Lamotrigine Extended-Release Tablets
TABLE OF CONTENTS
Lamotrigine is an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. The structural formula is:
Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C).
Lamotrigine extended-release (ER) tablets are supplied for oral administration as 25-mg (yellow with white center), 50-mg (green with white center), 100-mg (orange with white center), 200-mg (blue with white center), and 300-mg (gray with white center) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate; magnesium stearate; methacrylic acid copolymer dispersion, polyethylene glycol 400, polysorbate 80, silicon dioxide (25-mg and 50-mg tablets only), titanium dioxide, triethyl citrate, iron oxide black (50-mg and 300 mg tablets only), iron oxide yellow (25-mg, 50-mg, 100-mg tablets only), iron oxide red (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake (200-mg tablet only). Tablets are printed with edible black ink.
Lamotrigine extended-release tablets contain a modified-release eroding formulation as the core. The tablets are coated with a clear enteric coat and have an aperture drilled through the coats on both faces of the tablet (DiffCORE™) to enable a controlled release of drug in the acidic environment of the stomach. The combination of this and the modified-release core are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels.
|2. INDICATIONS AND USAGE|
2.1 Adjunctive Therapy
Lamotrigine ER is indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial onset seizures with or without secondary generalization in patients ≥ 13 years of age.
Lamotrigine ER is indicated for conversion to monotherapy in patients ≥13 years of age with partial seizures who are receiving treatment with a single antiepileptic drug (AED).
Safety and effectiveness of lamotrigine ER have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from two or more concomitant AEDs.
2.3 Limitation of Use
Safety and effectiveness of lamotrigine ER for use in patients less than 13 years of age have not been established.
|3. DOSAGE AND ADMINISTRATION|
Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided.
3.1 General Dosing Considerations
Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine ER with valproate, (2) exceeding the recommended initial dose of lamotrigine ER, or (3) exceeding the recommended dose escalation for lamotrigine ER. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.
The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine ER is exceeded and in patients with a history of allergy or rash to other AEDs.
Lamotrigine ER Patient Titration Kits provide lamotrigine ER at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications for patients with partial onset seizures and are intended to help reduce the potential for rash. The use of Lamotrigine ER Patient Titration Kits is recommended for appropriate patients who are starting or restarting lamotrigine ER [see How Supplied/Storage and Handling].
It is recommended that lamotrigine ER not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine ER, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications.
Lamotrigine ER Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Drug Interactions section have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine ER may require adjustment based on clinical response.
Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine ER should be based on therapeutic response.
Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine ER in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine ER should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine ER based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of lamotrigine ER in women taking estrogen-containing oral contraceptives.
Adjustments to the Maintenance Dose of Lamotrigine ER In Women Taking Estrogen-Containing Oral Contraceptives:
(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions], the maintenance dose of lamotrigine ER will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level.
(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine ER and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pillfree” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine ER consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking lamotrigine ER in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions], no adjustment to the dose of lamotrigine ER should be necessary.
(3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions], the maintenance dose of lamotrigine ER will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine ER should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise. For women taking lamotrigine ER in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions], no adjustment to the dose of lamotrigine ER should be necessary.
Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine ER in the presence of progestogens alone will likely not be needed.
Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations], 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.
Patients With Renal Impairment: Initial doses of lamotrigine ER should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, lamotrigine ER should be used with caution in these patients.
Discontinuation Strategy: For patients receiving lamotrigine ER in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. If a decision is made to discontinue therapy with lamotrigine ER, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions]. Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
3.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial Onset Seizures
This section provides specific dosing recommendations for patients ≥ 13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications.
Table 1. Escalation Regimen for Lamotrigine ER in Patients ≥ 13 Years of Age
a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions].
b These drugs induce lamotrigine glucuronidation and increase clearance [see Drug Interactions]. Other drugs which have similar effects include estrogen-containing oral contraceptives [see Drug Interactions]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect.
c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.
3.3 Conversion From Adjunctive Therapy to Monotherapy
The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine ER.
The recommended maintenance dosage range of lamotrigine ER as monotherapy is 250 to 300 mg given once daily.
The recommended initial dose and subsequent dose escalations for lamotrigine ER should not be exceeded [see Boxed Warning].
Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine ER: After achieving a dosage of 500 mg/day of lamotrigine ER using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. Two weeks after completion of withdrawal of the enzyme-inducing AED, the dosage of lamotrigine ER may be decreased no faster than 100 mg/day each week to achieve the monotherapy maintenance dosage range of 250 to 300 mg/day.
