Lamotrigine Chewable Dispersible

Description

11. DESCRIPTION Lamotrigine tablets for oral suspension USP (chewable dispersible tablets), 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 to pale cream-colored powder and has a pK a 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). The structural formula is: Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are supplied for oral administration. The tablets contain 5 mg (white to off white), or 25 mg (white to off white) of lamotrigine and the following inactive ingredients: mannitol, crospovidone, povidone K-30, microcrystalline cellulose, aspartame, black currant flavor, colloidal silicon dioxide, magnesium stearate and talc. Drug product complies with Organic Impurities procedure II. Structure

What Is Lamotrigine Chewable Dispersible Used For?

1. INDICATIONS AND USAGE Lamotrigine tablet for oral suspension USP (chewable dispersible tablet) is indicated for: Epilepsy - adjunctive therapy in patients aged 2 years and older: · partial-onset seizures. · primary generalized tonic-clonic seizures. · generalized seizures of Lennox-Gastaut syndrome. (1.1) Epilepsy - monotherapy in patients aged 16 years and older: Conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, phenytoin, primidone, or valproate as the single AED. (1.1) Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy. (1.2) Limitations of Use: Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets for oral suspension USP (chewable dispersible tablets) in the acute treatment of mood episodes has not been established. 1.1. Epilepsy Adjunctive Therapy Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: partial-onset seizures. primary generalized tonic-clonic (PGTC) seizures. generalized seizures of Lennox-Gastaut syndrome. Monotherapy Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of lamotrigine tablets for oral suspension USP (chewable dispersible tablets)have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. 1.2. Bipolar Disorder Lamotrigine tablets for oral suspension USP (chewable dispersible tablets) are indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Clinical Studies (14.2)] . Limitations of Use Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets for oral suspension USP (chewable dispersible tablets) in the acute treatment of mood episodes has not been established.

Dosage and Administration

2. DOSAGE AND ADMINISTRATION · Dosing is based on concomitant medications, indication, and patient age. (2.1, 2.2, 2.3, 2.4) · To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. (2.1) · Do not restart lamotrigine 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) Epilepsy: · Adjunctive therapy - See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years. (2.2) · Conversion to monotherapy - See Table 4. (2.3) Bipolar disorder: See Tables 5 and 6. (2.4) 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 with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. 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 is exceeded and in patients with a history of allergy or rash to other AEDs. It is recommended that lamotrigine 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, 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)]. L amotrigine 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 in patients on estrogen-containing contraceptives and...

Side Effects (Adverse Reactions)

6. ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Serious skin rashes [see Warnings and Precautions (5.1)] Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)] Blood dyscrasias [see Warnings and Precautions (5.3)] Suicidal behavior and ideation [see Warnings and Precautions (5.4)] Aseptic meningitis [see Warnings and Precautions (5.5)] Withdrawal seizures [see Warnings and Precautions (5.8)] Status epilepticus [see Warnings and Precautions (5.9)] Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10)] Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children in included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor. (6.1) Bipolar disorder: Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866 210 9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1.Clinical Trial Experience 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. Epilepsy Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions (5.1)] . Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3%), dizziness (2.8%), and headache (2.5%). In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions associated with the use of lamotrigine during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis....

Drug Interactions

7. DRUG INTERACTIONS Significant drug interactions with lamotrigine are summarized in this section. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] . Table 13. Established and Other Potentially Significant Drug Interactions Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment Estrogen-containing oral contraceptivepreparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine levels 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. ↓ = Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data. Effect of Lamotrigine 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 with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended. · 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)

Contraindications

4. CONTRAINDICATIONS Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1), (5.2) ] . Hypersensitivity to the drug or its ingredients. (Boxed Warning, 4)

Pregnancy and Breastfeeding

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 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...

8.3. Nursing Mothers Lamotrigine is present in milk from lactating women taking lamotrigine. Data from 904 multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have 905 been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are 906 at risk for high serum levels because maternal serum and milk levels can rise to high levels 907 postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to 908 the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the 909 infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness, 910 and poor sucking have been reported in infants who have been human milk-fed by mothers using 911 lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human 912 milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. 913 Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. 914 Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should 915 be exercised when lamotrigine is administered to a nursing woman.

Overdosage

10. OVERDOSAGE 10.1. 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. 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 should be kept in mind that immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)] . 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.

How Supplied

16. HOW SUPPLIED/STORAGE AND HANDLING Lamotrigine tablets for oral suspension USP (chewable dispersible tablets), 5 mg White to off white, caplet-shaped tablets debossed with ‘L217’ on one side and plain on other side. They are supplied as follows: NDC 46708-095-30 bottle of 30 tablets NDC 46708-095-31 bottle of 100 tablets NDC 46708-095-91 bottle of 1000 tablets Lamotrigine tablets for oral suspension USP (chewable dispersible tablets), 25 mg White to off white, super elliptical-shaped tablets debossed with ‘L’ on one side and ‘218’ on other side. They are supplied as follows: NDC 46708-096-30 bottle of 30 tablets NDC 46708-096-31 bottle of 100 tablets NDC 46708-096-91 bottle of 1000 tablets Store at 20 to 25°C (68 to 77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].