SUBVENITE

RECENT MAJOR CHANGES Boxed Warning 10/2025 Dosage and Administration ( 2.1 , 2.2 , 2.4 ) 4/2025 Warnings and Precautions, Serious Skin Rashes 10/2025 Concomitant Use with Estrogen-Containing Products, Including Oral Contraceptives ( 5.9 ) 4/2025 Sudden Unexplained Death in Epilepsy ( 5.12 ) – removal 4/2025

1 INDICATIONS AND USAGE SUBVENITE is indicated for: Epilepsy—adjunctive therapy in patients aged 2 years and older: partial-onset seizures. primary generalized tonic-clonic (PGTC) 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, primidone, or valproate as the single antiepileptic drug. ( 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 SUBVENITE in the acute treatment of mood episodes has not been established. 1.1 Epilepsy Adjunctive Therapy SUBVENITE is 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 SUBVENITE is 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 SUBVENITE 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 SUBVENITE is 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 SUBVENITE in the acute treatment of mood episodes has not been established.

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. SUBVENITE Starter Kits are available for the first 5 weeks of treatment. ( 2.1 , 16 ) Do not restart SUBVENITE 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 products, including oral contraceptives. ( 2.1 , 5.9 ) Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). ( 2.1 , 5.10 ) 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 that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of SUBVENITE with valproate, (2) exceeding the recommended initial dose of SUBVENITE, or (3) exceeding the recommended dose escalation for SUBVENITE. 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 SUBVENITE is exceeded and in patients with a history of allergy or rash to other AEDs. SUBVENITE Starter Kits provide SUBVENITE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash. The use of SUBVENITE Starter Kits is recommended for appropriate patients who are starting or restarting SUBVENITE [see How Supplied/Storage and Handling ( 16 )] . It is recommended that SUBVENITE 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 SUBVENITE, 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 )]. SUBVENITE 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 products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for SUBVENITE in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13. For dosing considerations for SUBVENITE in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5 to 6, and 13. Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of SUBVENITE should be based on therapeutic response [see Clinical Pharmacology ( 12.3 …

3 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. ( 3.1 , 16 ) 3.1 Tablets 25 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "2L" on one side and break line on other side. 100 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "10LA" on one side and break line on other side. 150 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "15LA" on one side and break line on other side. 200 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "20LA" on one side and break line on other side.

4 CONTRAINDICATIONS Hypersensitivity to the drug or its ingredients. ( Boxed Warning , 4 ) SUBVENITE 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 , 5.3 )] .

6 ADVERSE REACTIONS 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 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 OWP Pharmaceuticals Inc. at 1-800-273-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Serious Skin Rashes [see Warnings and Precautions ( 5.1 )] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions ( 5.2 )] Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions ( 5.3 )] Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions ( 5.4 )] Blood Dyscrasias [see Warnings and Precautions ( 5.5 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.6) ] Aseptic Meningitis [see Warnings and Precautions ( 5.7 )] Withdrawal Seizures [see Warnings and Precautions ( 5.10 )] Status Epilepticus [see Warnings and Precautions ( 5.11 )] 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 SUBVENITE and more common on drug than placebo) adverse reactions seen in association with SUBVENITE 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 SUBVENITE than in patients receiving other AEDs with SUBVENITE. 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 SUBVENITE as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%). In a dose-response trial in adults, the rate of discontinuation of SUBVENITE for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for SUBVENITE and more common on drug than placebo) adverse reactions seen in association with the use of SUBVENITE 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 SUBVENITE and more common on drug than placebo) adverse reactions associated with the use of SUBVENITE 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 vi …

7 DRUG INTERACTIONS 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 SUBVENITE are summarized in this section. Uridine 5 ́-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine. Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 13. Specific dosing guidance for these drugs is provided in the Dosage and Administration section, and, for women taking estrogen-containing products, including oral contraceptives, in the Warnings and Precautions section [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.9 )] . 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 ↓= 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 SUBVENITE 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 SUBVENITE with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm. ( 8.1 ) Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment. ( 2.1 , 8.6 ) Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment. ( 2.1 , 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including SUBVENITE, during pregnancy. Encourage women who are taking SUBVENITE during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population (see Data) . The majority of SUBVENITE pregnancy exposure data are from women with epilepsy. In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically. Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including SUBVENITE, due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.10)]. Dose Adjustments During Pregnancy and the Postpartum Period 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-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response. Data Human Data : Data from several international pregnancy registries have not shown an increased risk for malformations overall. The International Lamotrigine Pregnancy Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy. The NAAED Pregnancy Registry reported major congenital malformations among 2.0% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester. EURAP, a large international pregnancy registry focused outside of North America, reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester. The frequency of major congenital malformations was similar to estimates from the general population. The NAAED Pregnancy Registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls. This finding has not been observed in other large international pregnancy regis …

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 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. 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 μM of glycine) in cultured hippocampal neurons exceeded 100 μM. The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established.

11 DESCRIPTION Lamotrigine, USP 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, USP is a white to pale cream-colored powder and has a pK a of 5.7. Lamotrigine, USP 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: SUBVENITE (lamotrigine) tablets, USP are supplied for oral administration as 25-mg (white to off white), 100-mg (white to off white), 150-mg (white to off white), and 200-mg (white to off white) tablets. Each tablet contains the labeled amount of lamotrigine, USP and the following inactive ingredients: lactose monohydrate; magnesium stearate; microcrystalline cellulose; povidone; and sodium starch glycolate. Meets USP Dissolution Test 3 structure

10 OVERDOSAGE 10.1 Human Overdose Experience Overdoses involving quantities up to 15 g have been reported for SUBVENITE, 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 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 SUBVENITE.

16 HOW SUPPLIED/STORAGE AND HANDLING SUBVENITE (lamotrigine) tablets, USP 25 mg White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side. Bottle of 100 NDC-69102-301-01 Bottle of 6600 NDC-69102-301-02 SUBVENITE (lamotrigine) tablets, USP 100 mg White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side. Bottle of 100 NDC-69102-319-01 Bottle of 2500 NDC-69102-319-02 SUBVENITE (lamotrigine) tablets, USP 150 mg White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “15LA” on one side and break line on other side. Bottle of 100 NDC-69102-150-06 SUBVENITE (lamotrigine) tablets, USP 200 mg White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “20LA” on one side and break line on other side. Bottle of 100 NDC-69102-320-01 SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange Kit). 25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side. 100-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side. Blister pack of 42, 25 mg tablets and 7, 100 mg tablets NDC-69102-300-01 SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green Kit). 25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side. 100-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side. Blister pack of 84, 25 mg tablets and 14, 100 mg tablets NDC-69102-312-01 SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Taking Valproate (Blue Kit). 25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side. Blister pack of 35 tablets NDC-69102-306-01 Storage Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature].