lamoTRIgine 200 MG 24HR Extended Release Oral Tablet

DRUG INTERACTIONS

7 Valproate increases lamotrigine concentrations more than 2-fold.

( 7 , 12.3 ) Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease lamotrigine concentrations by approximately 40%.

( 7 , 12.3 ) Estrogen-containing oral contraceptives decrease lamotrigine concentrations by approximately 50%.

( 7 , 12.3 ) Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50% and 32%, respectively.

( 7 , 12.3 ) Coadministration with organic cationic transporter 2 substrates with narrow therapeutic index is not recommended ( 7 , 12.3 ) Significant drug interactions with lamotrigine are summarized in this section.

Additional details of these drug interaction studies, which were conducted using immediate-release lamotrigine, are provided in the Clinical Pharmacology section [ see Clinical Pharmacology (12.3) ].

Table 5.

Established and Other Potentially Significant Drug Interactions ↓ = Decreased (induces lamotrigine glucuronidation).

↑ = Increased (inhibits lamotrigine glucuronidation).

? = Conflicting data.

Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine concentrations approximately 50%.

Decrease in levonorgestrel component by 19%.

Carbamazepine and carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%.

May increase carbamazepine epoxide levels.

Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%.

Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%.

Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.

Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%.

Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%.

Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold.

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Effect of Lamotrigine Extended-Release Tablets on Organic Cationic Transporter 2 Substrates Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins [see Clinical Pharmacology (12.3) ] .

This may result in increased plasma levels of certain drugs that are substantially excreted via this route.

Coadministration of lamotrigine extended-release tablets with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

OVERDOSAGE

10 10.1 Human Overdose Experience Overdoses involving quantities up to 15 g have been reported for immediate-release lamotrigine, some of which have been fatal.

Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.

10.2 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; usual precautions should be taken to protect the airway.

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 extended-release tablets.

DESCRIPTION

11 Lamotrigine, an AED of the phenyltriazine class, is chemically unrelated to existing AEDs.

Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)- as -triazine, its molecular formula is C 9 H 7 N 5 Cl 2 , and its molecular weight is 256.09.

Lamotrigine is a white or almost white powder and has a pK a of 5.7.

Lamotrigine is very slightly soluble in water and in 0.1M hydrochloric acid.

The structural formula is: Lamotrigine extended-release tablets are supplied for oral administration as 25 mg (yellow, enteric-coated, circular shaped tablet), 50 mg (pink, enteric-coated, circular shaped tablet), 100 mg (light brown, enteric-coated, circular shaped tablet), 200 mg (pink, enteric-coated, circular shaped tablet), and 300 mg (pink, enteric-coated, circular shaped tablet).

Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: diethyl phthalate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol, talc, titanium dioxide, iron oxide yellow for (25 mg and 100 mg) and iron oxide red for (50 mg, 100 mg, 200 mg, and 300 mg).

Lamotrigine extended-release tablets contain a modified-release eroding formulation as the core.

The tablets are coated with enteric coat 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.

Structure

CLINICAL STUDIES

14 14.1 Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures The effectiveness of lamotrigine extended-release tablets 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 lamotrigine extended-release tablets, 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets compared with the placebo group.

For example, 70% of patients randomized to lamotrigine extended-release tablets 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 Lamotrigine Extended-Release Tablets and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study) Figure 1 14.2 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets (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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets compared with the placebo group.

For example, 44% of patients randomized to lamotrigine extended-release tablets 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 Lamotrigine Extended-Release Tablets and Placebo Group (Partial-Onset Seizure Study) Figure 2 14.3 Conversion to Monotherapy for Partial-Onset Seizures The effectiveness of lamotrigine extended-release tablets 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 lamotrigine extended-release tablets 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 lamotrigine extended-release tablets 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.

Lamotrigine extended-release tablet 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 lamotrigine extended-release tablets 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 controlled 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.

HOW SUPPLIED

16 /STORAGE AND HANDLING Lamotrigine extended-release tablets 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 Storage Store at 20°-25°C (68°-77°F); [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Dosage and Administration ( 2.1 , 2.2 ) 12/2014 Warnings and Precautions, Laboratory Tests ( 5.13 ) 3/2015

GERIATRIC USE

8.5 Geriatric Use Clinical trials of lamotrigine extended-release tablets 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.

