EQUETRO

Warnings and Precautions ( 5.5 ) 10/2022

1INDICATIONS AND USAGE EQUETRO is: A mood stabilizer indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder ( 1.1 ) Indicated for the treatment of the pain associated with trigeminal neuralgia ( 1.2 ) An anti-epileptic drug (AED) indicated for the treatment of partial seizures with complex symptomatology, generalized tonic-clonic seizures, and mixed seizures ( 1.3 ) 1.1Acute Manic or Mixed Episodes associated with Bipolar I Disorder EQUETRO is indicated for treatment of patients with acute manic or mixed episodes associated with bipolar I disorder [see Clinical Studies ( 14.1 ) ] . 1.2 Pain of Trigeminal Neuralgia EQUETRO is indicated in the treatment of the pain associated with trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. 1.3 Epilepsy EQUETRO is indicated for the treatment of partial seizures with complex symptomatology (e.g., psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns, which include the seizure types listed here or other partial or generalized seizures. Limitations of Usage EQUETRO is not indicated for the treatment of absence seizures (petit mal).Carbamazepine has been associated with increased frequency of generalized convulsions in these patients.

2 DOSAGE AND ADMINISTRATION SEE DOSAGE FOR BIPOLAR DISORDER, TRIGEMINAL NEURALGIA, AND EPILEPSY ( 2.2 , 2.3 , 2.4 ) When discontinuing treatment, reduce dose gradually ( 2.6 , 5.6 ) Monitoring serum carbamazepine concentrations may be useful in dose selection and minimizing risk of toxicity ( 2.7 ) Swallow capsules whole or open capsules and sprinkle beads over food ( 2.8 ) Do not crush or chew the capsule or beads ( 2.8 ) 2.1 Pretreatment Screening Prior to initiating treatment with EQUETRO, test patients with ancestry in genetically at-risk populations for the presence of the HLA-B*1502 allele. The high resolution genotype test is positive if one or two HLA-B*1502 alleles are present. Avoid use of EQUETRO in patients testing positive for the allele, unless the benefit clearly outweighs the risk [see Boxed Warning , Warnings and Precautions ( 5.1 )] . Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of EQUETRO should be considered if any evidence of significant bone marrow depression develops [see Warnings and Precautions ( 5.2 )]. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with EQUETRO because liver damage may occur. Discontinue EQUETRO in cases of aggravated liver dysfunction or active liver disease [see Warnings and Precautions ( 5.10 )] . Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes [see Warnings and Precautions ( 5.13 )] . Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction. 2. 2 Dosage for Acute Manic or Mixed Episodes A ssociated with Bipolar I Disorder The recommended initial dose of EQUETRO is 200 mg administered twice daily. The dose may be increased by 200 mg per day to achieve optimal clinical response. Doses higher than 1600 mg per day have not been studied in mania associated with bipolar disorder. 2. 3 Dosage for Pain of Trigeminal Neuralgia Initial: On the first day, start with one 200 mg capsule once daily. This dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours only as needed to reach an effective and tolerated dose. Do not exceed a total daily dose of 1200 mg. Maintenance: Control of pain can be maintained in most patients with 400 mg to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. 2. 4 Dosage for Epilepsy Adults and C hildren over 12 Y ears of A ge The recommended initial dose is 200 mg administered twice daily. Increase in weekly increments of 200 mg a day, administered as an equally divided, twice daily dose, until an optimal response is obtained. Dosage generally should not exceed 500 mg twice daily in children 12 to 15 years old; 600 mg twice daily in children 15 to 18 years old; and 800 mg twice daily in adults. Children U nder 12 Y ears of A ge Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg [see Dosage and Administration ( 2.5 )] . No recommendation regarding the safety of EQUETRO for use at doses above 35 mg/kg/24 hours can be made. Co -Administration with Other AEDs EQUETRO may be used alone or with other AEDs. When added to existing AEDs, add EQUETRO gradually while the dosage(s) of other AEDs are maintained or gradually decreased. Potential drug interactions should be considered when using carbama …

3 DOSAGE FORMS AND STRENGTHS EQUETRO (carbamazepine) extended-release capsules for oral administration is supplied in three dosage strengths: 100 mg — Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink. 200 mg — Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink. 300 mg — Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink. Extended-Release Capsules: 100 mg, 200 mg, and 300 mg ( 3 )

4 CONTRAINDICATIONS Bone marrow depression [see Warnings and Precautions ( 5.2 ) ] . Known hypersensitivity to carbamazepine, such as anaphylaxis or serious hypersensitivity reaction [see Warnings and Precautions ( 5.3 ) ] . Known hypersensitivity to any of the tricyclic compounds (e.g., amitriptyline, desipramine, imipramine, protriptyline, and nortriptyline.) Hypersensitivity reactions include anaphylaxis and serious rash. Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. EQUETRO can substantially reduce the concentrations of these drugs through induction of CYP3A4. This can lead to loss of virologic response and possible resistance to these medications [see Warnings and Precautions ( 5.9 ) and Drug Interactions ( 7.2 ) ] . Concomitant use of monoamine oxidase inhibitors (MAOIs). Before beginning treatment with EQUETRO, MAOIs should be discontinued for a minimum of 14 days. Concomitant use can cause serotonin syndrome. Concomitant use of nefazodone. This may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Bone marrow depression ( 4 ) Known hypersensitivity to carbamazepine ( 4 ) Known hypersensitivity to tricyclic antidepressants ( 4 ) Concomitant use with monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing an MAOI ( 4 ) Concomitant use with delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. EQUETRO decreases efficacy of these drugs ( 4 , 5.9 ) Concomitant use of nefazodone ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Serious Dermatologic Reactions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome [see Warnings and Precautions ( 5.1 ) Aplastic anemia/agranulocytosis [see Warnings and Precautions ( 5.2 )] Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.3 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.4 )] Embryofetal Toxicity [see Warnings and Precautions ( 5.5 )] Abrupt Discontinuation and Seizure Risk [see Warnings and Precautions ( 5.6 )] Hyponatremia [see Warnings and Precautions ( 5.7 )] Cognitive and Motor Impairment [see Warnings and Precautions ( 5.8 )] Drug Interaction with Non-Nucleoside Reverse Transcriptase Inhibitors [see Warnings and Precautions ( 5.9 )] Liver Damage [see Warnings and Precautions ( 5.10 )] AV Heart Block [see Warnings and Precautions ( 5.11 )] Hepatic Porphyria [see Warnings and Precautions ( 5.12 )] Increased Intraocular Pressure [see Warnings and Precautions ( 5.13 )] Most common ( > 5% and 2 times placebo) adverse reactions were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions ( > 5% in the EQUETRO group and at least twice placebo) in the pooled 3-week placebo-controlled trials in patients with acute mania associated with Bipolar I Disorder (Studies 1 and 2) were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder [see Clinical Studies ( 14.1 )] . The EQUETRO doses used were 400 to 1600 mg per day. (Incidence > 2% and greater than placebo) Adverse Reactions EQUETRO ® (N = 251) Placebo (N = 248) Dizziness 44% 12% Somnolence 32% 13% Nausea 29% 10% Vomiting 18% 3% Ataxia 15% 0.4% Constipation 10% 5% Pruritus 8% 2% Dry Mouth 8% 3% Asthenia 8% 4% Rash 7% 4% Blurred vision 6% 2% Speech Disorder 6% 0.4% Hypertension 3% 0.4% Paresthesia 2% 1% Thinking abnormal 2% 0.4% Tremor 3% 1% Twitching 2% 1% Vertigo 2% 1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of EQUETRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System: confusion, diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, tinnitus. Digestive System: gastric distress, abdominal pain, diarrhea, anorexia. Laboratory Tests: thyroid function tests (T3, T4)- decreased values Other: lupus erythematosus-like syndrome One case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine. 6.3 Additional Adverse Reactions Associated with Carbamazepine The following is a list of additional adverse reactions identified in clinical trials or postmarketing reports of other forms of carbamazepine and not reported above for EQUETRO. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposur …

7 DRUG INTERACTIONS Cytochrome (CYP) 3A4 inhibitors, epoxide hydrolase inhibitors, CYP3A4 inducers, drugs metabolized by CYP1A2 or CYP3A4 (oral contraceptives, delavirdine, nefazodone), phenytoin, CNS depressants, lithium, chloroquine, mefloquine ( 7.1 , 7.2 , 7.3 ) Equetro may decrease the effectiveness of hormonal contraceptives. Use alternative form of birth control ( 7.2 ) 7.1 Pharmacokinetic Effect s of other Drugs on EQ U ETRO Drugs that Inhibit Cytochrome P450 3A4 (CYP3A4) EQUETRO is metabolized primarily by CYP3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Inhibitors of CYP 3A4 and/or epoxide hydrolase can increase plasma levels of EQUETRO and its active metabolites, increasing plasma concentrations of EQUETRO and the risk of adverse reactions. It may be necessary to reduce the EQUETRO dose if used concomitantly with inhibitors of CYP3A4 and/or epoxide hydrolase. The following drugs are CYP3A4 inhibitors: Acetazolamide, aprepitant, azole antifungals (e.g., ketoconazole, itraconazole, fluconazole, voriconazole ) , cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton. Drugs that Inhibit Epoxide H ydrolase and CYP3A4 Clarithromycin, erythromycin, loxapine, quetiapine, and valproate also inhibit epoxide hydrolase, resulting in increased levels of the active metabolite carbamazepine-10,11-epoxide [see Clinical Pharmacology ( 12.3 )] . Drugs that Induce CYP3A4 CYP3A4 inducers can decrease serum concentrations of EQUETRO and decrease its effectiveness. It may be necessary to increase the dose of EQUETRO if used concomitantly with a CYP3A4 inducer. Such drugs include the following: Aminophylline, c isplatin, doxorubicin, felbamate, phosphenytoin, methsuximide , phenobarbital, phenytoin, primidone, rifampin and theophylline. 7.2 Pharmacokinetic Effect s of EQUETRO on other Drugs EQUETRO is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with EQUETRO, monitoring of concentrations or dosage adjustment of these agents may be necessary. EQUETRO decreases the concentrations of the following drugs through induction of their metabolism: Hormonal Contraceptives (CYP3A4 Substrates) EQUETRO is a strong inducer of CYP3A4. EQUETRO can increase the metabolism of certain hormonal contraceptives (through CYP3A4 induction) such as oral and subdermal implant contraceptives, leading to significantly lower plasma concentrations of hormones. This can cause contraceptive failure or breakthrough bleeding. Consider alternatives to oral and subdermal implant contraceptives that are significantly affected by induction of CYP3A4; or consider alternatives to EQUETRO [see Warnings and Precautions ( 5.5 ) and Use in Specific Populations ( 8.3 )] . Delavirdine and other Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Substrates) Through induction of CYP3A4, EQUETRO increases the metabolism of delavirdine and certain non-nucleoside reverse transcriptase inhibitors and significantly reduces the plasma concentrations of these drugs. This can cause inadequate antiviral activity, loss of virologic response, and possible resistance to delavirdine or other non-nucleoside reverse transcriptase inhibitors. Therefore, the use of EQUETRO with these non-nucleoside reverse transcriptase inhibitors is contraindicated [see Contraindications ( 4 ) and Warnings and Precautions ( 5.9 )] . Nefazodone (CYP3A4 Substrate) The use of EQUETRO is contraindicated with the use of nefazodone because …

