Lamictal XR

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Lamotrigine is used alone or together with other medicines to help control certain types of seizures (e.g., partial seizures, tonic-clonic seizures, or Lennox-Gastaut syndrome) in the treatment of epilepsy. This medicine cannot cure epilepsy and will only work to control seizures for as long as you continue to take it. It can also be used in the treatment of bipolar disorder (manic-depressive illness) in adults older than 18 years of age.

This medicine is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Blurred vision
• changes in vision
• clumsiness or unsteadiness
• double vision
• poor coordination
• skin rash

• Anxiety
• chest pain
• confusion
• continuous, uncontrolled back and forth or rolling eye movements
• depression
• increase in seizures
• infection
• irritability

• Blistering, peeling, or loosening of the skin
• chills
• dark-colored urine
• fever
• flu-like symptoms
• itching
• memory loss
• muscle cramps, pain, or weakness
• red or irritated eyes
• small red or purple spots on the skin
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swelling of the face, mouth, hands, or feet
• swollen lymph nodes
• trouble with breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

• Back, leg, or stomach pains
• bleeding gums
• bloating
• blood in the urine
• bloody, black or tarry stools
• bluish lips or skin
• bruising
• constipation
• cough or hoarseness
• coughing or vomiting blood
• difficulty with breathing
• difficulty with swallowing
• fainting
• fast heartbeat
• general body swelling
• general feeling of discomfort or illness
• general feeling of tiredness or weakness
• heartburn
• high fever
• lightheadedness
• loss of appetite
• loss of balance control
• lower back or side pain
• mask-like face
• muscle spasms
• nosebleeds
• not breathing
• pain or burning in the throat
• painful or difficult urination
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• persistent bleeding or oozing from puncture sites, mouth, or nose
• rapid, shallow breathing
• redness, soreness, or itching skin
• shortness of breath
• shuffling walk
• slowed movement
• slurred speech
• sores, welting, or blisters
• stiffness of the arms and legs
• swollen or painful glands
• tic-like (jerky) movements
• tightness in the chest
• unexplained bleeding or bruising
• wheezing

Get emergency help immediately if any of the following symptoms of overdose occur:

• Clumsiness or unsteadiness (severe)
• coma
• continuous, uncontrolled back and forth or rolling eye movements (severe)
• dizziness (severe)
• drowsiness (severe)
• dryness of the mouth (severe)
• headache (severe)
• increased heart rate
• slurred speech (severe)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Dizziness
• drowsiness
• headache
• nausea
• vomiting

• Diarrhea
• indigestion
• loss of strength
• menstrual pain
• pain
• runny nose
• trembling or shaking
• trouble with sleeping
• unusual weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you have an allergy to lamotrigine or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking dofetilide.

This is not a list of all drugs or health problems that interact with Lamictal XR.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use Lamictal XR as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food. Take with food if it causes an upset stomach.
• Swallow whole. Do not chew, break, or crush.
• If you have trouble swallowing, talk with your doctor.
• To gain the most benefit, do not miss doses.
• Do not change the dose or stop this medicine. This could cause seizures. Talk with your doctor.
• Keep taking Lamictal XR as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Pregnancy

As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, lamotrigine was developmentally toxic at doses lower than those administered clinically. Lamictal XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2) basis.

In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, behavioral abnormalities were observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the higher dose tested.

When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the 2 highest doses tested.

Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with adverse pregnancy outcomes in animals and humans.

Pregnancy Registry

To provide information regarding the effects of in utero exposure to Lamictal XR, physicians are advised to recommend that pregnant patients taking LAMICTAL XR enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org.

Labor and Delivery

The effect of LAMICTAL XR on labor and delivery in humans is unknown.

Nursing Mothers

Lamotrigine is present in milk from lactating women taking Lamictal XR. Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness, and poor sucking have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should be exercised when Lamictal XR is administered to a nursing woman.

Pediatric Use

Lamictal XR is indicated as adjunctive therapy for PGTC and partial-onset seizures with or without secondary generalization in patients aged 13 years and older. Safety and effectiveness of Lamictal XR for any use in patients younger than 13 years have not been established.

Immediate-release lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of immediate-release lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged 1 to 24 months). Immediate-release lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.

In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m2 basis.

Geriatric Use

Clinical trials of LAMICTAL XR for epilepsy did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Hepatic Impairment

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study with immediate-release lamotrigine in 24 subjects with mild, moderate, and severe liver impairment [see Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response [see Dosage and Administration (2.1)].

Renal Impairment

Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of immediate-release lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see Clinical Pharmacology (12.3)].

Initial doses of LAMICTAL XR should be based on patients’ AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, Lamictal XR should be used with caution in these patients [see Dosage and Administration (2.1)].

Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures

The effectiveness of Lamictal XR as adjunctive therapy in subjects with PGTC seizures was established in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled trial in 143 patients aged 13 years and older (n = 70 on Lamictal XR, n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with Lamictal XR or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 200 to 500 mg/day of Lamictal XR based on concomitant AEDs (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for enzyme-inducing AEDs).

The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with Lamictal XR and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value <0.05.

Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with Lamictal XR compared with the placebo group. For example, 70% of patients randomized to Lamictal XR experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.

Figure 1. Proportion of Patients by Responder Rate for Lamictal XR and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)

Adjunctive Therapy for Partial-Onset Seizures

The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures.

The effectiveness of Lamictal XR as adjunctive therapy in partial-onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial-onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with LAMICTAL XR (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of LAMICTAL XR based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for LAMICTAL XR and 2.1 for placebo.

The primary endpoint was the median percent change from baseline in partial-onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial-onset seizures were 47% in patients treated with Lamictal XR and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value ≤0.05.

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial-onset seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial-onset seizure frequency was consistently higher for the group treated with Lamictal XR compared with the placebo group. For example, 44% of patients randomized to Lamictal XR experienced a 50% or greater reduction in partial-onset seizure frequency compared with 21% of patients randomized to placebo.

Figure 2. Proportion of Patients by Responder Rate for Lamictal XR and Placebo Group (Partial-Onset Seizure Study)

Conversion to Monotherapy for Partial-Onset Seizures

The effectiveness of Lamictal XR as monotherapy for partial-onset seizures was established in a historical control trial in 223 adults with partial-onset seizures. The historical control methodology is described in a publication by French, et al. [see References (15)]. Briefly, in this study, patients were randomized to ultimately receive either Lamictal XR 300 or 250 mg once a day, and their responses were compared with those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper 95% confidence interval for the proportion of patients meeting escape criteria in patients receiving LAMICTAL XR remained below the lower 95% prediction interval of 65.3% derived from the historical control data.

In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures during an 8-week baseline period with at least 1 seizure occurring during each of 2 consecutive 4-week periods while receiving valproate or a non–enzyme-inducing AED. Lamictal XR was added to either valproate or a non–enzyme-inducing AED over a 6- to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with LAMICTAL XR for 12 weeks. The escape criteria were 1 or more of the following: (1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure type compared with baseline (4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted.

The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical control data.

Although the study population was not fully comparable with the historical control population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.

LAMICTAL XR (lamotrigine) extended-release tablets

25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 25”, unit-of-use bottles of 30 with orange caps (NDC 0173-0754-00).

50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”, unit-of-use bottles of 30 with orange caps (NDC 0173-0755-00).

100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 100”, unit-of-use bottles of 30 with orange caps (NDC 0173-0756-00).

200 mg, blue with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 200”, unit-of-use bottles of 30 with orange caps (NDC 0173-0757-00).

250 mg, purple with a white center, caplet-shaped, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 250”, unit-of-use bottles of 30 with orange caps (NDC 0173-0781-00).

300 mg, gray with a white center, caplet-shaped, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 300”, unit-of-use bottles of 30 with orange caps (NDC 0173-0761-00).

LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Taking Valproate (Blue XR Kit)

25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 25” and 50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”; blisterpack of 21/25-mg tablets and 7/50-mg tablets (NDC 0173-0758-00).

LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone, and Not Taking Valproate (Green XR Kit)

50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”; 100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 100”; and 200 mg, blue with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 200”; blisterpack of 14/50-mg tablets, 14/100-mg tablets, and 7/200-mg tablets (NDC 0173-0759-00).

LAMICTAL XR (lamotrigine) Patient Titration Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange XR Kit)

25 mg, yellow with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 25”; 50 mg, green with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 50”; and 100 mg, orange with a white center, round, biconvex, film-coated tablets printed on one face in black ink with “LAMICTAL” and “XR 100”; blisterpack of 14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets (NDC 0173-0760-00).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Common side effects of Lamictal XR include: ataxia, blurred vision, diplopia, dizziness, drowsiness, headache, insomnia, nausea, rhinitis, skin rash, tremor, vomiting, abdominal pain, and fever. Other side effects include: dysmenorrhea, dyspepsia, vaginitis, abnormal gait, asthenia, bronchitis, constipation, pain, pruritus, and emotional lability. See below for a comprehensive list of adverse effects.

You should not take Lamictal XR if you are allergic to it.

Lamictal XR may cause a severe or life-threatening skin rash, especially in children and in people who take too high a dose at the start of treatment. Serious skin rash may also be more likely to occur if you are taking this medicine together with valproic acid (Depakene) or divalproex (Depakote).

To make sure Lamictal XR is safe for you, tell your doctor if you have:

• kidney or liver disease;

• a history of depression or suicidal thoughts or actions; or

• if you are allergic to other seizure medications.

Some people have thoughts about suicide while taking this medicine. Your doctor will need to check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Do not start or stop taking seizure medication during pregnancy without your doctor's advice. Having a seizure during pregnancy could harm both mother and baby. Tell your doctor right away if you become pregnant.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of Lamictal XR on the baby.

Birth control pills can make Lamictal XR less effective, resulting in increased seizures. Tell your doctor if you start or stop using birth control pills while you are taking this medicine. Your this medicine dose may need to be changed.

Lamotrigine can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include blurred vision, problems with coordination, increased seizures, feeling light-headed, or fainting.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2018 Cerner Multum, Inc. Version: 17.03.

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