DOSAGE FORMS AND STRENGTHS

3 Extended-release tablets: 25 mg, 50 mg, 100 mg, 200 mg, and 300 mg.

( 3.1 , 16 ) 3.1 Extended-Release Tablets 25 mg, yellow, enteric-coated, circular shaped tablet, debossed with “W” on one side and “271” on the other side.

50 mg, pink, enteric-coated, circular shaped tablet, debossed with “W” on one side and “274” on the other side.

100 mg, light brown, enteric-coated, circular shaped tablet, debossed with “W” on one side and “273” on the other side.

200 mg, pink, enteric-coated, circular shaped tablet, debossed with “W” on one side and “272” on the other side.

300 mg, pink, enteric-coated, circular shaped tablet, debossed with “W” on one side and “275” on the other side.

MECHANISM OF ACTION

12.1 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 a 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.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels.

In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP).

The IC 50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 microM of glycine) in cultured hippocampal neurons exceeded 100 microM.

INDICATIONS AND USAGE

1 Lamotrigine extended-release tablet is an antiepileptic drug (AED) indicated for: Adjunctive therapy for primary generalized tonic-clonic seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older.

( 1.1 ) Conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single AED.

( 1.2 ) Limitation of use: Safety and effectiveness in patients younger than 13 years have not been established.

( 1.3 ) 1.1 Adjunctive Therapy Lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older.

1.2 Monotherapy Lamotrigine extended-release tablets are is indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED).

Safety and effectiveness of lamotrigine extended-release tablets have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

1.3 Limitation of Use Safety and effectiveness of lamotrigine extended-release tablets for use in patients younger than 13 years have not been established.

PEDIATRIC USE

8.4 Pediatric Use Lamotrigine extended-release tablet 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 lamotrigine extended-release tablets 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/m 2 basis.

PREGNANCY

8.1 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.

Lamotrigine extended-release tablets 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/m 2 ) 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/m 2 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/m 2 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 extended-release tablets, physicians are advised to recommend that pregnant patients taking lamotrigine extended-release tablets 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.

NUSRING MOTHERS

8.3 Nursing Mothers Lamotrigine is present in milk from lactating women taking lamotrigine extended-release tablets.

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 extended-release tablets are administered to a nursing woman.

BOXED WARNING

WARNING: SERIOUS SKIN RASHES WARNING: SERIOUS SKIN RASHES See full prescribing information for complete boxed warning.

Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine.

The rate of serious rash is greater in pediatric patients than in adults.

Additional factors that may increase the risk of rash include: coadministration with valproate.

exceeding recommended initial dose of lamotrigine extended-release tablets.

exceeding recommended dose escalation for lamotrigine extended-release tablets.

( 5.1 ) Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening.

Lamotrigine extended-release tablets should be discontinued at the first sign of rash, unless the rash is clearly not drug related.

( 5.1 ) Lamotrigine extended-release tablets can cause serious rashes requiring hospitalization and discontinuation of treatment.

The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16 years) receiving immediate-release lamotrigine as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy.

In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive immediate-release lamotrigine, there was 1 rash-related death.

Lamotrigine extended-release tablet is not approved for patients younger than 13 years.

In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate.

The risk of serious rash caused by treatment with lamotrigine extended-release tablet is not expected to differ from that with immediate-release lamotrigine.

However, the relatively limited treatment experience with lamotrigine extended-release tablets makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release tablets.

Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine extended-release tablets.

There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine extended-release tablets with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets.

However, cases have occurred in the absence of these factors.

Nearly all cases of life-threatening rashes caused by immediate-release lamotrigine have occurred within 2 to 8 weeks of treatment initiation.

However, isolated cases have occurred after prolonged treatment (e.g., 6 months).

Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash.

Although benign rashes are also caused by lamotrigine extended-release tablets, it is not possible to predict reliably which rashes will prove to be serious or life threatening.

Accordingly, lamotrigine extended-release tablets should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related.

Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring [ see Warnings and Precautions (5.1) ].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related.

( Boxed Warning , 5.1 ) Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), may be fatal or life threatening.

Early signs may include rash, fever, and lymphadenopathy.

These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure.

Lamotrigine extended-release tablets should be discontinued if alternate etiology for this reaction is not found.

( 5.2 ) Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome.

Monitor for signs of anemia, unexpected infection, or bleeding.

( 5.3 ) Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.

( 5.4 ) Aseptic meningitis: Monitor for signs of meningitis.

( 5.5 ) Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct.

( 5.6 , 16 , 17 ) 5.1 Serious Skin Rashes [see Boxed Warning] The risk of serious rash caused by treatment with lamotrigine extended-release tablet is not expected to differ from that with immediate-release lamotrigine [ see Boxed Warning ].

However, the relatively limited treatment experience with lamotrigine extended-release tablets makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release tablets.

Pediatric Population The incidence of serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine 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 with 0.6% (6 of 952) patients not taking valproate.

Lamotrigine extended-release tablet is not approved in patients younger than 13 years.

Adult Population Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediate-release lamotrigine in premarketing clinical trials of epilepsy.

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 those associated with multiorgan hypersensitivity [ see Warnings and Precautions (5.2) ].

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 immediate-release 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 immediate-release lamotrigine in the absence of valproate were hospitalized.

Patients With History of Allergy or Rash to Other Antiepileptic Drugs The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablets are exceeded and in patients with a history of allergy or rash to other AEDs.

5.2 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 extended-release tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with lamotrigine extended-release tablets, 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.

5.3 Blood Dyscrasias There have been reports of blood dyscrasias with immediate-release lamotrigine that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [ see Warnings and Precautions (5.2) ].

These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

5.4 Suicidal Behavior and Ideation AEDs, including lamotrigine extended-release tablets, 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.

Pooled analyses of 199 placebo-controlled clinical trials of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated.

There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3.

Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events per 1 , 000 Patients Drug Patients With Events per 1 , 000 Patients Relative Risk : Incidence of Events in Drug Patients / Incidence in Placebo Patients Risk Difference : Additional Drug Patients With Events per 1 , 000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing lamotrigine extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.5 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 (5.2) ].

5.6 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 extended-release tablets clearly.

Depictions of the lamotrigine extended-release tablets can be found in the Medication Guide.

Each lamotrigine extended-release tablet has a distinct debossing and is debossed with “W” on one side and “271” on the other side for 25 mg, “W” on one side and “274” on the other side for 50 mg, “W” on one side and “273” on the other side for 100 mg, “W” on one side and “272” on the other side for 200 mg, and “W” on one side and “275” on the other side for 300 mg.

These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors.

Lamotrigine extended-release tablets are supplied in circular, unit-of-use bottles containing 30 tablets and 100 unit dose blister pack.

Additionally, Lamotrigine extended-release tablets are also supplied as 500 count bottle pack.

The label on the bottle includes a depiction of the tablets that further communicates to patients and pharmacists that the medication is lamotrigine extended-release tablets and the specific tablet strength included in the bottle.

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 extended-release tablets each time they fill their prescription.

5.7 Concomitant Use With Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [ see Clinical Pharmacology (12.3) ].

Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine extended-release tablets [ see Dosage and Administration (2.1) ].

During the week of inactive hormone preparation (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.

5.8 Withdrawal Seizures As with other AEDs, lamotrigine extended-release tablets 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 extended-release tablets should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [ see Dosage and Administration (2.1) ].

5.9 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) were made.

5.10 Sudden Unexplained Death in Epilepsy (SUDEP) During the premarketing development of immediate-release 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 death in epilepsy (SUDEP) in patients 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 with 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.

5.11 Addition of Lamotrigine Extended-Release Tablets 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 [ see Dosage and Administration ( 2.1 , 2.2 ), Drug Interactions (7) ].

5.12 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 1 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’s 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.

5.13 Laboratory Tests False-Positive Drug Test Results Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP).

A more specific analytical method should be used to confirm a positive result.

Plasma Concentrations of Lamotrigine The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine extended-release tablets 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 extended-release tablets 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 extended-release tablets % – Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Rash Prior to initiation of treatment with lamotrigine extended-release tablets, inform patients that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and instruct them to report any such occurrence to their physician immediately.

Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine.

Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur.

Instruct patients to contact their physician immediately if they experience any signs or symptoms of these conditions [ see Warnings and Precautions ( 5.2 , 5.3 ) ].

Suicidal Thinking and Behavior Inform patients, their caregivers, and families that AEDs, including lamotrigine extended-release tablets, may increase the risk of suicidal thoughts and behavior.

Instruct them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior or thoughts about self-harm.

Instruct them to immediately report behaviors of concern to their physician.

Worsening of Seizures Advise patients to notify their physician if worsening of seizure control occurs.

Central Nervous System Adverse Effects Inform patients that lamotrigine extended-release tablets may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression.

Accordingly, instruct them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine extended-release tablets to gauge whether or not it adversely affects their mental and/or motor performance.

Pregnancy and Nursing Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.

Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

To enroll, patients can call the toll-free number 1-888-233-2334 [ see Use in Specific Populations (8.1) ].

Inform patients who intend to breastfeed that lamotrigine extended-release tablet is present in breast milk and advise them to monitor their child for potential adverse effects of this drug.

Discuss the benefits and risks of continuing breastfeeding.

Oral Contraceptive Use Instruct women to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations.

Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels [ see Warnings and Precautions (5.7) , Clinical Pharmacology (12.3) ].

Also instruct women to promptly notify their physician if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine extended-release tablets in combination with these medications.

Discontinuing Lamotrigine Extended-Release Tablets Instruct patients to notify their physician if they stop taking lamotrigine extended-release tablets for any reason and not to resume lamotrigine extended-release tablets without consulting their physician.

Aseptic Meningitis Inform patients that lamotrigine extended-release tablets may cause aseptic meningitis.

Instruct them to notify their physician immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking lamotrigine extended-release tablets.

Potential Medication Errors To avoid a medication error of using the wrong drug or formulation, strongly advise patients to visually inspect their tablets to verify that they are lamotrigine extended-release tablets each time they fill their prescription [ see Dosage Forms and Strengths (3) , How Supplied/Storage and Handling (16) ].

Refer the patient to the Medication Guide that provides depictions of the lamotrigine extended-release tablets extended-release tablets.

Manufactured by: Wockhardt Limited H-14/2, M.I.D.C.

Area, Waluj, Aurangabad, Maharashtra, India.

Distributed by: Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054 USA.

Rev.020715

DOSAGE AND ADMINISTRATION

2 Do not exceed the recommended initial dosage and subsequent dose escalation.

( 2.1 ) Initiation of adjunctive therapy and conversion to monotherapy requires slow titration dependent on concomitant AEDs; the prescriber must refer to the appropriate algorithm in Dosage and Administration.

( 2.2 , 2.3 ) Adjunctive therapy: Target therapeutic dosage range is 200 to 600 mg daily and is dependent on concomitant AEDs.

( 2.2 ) Conversion to monotherapy: Target therapeutic dosage range is 250 to 300 mg daily.

( 2.3 ) Conversion from immediate-release lamotrigine to lamotrigine extended-release tablets: The initial dose of lamotrigine extended-release tablets should match the total daily dose of the immediate-release lamotrigine.

Patients should be closely monitored for seizure control after conversion.

( 2.4 ) Do not restart lamotrigine extended-release tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks.

( 2.1 , 5.1 ) Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives.

( 2.1 , 5.7 ) Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week).

( 2.1 , 5.8 ) 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.

2.1 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 extended-release tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets.

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 for lamotrigine extended-release tablet is exceeded and in patients with a history of allergy or rash to other AEDs.

It is recommended that lamotrigine extended-release tablets 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 extended-release tablets, 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 [ see Clinical Pharmacology (12.3) ].

Lamotrigine Extended-Release Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation 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.

Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Valproate inhibits glucuronidation.

For dosing considerations for lamotrigine extended-release tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 5.

For dosing considerations for lamotrigine extended-release tablets in patients on other drugs known to induce or inhibit glucuronidation, see Table 1 and Table 5.

Target Plasma Levels A therapeutic plasma concentration range has not been established for lamotrigine.

Dosing of lamotrigine extended-release tablets should be based on therapeutic response [ see Clinical Pharmacology (12.3) ].

Women Taking Estrogen-Containing Oral Contraceptives Starting lamotrigine extended-release tablets in Women Taking Estrogen-Containing Oral Contraceptives : Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [ see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets 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 extended-release tablets based on the concomitant AED or other concomitant medications (see Table 1).

See below for adjustments to maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of lamotrigine extended-release tablets in Women Taking Estrogen-Containing Oral Contraceptives: (1) Taking Estrogen-Containing Oral Contraceptives : In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

(2) Starting Estrogen-Containing Oral Contraceptives : In women taking a stable dose of lamotrigine extended-release tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose will in most cases need to be increased by as much as 2-fold 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 (pill-free 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 extended-release tablets 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 extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ], no adjustment to the dose of lamotrigine extended-release tablets should be necessary.

(3) Stopping Estrogen-Containing Oral Contraceptives : In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose of lamotrigine extended-release tablets 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 extended-release tablets 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 [ see Clinical Pharmacology (12.3) ].

In women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ], no adjustment to the dose of lamotrigine extended-release tablets 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 extended-release tablets in the presence of progestogens alone will likely not be needed.

Patients Taking Atazanavir/Ritonavir While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of atazanavir/ritonavir.

Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on concomitant AED or other concomitant medications (see Tables 1 and 5).

In patients already taking maintenance doses of lamotrigine extended-release tablets and not taking glucuronidation inducers, the dose of lamotrigine extended-release tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [ see Clinical Pharmacology (12.3) ].

Patients With Hepatic Impairment Experience in patients with hepatic impairment is limited.

Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [ see Use in Specific Populations (8.6) , 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.

Patients With Renal Impairment Initial doses of lamotrigine extended-release tablets 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 (8.7) , Clinical Pharmacology (12.3) ].

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 extended-release tablets should be used with caution in these patients.

Discontinuation Strategy For patients receiving lamotrigine extended-release tablets 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 extended-release tablets, 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 (5.8) ].

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

2.2 Adjunctive Therapy for Primary Generalized Tonic-Clonic and Partial-Onset Seizures This section provides specific dosing recommendations for patients aged 13 years and older.

Specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications.

Table 1.

Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients Aged 13 Years and Older a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [ see Dosage and Administration (2.1) ].

Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [ see Dosage and Administration (2.1) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ].

c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidone , b or Valproate a In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg every day Weeks 3 and 4 25 mg every day 50 mg every day 100 mg every day Week 5 50 mg every day 100 mg every day 200 mg every day Week 6 100 mg every day 150 mg every day 300 mg every day Week 7 150 mg every day 200 mg every day 400 mg every day Maintenance range (week 8 and onward) 200 to 250 mg every day c 300 to 400 mg every day c 400 to 600 mg every day c 2.3 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 extended-release tablets.

To avoid an increased risk of rash, the recommended maintenance dosage range of lamotrigine extended-release tablets as monotherapy is 250 to 300 mg given once daily.

The recommended initial dose and subsequent dose escalations for lamotrigine extended-release tablets should not be exceeded [ see Boxed Warning ].

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine Extended-Release Tablets After achieving a dose of 500 mg/day of lamotrigine extended-release tablets 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 extended-release tablets 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 Extended-Release Tablets The conversion regimen involves the 4 steps outlined in Table 2.

Table 2.

Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Extended-Release Tablets in Patients Aged 13 Years and Older With Epilepsy Lamotrigine Extended – Release Tablets Valproate Step 1 Achieve a dose of 150 mg/day according to guidelines in Table 1.

Maintain established stable dose.

Step 2 Maintain at 150 mg/day.

Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

Step 3 Increase to 200 mg/day.

Simultaneously decrease to 250 mg/day and maintain for 1 week.

Step 4 Increase to 250 or 300 mg/day.

Discontinue.

Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With Lamotrigine Extended-Release Tablets After achieving a dosage of 250 to 300 mg/day of lamotrigine extended-release tablets 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 extended-release tablets is needed.

2.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release Tablets Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release tablets.

The initial dose of lamotrigine extended-release tablets 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 [ see Clinical Pharmacology (12.3) ].

Following conversion to lamotrigine extended-release tablets, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [ see Drug Interactions (7) ].

Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).