8 USE IN SPECIFIC POPULATIONS Pregnancy : Can cause fetal harm. ( 5.5 , 8.1 ) Infertility : May impair male fertility ( 8.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as EQUETRO, during pregnancy. Healthcare providers are encouraged to recommend that pregnant patients taking EQUETRO enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/ . Risk Summary EQUETRO can cause fetal harm when administered to a pregnantfemale [see Warnings and Precautions ( 5.5 )] . Pregnancy registry and epidemiological data suggest a potential association between the use of carbamazepine during pregnancy and major congenital malformations, including neural tube defects and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations). The available data are insufficient to identify an association with carbamazepine use and miscarriage (see Data). There are risks to the mother and fetus associated with untreated bipolar I disorder or epilepsy and with exposure to carbamazepine during pregnancy (see Clinical Considerations). In animal studies, administration of carbamazepine at clinically relevant doses during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformation. Advise pregnant females of the potential risk of major congenital malformations with use of EQUETRO during pregnancy. Assess the risk and benefits of EQUETRO and discuss with the patient to determine if an alternative treatment should be considered during pregnancy. Dietary folic acid supplementation both prior to conception and during pregnancy should be recommended for patients using carbamazepine. However, it is not known whether the risk of neural tube defects in the offspring of women receiving carbamazepine is reduced by folic supplementation. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk There are risks to the mother from untreated bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Bipolar I disorder is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. 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. Females with epilepsy should not discontinue carbamazepine abruptly due to the risk of status epilepticus and less severe seizures which may be life-threatening [see Warnings and Precautions ( 5.6 )] . Fetal/Neonatal Adverse Reactions There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome. Pu …

1 2 .1 Mechanism of Action The mechanism of action of carbamazepine in the treatment of acute manic or mixed episodes associated with bipolar disorder is unclear.

1 1 DESCRIPTION EQUETRO (carbamazepine) is a mood stabilizer available for oral administration as 100 mg, 200 mg, and 300 mg extended-release capsules of carbamazepine, USP. Carbamazepine is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. The chemical name of carbamazepine is 5H-dibenz[b,f]azepine-5-carboxamide, and the structural formula is: EQUETRO ® is a multi-component capsule formulation consisting of three different types of beads: immediate-release beads, extended-release beads, and enteric-release beads. The three bead types are combined in a specific ratio to provide twice-daily dosing of EQUETRO ® . Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate, and other ingredients. The 100 mg capsule shells contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink; the 200 mg capsule shells contain gelatin-NF, Yellow Iron Oxide, FD&C Blue #2, and Titanium Dioxide, and are imprinted with white ink; and the 300 mg capsule shells contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink. The structural formula for EQUETRO (carbamazepine) is a mood stabilizer available for oral administration as 100 mg, 200 mg, and 300 mg extended-release capsules of carbamazepine, USP. Carbamazepine i

10 OVERDOSAGE 10.1 Human Experience Lowest known lethal dose of carbamazepine: adults, greater than 60 grams (39-year-old man). Highest known doses survived: adults, 30 grams (31-year-old woman); children, 10 grams (6-year-old boy); small children, 5 grams (3-year-old girl). Signs and Symptoms: The first signs and symptoms of carbamazepine overdose appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 grams) have been ingested. Respiration: Irregular breathing, respiratory depression. Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders. Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia. Gastrointestinal Tract: Nausea, vomiting. Kidneys and Bladder: Anuria or oliguria, urinary retention. Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. ECG may show dysrhythmias. Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified. 10 .2 Management of Overdosage For the most up to date information on management of EQUETRO overdose, contact the certified poison center for your area by calling 1-800-222-1222 (or at www.poison.org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

16 HOW SUPPLIED/STORAGE AND HANDLING 16. 1 How Supplied EQUETRO (carbamazepine) extended-release capsules are supplied in three dosage strengths. 100 mg — Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink: Supplied in bottles of 120 NDC 30698-419-12 200 mg — Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink: Supplied in bottles of 120 NDC 30698-421-12 300 mg — Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink: Supplied in bottles of 120 NDC 30698-423-12 16.2 Storage Store at 25° C (77° F); excursions permitted to 15° –30° C (59° –86° F) [see USP controlled room temperature]. Protect from light and moisture.

16. 1 How Supplied EQUETRO (carbamazepine) extended-release capsules are supplied in three dosage strengths. 100 mg — Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink: Supplied in bottles of 120 NDC 30698-419-12 200 mg — Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink: Supplied in bottles of 120 NDC 30698-421-12 300 mg — Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink: Supplied in bottles of 120 NDC 30698-423-12