (DRESS). This can lead to liver failure, myocarditis (heart inflammation), or nephritis (kidney inflammation).
• Suicidality: A 2008 FDA meta-analysis of 199 clinical trials showed that patients taking AEDs like lamotrigine have roughly twice the risk of suicidal thinking and behavior (0.43%) compared to patients taking a placebo (0.22%). This risk can emerge as early as one week after starting the drug.
• Aseptic Meningitis: Patients should be warned that if they experience a stiff neck, headache, and fever, they must seek emergency care. Symptoms typically occur within 1 to 42 days of starting treatment.
• Cardiac Risks: Recent 2021 FDA safety communications warn that lamotrigine may increase the risk of serious heart rhythm problems in patients with underlying heart disease (such as heart failure, previous heart attack, or Brugada syndrome).

• Skin Exams: Regular self-checks and clinical exams for any new spots or sores, especially in the mouth or around the eyes.
• Liver and Kidney Function: Periodic blood tests (CMP - Complete Metabolic Panel) to ensure the organs are processing the medication correctly.
• Blood Counts: A CBC (Complete Blood Count) may be ordered to check for rare blood disorders.
• Therapeutic Drug Monitoring: While not always routine, measuring lamotrigine blood levels can be helpful if a patient is also taking interacting drugs like valproate or oral contraceptives.

Lamotrigine can cause dizziness, double vision, and lack of coordination. Patients should not drive or operate heavy machinery until they know how the medication affects them. In many jurisdictions, patients with epilepsy are legally restricted from driving until they have been seizure-free for a specific period (e.g., 6 to 12 months).

Alcohol can exacerbate the CNS depressant effects of lamotrigine, leading to increased dizziness and impaired motor skills. While not strictly contraindicated, patients are advised to limit or avoid alcohol consumption while taking this medication.

Never stop taking lamotrigine abruptly. Sudden withdrawal in patients with epilepsy can lead to status epilepticus (prolonged, life-threatening seizures). In patients with bipolar disorder, sudden stopping can cause a rapid return of mood symptoms. If the drug must be stopped, it should be tapered over at least two weeks unless a serious rash requires immediate cessation.

> Important: Discuss all your medical conditions, especially heart, liver, or kidney problems, with your healthcare provider before starting Lamotrigine.

There are few absolute contraindications for lamotrigine combinations, but use with other drugs that cause severe QT prolongation or those that have a high cross-sensitivity for SJS (like certain other AEDs) requires extreme caution. The most critical "do not use" scenario is restarting lamotrigine at a high dose after a treatment gap without a new titration.

• Valproate (Depakene, Depakote): This is the most significant interaction. Valproate inhibits the glucuronidation of lamotrigine, effectively doubling its concentration in the blood. This dramatically increases the risk of life-threatening rashes. The lamotrigine dose must be reduced by more than 50% when used with valproate.
• Enzyme Inducers (Carbamazepine, Phenytoin, Phenobarbital, Rifampin): These drugs speed up the metabolism of lamotrigine, reducing its blood levels by approximately 40-50%. This can lead to a loss of seizure control or a return of bipolar symptoms. Higher doses of lamotrigine are usually required.
• Oral Contraceptives (Birth Control Pills): Estrogen-containing contraceptives induce the enzymes that clear lamotrigine. Starting birth control can drop lamotrigine levels by 50%, while the "pill-free" week can cause lamotrigine levels to double, potentially leading to toxicity. Dose adjustments are almost always necessary.

• Atypical Antipsychotics: Drugs like olanzapine or risperidone may have minor effects on lamotrigine levels, but generally, these combinations are used safely with monitoring.
• Atazanavir/Ritonavir: These HIV medications can reduce lamotrigine levels by about 30%.

• General Food: There are no known significant interactions with specific foods. Lamotrigine can be taken with or without meals.
• Alcohol: As noted, alcohol increases the sedative effects of lamotrigine and should be avoided or used with extreme caution.

• St. John’s Wort: This herbal supplement is a potent enzyme inducer and may decrease the effectiveness of lamotrigine. It should be avoided by patients with epilepsy or bipolar disorder.
• Ginkgo Biloba: Some evidence suggests ginkgo may lower the seizure threshold, potentially counteracting the effects of lamotrigine.
• CBD/Cannabis: Cannabidiol may interact with the metabolism of various AEDs. Patients should consult their doctor before using CBD products.

Lamotrigine has been reported to interfere with some rapid urine drug screens, specifically leading to false-positive results for phencyclidine (PCP). If a drug screen is required, a more specific confirmatory test (such as GC/MS or LC/MS) should be requested.

For each major interaction, the mechanism usually involves the UGT1A4 enzyme pathway. Inhibition (by valproate) leads to toxicity risk, while induction (by carbamazepine or estrogen) leads to reduced efficacy. Management strategies always involve frequent blood level monitoring and precise dose titration.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, as even over-the-counter drugs can affect lamotrigine levels.

Lamotrigine must NEVER be used in the following circumstances:

• Hypersensitivity: If a patient has a known history of hypersensitivity (severe allergy) to lamotrigine or any of the inactive ingredients in the tablet (such as lactose or magnesium stearate). A previous history of a lamotrigine-induced rash is an absolute contraindication to restarting the drug, as a second exposure can lead to a faster and more severe reaction.
• Severe SJS/TEN History: Patients who have experienced Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis from any medication should be treated with extreme caution, and lamotrigine is generally avoided due to the high risk of cross-reactivity.

These are conditions where the benefit must clearly outweigh the risk, and intensive monitoring is required:

• Brugada Syndrome and Cardiac Disease: Because lamotrigine has Class IB antiarrhythmic activity at high concentrations, it can slow ventricular conduction and trigger arrhythmias in patients with pre-existing heart block or Brugada syndrome. A baseline EKG may be recommended for these patients.
• Renal or Hepatic Failure: While not an absolute contraindication, the inability to clear the drug increases the risk of toxicity. Doses must be adjusted downward.
• Active Suicidality: In patients with active suicidal ideation, the risk of using an AED must be weighed against the need for mood stabilization. Close supervision by a caregiver or hospitalization may be necessary during the start of treatment.

There is a known risk of cross-sensitivity between lamotrigine and other anticonvulsants. Approximately 25% to 30% of patients who have had a rash with carbamazepine or phenytoin may also develop a rash with lamotrigine. Healthcare providers must be informed of any previous adverse reactions to other anti-epileptic medications.

> Important: Your healthcare provider will evaluate your complete medical history, including cardiac and dermatological history, before prescribing Lamotrigine.

Lamotrigine is often considered one of the safer anti-epileptic drugs during pregnancy, but it is not without risks. It is classified as Pregnancy Category C (under the old system).

• Teratogenicity: Large pregnancy registries (like the North American Antiepileptic Drug Pregnancy Registry) suggest that lamotrigine does not significantly increase the risk of major malformations (like cleft lip/palate) compared to the general population, especially when compared to valproate.
• Physiological Changes: During pregnancy, the body clears lamotrigine much faster (up to 50-100% faster). This can lead to a drop in blood levels and a breakthrough seizure, which can be dangerous for both the mother and the fetus. Doses usually need to be increased during pregnancy and then rapidly decreased after delivery.

Lamotrigine passes into breast milk in significant amounts. The milk-to-plasma ratio is approximately 0.6. While many infants do not show adverse effects, there is a risk of the infant developing a rash or experiencing breathing problems (apnea). If breastfeeding, the infant must be monitored closely for any skin changes, drowsiness, or poor feeding. The decision to breastfeed should be a shared decision between the mother, neurologist, and pediatrician.

Lamotrigine is FDA-approved for adjunctive therapy for seizures in children aged 2 years and older. It is NOT approved for Bipolar Disorder in patients under 18. The risk of a serious, life-threatening rash is significantly higher in children than in adults. Healthcare providers must use the specific pediatric titration schedules and weigh the child frequently to ensure accurate dosing.

Clinical studies of lamotrigine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. However, because elderly patients are more likely to have decreased hepatic, renal, or cardiac function and are often on multiple medications (polypharmacy), they should be started at the lowest possible dose. There is an increased risk of falls due to the side effects of dizziness and ataxia.

In patients with end-stage renal disease, the half-life of lamotrigine is prolonged. While the initial dose may follow standard protocols, the maintenance dose must be reduced. Lamotrigine is removed by hemodialysis; about 20% of the drug is cleared during a 4-hour dialysis session. Supplemental doses may be needed after dialysis.

Hepatic impairment reduces the glucuronidation of lamotrigine. For patients with Child-Pugh Grade B or C impairment, dose reductions of 25% to 50% are mandatory to prevent toxic accumulation of the drug.

> Important: Special populations require individualized medical assessment and more frequent blood level monitoring.

Lamotrigine's primary mechanism is the inhibition of voltage-gated sodium channels. It binds specifically to the inactive state of the channel, which prevents the rapid, repetitive firing of action potentials in neurons. This action is "use-dependent," meaning it targets overactive neurons while sparing normal neuronal activity. Additionally, lamotrigine inhibits the presynaptic release of glutamate, the brain's main excitatory neurotransmitter. By reducing glutamate-mediated excitability, it prevents the initiation and spread of seizure activity and stabilizes the mood fluctuations seen in Bipolar I Disorder.

Lamotrigine shows a clear dose-response relationship for both its therapeutic effects and its side effects. The onset of action for epilepsy can be seen within 1-2 weeks of reaching a therapeutic dose, but for Bipolar Disorder, the full prophylactic effect may not be evident for several weeks or months. Tolerance to the anticonvulsant effects is rarely reported, making it suitable for long-term maintenance therapy.

| Parameter | Value |

|---|---|

| Bioavailability | ~98% |

| Protein Binding | ~55% |

| Half-life (Monotherapy) | 25 - 33 hours |

| Half-life (with Valproate) | ~70 hours |

| Half-life (with Inducers) | ~14 hours |

| Tmax | 1.5 - 4.8 hours |

| Metabolism | Hepatic (UGT1A4 Glucuronidation) |

| Excretion | Renal (94%), Fecal (2%) |

• Molecular Formula: C9H7Cl2N5
• Molecular Weight: 256.09 g/mol
• Solubility: Very slightly soluble in water (0.17 mg/mL at 25°C); slightly soluble in 0.1 M HCl.
• Structure: It is a triazine derivative (3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine). Its structure is unique among anticonvulsants, contributing to its distinct side-effect profile.

Lamotrigine belongs to the Phenyltriazine class of anti-epileptic agents. It is often grouped with other "sodium channel blockers" like carbamazepine and oxcarbazepine, but its lack of CYP450 induction and its specific efficacy in bipolar depression distinguish it from these older medications.