The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial using immediate-release lamotrigine.
Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine ER: The conversion regimen involves the 4 steps outlined in Table 2.
Table 2. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine ER in Patients ≥ 13 Years of Age With Epilepsy
Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine ER: After achieving a dosage of 250 to 300 mg/day of lamotrigine ER using the guidelines in Table 1, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. No adjustment to the monotherapy dose of lamotrigine ER is needed.
3.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine ER
Patients may be converted directly from immediate-release lamotrigine to lamotrigine ER extended-release tablets. The initial dose of lamotrigine ER should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored.
Following conversion to lamotrigine ER, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).
Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
|5. MECHANISM OF ACTION|
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
Pregnancy Category C
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.
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. Lamotrigine ER 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 embryo-fetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than 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 lamotrigine ER, physicians are advised to recommend that pregnant patients taking lamotrigine ER 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.
6.2 Labor and Delivery
The effect of lamotrigine ER on labor and delivery in humans is unknown.
6.3 Nursing Mothers
Lamotrigine is present in milk from lactating women taking lamotrigine ER. 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 lamotrigine ER is administered to a nursing woman.
6.4 Pediatric Use
Lamotrigine ER is indicated as adjunctive therapy for PGTC and partial onset seizures with or without secondary generalization in patients over 13 years of age. Safety and effectiveness of lamotrigine ER for any use in patients below the age of 13 have not been established.
The immediate-release formulation of lamotrigine is indicated for adjunctive therapy in patients above 2 years of age for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures.
Safety and efficacy of the immediate-release formulation of lamotrigine, used as adjunctive treatment for partial seizures, were not demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal study in very young pediatric patients (1 to 24 months). The immediate-release formulation of 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.
6.5 Geriatric Use
Clinical studies of lamotrigine ER for epilepsy did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently from younger subjects 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.
6.6 Patients With Hepatic Impairment
Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study with the immediate-release formulation of lamotrigine in 24 patients with mild, moderate, and severe liver impairment, 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].
6.7 Patients With 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 patients with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was significantly longer in the patients with renal impairment.
Initial doses of lamotrigine ER 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, lamotrigine ER should be used with caution in these patients [see Dosage and Administration].
|7. WARNINGS AND PRECAUTIONS|
7.1 Serious Skin Rashes
The risk of serious rash caused by treatment with lamotrigine ER is not expected to differ from that with the immediate-release formulation of lamotrigine [see Boxed Warning]. However, the relatively limited treatment experience with lamotrigine ER makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine ER.
Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience.
There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of 952) patients not taking valproate.
Adult Population: Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received lamotrigine in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.
Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic abnormalities.
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.
Other examples of serious and potentially life-threatening rash that did not lead to hospitalization also occurred in premarketing development. Among these, 1 case was reported to be Stevens-Johnson–like.
7.2 Multiorgan Hypersensitivity Reactions and Organ Failure
Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression and other organ systems not noted here may be involved.
Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use.
Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine.
It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine ER should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with lamotrigine ER, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
7.3 Blood Dyscrasias
There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
7.4 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including lamotrigine ER, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
7.5 Aseptic Meningitis
Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate. Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions].
7.6 Potential Medication Errors
Medication errors involving lamotrigine have occurred. In particular, the names lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine ER or lamotrigine ER clearly. Depictions of the lamotrigine ER tablets can be found in the Medication Guide. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine ER each time they fill their prescription.
7.7 Concomitant Use With Oral Contraceptives
Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine ER [see Dosage and Administration]. During the week of inactive hormpreparation (“pill-free” week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
7.8 Withdrawal Seizures
As with other AEDs, lamotrigine ER should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine ER should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration].
7.9 Status Epilepticus
Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with immediate-release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.
7.10 Sudden Unexplained Death in Epilepsy (SUDEP)
During the premarketing development of the immediate-release formulation of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure). Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for immediate-release lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving immediate-release lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving immediate-release lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.
7.11 Addition of Lamotrigine ER to a Multidrug Regimen That Includes Valproate
Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence.
7.12 Binding in the Eye and Other Melanin-Containing Tissues
Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine binding to melanin is unknown.
Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
7.13 Laboratory Tests
Plasma Concentrations of Lamotrigine: The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine ER has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 6), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
Effect on Leukocytes: Treatment with lamotrigine ER caused an increased incidence of subnormal (below the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes). The treatment effect (Lamotrigine ER % - Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes.
|8. ADVERSE REACTIONS|
8.1 Clinical Trial Experience With Lamotrigine ER for Treatment of Primary Generalized Tonic-Clonic and Partial Onset Seizures
Most Common Adverse Reactions in Clinical Studies
Adjunctive Therapy in Patients With Epilepsy:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Lamotrigine ER has been evaluated for safety in patients ≥ 13 years of age with PGTC and partial onset seizures. The most commonly observed adverse reactions ( ≥ 4% for lamotrigine ER and more common on drug than placebo) in these 2 double-blind, placebo-controlled trials of adjunctive therapy with lamotrigine ER were, in order of decreasing treatment difference (lamotrigine ER % - placebo %) incidence: dizziness, tremor/intention tremor, vomiting, and diplopia.
In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo and 10 (5%) patients in the group receiving lamotrigine ER. Dizziness was the most common reason for withdrawal in the group receiving lamotrigine ER (5 patients [3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and nystagmus.
Table 3 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-controlled studies of patients with PGTC and partial onset seizures.
Table 3. Treatment-Emergent Adverse Reaction Incidence in Double-Blind, Placebo-Controlled Adjunctive Trials of Patients With Epilepsy (Adverse Reactions ≥ 2% of Patients Treated With Lamotrigine ER and Numerically More Frequent Than in the Placebo Group)
Note: In these trials the incidence of nonserious rash was 2% for lamotrigine ER and 3% for placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was 0.3% in adults on adjunctive therapy for epilepsy [see Boxed Warning]. Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted in the maintenance phase.
The incidence for many adverse reactions caused by treatment with lamotrigine ER was increased relative to placebo (i.e., treatment difference between lamotrigine ER and placebo ≥2%) in either the titration or maintenance phases of the study. During the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety. During the maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia. Some adverse reactions developing in the titration phase were notable for persisting (>7 days) into the maintenance phase. These “persistent” adverse reactions included somnolence and dizziness.
There were inadequate data to evaluate the effect of dose and/or concentration on the incidence of adverse reactions because, although patients were randomized to different target doses based upon concomitant AED, the plasma exposure was expected to be generally similar among all patients receiving different doses. However, in a randomized, parallel study comparing placebo and 300 and 500 mg/day of immediate-release lamotrigine, the incidence of the most common adverse reactions (≥5%) such as ataxia, blurred vision, diplopia, and dizziness were dose related. Less common adverse reactions (< 5%) were not assessed for dose-response relationships.
Monotherapy in Patients With Epilepsy: Adverse reactions observed in this study were generally similar to those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and adjunctive lamotrigine ER placebo-controlled studies. Only 2 adverse events, nasopharyngitis and upper respiratory tract infection, were observed at a rate of ≥3% and not reported at a similar rate in previous studies. Because this study did not include a placebo control group, causality could not be established.
8.2 Other Adverse Reactions Observed During the Clinical Development of Immediate-Release Lamotrigine
All reported reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.
Adjunctive Therapy in Adults With Epilepsy: In addition to the adverse reactions reported above from the development of lamotrigine ER, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in ≥2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.
Body as a Whole: Headache, flu syndrome, fever, neck pain.
Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.
Respiratory: Pharyngitis, cough increased.
Skin and Appendages: Rash, pruritus.
Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.
Monotherapy in Adults With Epilepsy: In addition to the adverse reactions reported above from the development of lamotrigine ER, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in >2% of patients receiving immediaterelease lamotrigine and more frequently than in the placebo group.
Body as a Whole: Chest pain.
Digestive: Rectal hemorrhage, peptic ulcer.
Metabolic and Nutritional: Weight decrease, peripheral edema.
Nervous: Hypesthesia, libido increase, decreased reflexes.
Respiratory: Epistaxis, dyspnea.
Skin and Appendages: Contact dermatitis, dry skin, sweating.
Special Senses: Vision abnormality.
Urogenital (female patients only): Dysmenorrhea.
8.3 Postmarketing Experience with the Immediate-Release Formulation of Lamotrigine
The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of the immediate-release formulation of lamotrigine. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.
Hepatobiliary Tract and Pancreas: Pancreatitis.
Immunologic: Lupus-like reaction, vasculitis.
Lower Respiratory: Apnea.
Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.
Nervous System: Aseptic meningitis.
Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics.
Non-site Specific: Progressive immunosuppression.
Human Overdose Experience: Overdoses involving quantities up to 15 g have been reported for lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay.
Management of Overdose: There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced or gastric lavage should be performed; usual precautions should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly absorbed. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of lamotrigine.
|10. DRUG INTERACTIONS|
Significant drug interactions with lamotrigine are summarized in Table 4.
Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
In comparison to immediate-release lamotrigine, the plasma lamotrigine levels following administration of lamotrigine ER are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuation, as described in detail below.
Absorption: Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food.
In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of lamotrigine ER given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (Tmax) following administration of lamotrigine ER was 4 to 6 hours in patients taking carbamazepine, phenytoin, phenobarbital, or primidone; 9 to 11 hours in patients taking VPA; and 6 to 10 hours in patients taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or VPA. In comparison, the median Tmax following administration of immediate-release lamotrigine was between 1 and 1.5 hours. The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED. A mean reduction in the lamotrigine Cmax by 11% to 29% was observed for lamotrigine ER compared to immediate-release lamotrigine resulting in a decrease in the peak-to-trough fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzyme-inducing AEDs, a reduction in Cmax of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in patients taking enzyme-inducing AEDs, 34% in patients taking VPA, and 37% in patients taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or VPA. Lamotrigine ER and immediate-release lamotrigine regimens were similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for patients receiving AEDs other than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-release lamotrigine was approximately 21% lower than immediate-release lamotrigine in subjects receiving enzyme-inducing AEDs. However, in some subjects in this group a reduction in exposure of up to 70% was observed when switched to lamotrigine ER. Therefore, doses may need to be adjusted in some subjects based on therapeutic response.
Dose Proportionality: In healthy volunteers not receiving any other medications and given lamotrigine ER once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic exposure.
Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.
Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.
Metabolism: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
Elimination: The elimination half-life and apparent clearance of lamotrigine following administration of immediate-release lamotrigine to adult patients with epilepsy and healthy volunteers is summarized in Table 5. Half-life and apparent oral clearance vary depending on concomitant AEDs. Since the half-life of lamotrigine following administration of single doses of immediate-release lamotrigine is comparable to that observed following administration of lamotrigine ER, similar changes in the half-life of lamotrigine would be expected for lamotrigine ER.
Table 5. Mean Pharmacokinetic Parameters of Immediate-Release Lamotrigine in Healthy Volunteers and Adult Patients With Epilepsy
a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.
b Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions].
Patients With Renal Insufficiency: Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session.
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patient With Hepatic Impairment).
Pediatric Patients: Safety and effectiveness of lamotrigine ER for use in patients below the age of 13 have not been established.
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).
Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of lamotrigine in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: LAMICTAL XR, by SMITHKLINE BEECHAM.
b) Generic drugs: Lamotrigine, by various manufacturers.
2) How Supplied:
Lamotrigine extended-release tablets (by Wockhardt)
25 mg are available as yellow, enteric-coated, circular shaped tablets, debossed with "W" on one side and "271" on the other side.
NDC 64679-271-01, bottle of 30 tablets
NDC 64679-271-02, bottle of 500 tablets
NDC 64679-271-04, unit dose of 100 tablets
50 mg are available as pink, enteric-coated, circular shaped tablets, debossed with "W" on one side and "274" on the other side.
NDC 64679-274-01, bottle of 30 tablets
NDC 64679-274-02, bottle of 500 tablets
NDC 64679-274-03, unit dose of 100 tablets
100 mg are available as light brown, enteric-coated, circular shaped tablets, debossed with "W" on one side and "273" on the other side.
NDC 64679-273-01, bottle of 30 tablets
NDC 64679-273-02, bottle of 500 tablets
NDC 64679-273-04, unit dose of 100 tablets
200 mg are available as pink, enteric-coated, circular shaped tablets, debossed with "W" on one side and "272" on the other side.
NDC 64679-272-01, bottle of 30 tablets
NDC 64679-272-02, bottle of 500 tablets
NDC 64679-272-04, unit dose of 100 tablets
300 mg are available as pink, enteric-coated, circular shaped tablets, debossed with "W" on one side and "275" on the other side.
NDC 64679-275-01, bottle of 30 tablets
NDC 64679-275-02, bottle of 500 tablets
NDC 64679-275-04, unit dose of 100 tablets
3) Storage: Store at 20°-25°C (68°-77°F). Excursions permitted to 15-30°C (59-86°F).