EQUETRO

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 exposure. Nervous System: Isolated cases of neuroleptic malignant syndrome have been reported in carbamazepine use both with and without concomitant use of other psychotropic drugs. Skin: onychomadesis, acute generalized exanthematous pustulosis (AGEP). 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 .

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 )

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 is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.

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 carbamazepine with other AEDs [ see Drug Interactions ( 7.1 , 7.2 ) ] . 2. 5 Switching from Immediate-Release Carbamazepine to EQUETRO EQUETRO is an extended-release formulation for twice a day administration. When converting patients from immediate release carbamazepine to EQUETRO extended-release capsules, the same total daily mg dose of carbamazepine should be administered. Following conversion to EQUETRO, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions. 2. 6 Discontinuation of EQUETRO When discontinuing EQUETRO used for any indication, reduce the dose gradually and avoid abrupt discontinuation in order to decrease the risk of seizure [see Warnings and Precautions ( 5.6 )]. 2. 7 Mon itoring Serum Carbamazepine Concentration Monitoring serum carbamazepine concentrations may be useful for dose selection, minimizing toxicity, and verifying drug compliance, especially in clinical conditions in which alterations in EQUETRO metabolism can occur (e.g., drug interactions) [see Drug Interactions ( 7 ) ] . In pediatric patients treated with EQUETRO for epilepsy, if satisfactory clinical response has not been achieved, measure plasma levels to determine whether or not they are in the therapeutic range. 2. 8 Administration Instructions Swallow EQUETRO capsules whole or open and sprinkle the beads over food, such as a teaspoon of applesauce. Do not crush or chew EQUETRO capsules or the beads inside the capsule. EQUETRO can be taken with or without meals.

1 INDICATIONS 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 ) 1.1 Acute Manic or Mixed Episodes associated with Bipolar I Di sorder 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.

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.

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 the concomitant use may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect of nefazodone. Warfarin (CYP1A2 and CYP3A4 Substrate) Through induction of CYP1A2 and CYP3A4, EQUETRO decreases the concentration of warfarin and decreases its anticoagulant effectiveness. Aripiprazole When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced. Tacrolimus When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. Temsirolimus The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered. Lapatinib The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced. HIV Protease Inhibitors Due to strong induction of CYP3A4 caused by carbamazepine, use of EQUETRO with HIV protease inhibitors is not recommended. Other CYP1A2 and CYP3A4 Substrates EQUETRO induces CYP1A2 and CYP3A4, leading to decreased concentrations of drugs metabolized by CYP3A4 or CYP1A2. It may be necessary to increase the doses of such drugs when used concomitantly with EQUETRO. Drugs metabolized by CYP3A4 or CYP1A2 include the following: Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, felbamate, glucocorticoids, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, methsuxamide, mianserin, midazolam, mirtazapine, nefazodone, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phenytoin, praziquantel, quetiapine, risperidone, sertraline, sirolimus, tadalafil, theophylline, topiramate, tiagabine, tramadol, triazolam, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), trazodone, valproate, warfarin , ziprasidone, and zonisamide. EQUETRO increases the plasma levels of the following drugs by inhibition of their metabolism : Clomipramine, P henytoin, and P rimidone EQUETRO can increase the concentrations of clomipramine, phenytoin, and primidone. If a patient has been titrated to a stable dosage on one of these agents in this category, and then begins treatment with EQUETRO, it may be necessary to decrease the dose of these drugs. Phenytoin Phenytoin levels have been reported to increase or decrease in the presence of carbamazepine. There are multiple pharmacokinetic mechanisms for changes in phenytoin levels when used concomitantly with EQUETRO. Monitor phenytoin serum levels carefully when used concomitantly with EQUETRO. Cyclophosphamide Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine. 7.3 Pharmacodynamic Drug Interactions M onoamine O xidase I nhibitors Concomitant treatment with EQUETRO is contraindicated during use of an MAOI or within 14 days after discontinuing an MAOI. Concomitant use can cause serotonin syndrome. Lithium Concomitant administration of EQUETRO and lithium can increase the risk of neurotoxic adverse reactions. Consider reducing the dose of lithium or EQUETRO when using these drugs concomitantly. Isoniazid Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. CNS Depressants The concomitant use of EQUETRO and other CNS depressants can increase the risk of respiratory depression, profound sedation, hypotension, and syncope. CNS depressants include: alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticonvulsants, antipsychotics, antihistamines, anticholinergics, alpha and beta blockers, general anesthetics, muscle relaxants, and illicit CNS depressants. Consider reducing the dose of CNS depressants or EQUETRO when using these drugs concomitantly. Chloroquine and Mefloquine The anti-malarial drugs chloroquine and mefloquine can antagonize the activity of EQUETRO. N e uromuscular Blocking Agents Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.

1 2 CLINICAL PHARMACOLOGY 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 2.3 Pharmacokinetics Carbamazepine (CBZ) Absorption: Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 mcg/mL and the time to reach the peak was 19 ± 7 hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 mcg/mL and the time to reach the peak was 5.9 ± 1.8 hours. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200–800 mg. Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. The average half-life ranged from 35 to 40 hours following a single extended-release dose of carbamazepine and from 12 to 17 hours following repeated dosing. The apparent oral clearance was 25 ± 5 mL/min following a single dose and 80 ± 30 mL/min following multiple dosing. Carbamazepine-10,11-epoxide (CBZ-E): Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following a single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was 0.11 ± 0.012 mcg/mL and the time to reach the peak was 36 ± 6 hours. Following chronic administration of an extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 ± 0.9 mcg/mL and the time to reach the peak was 14 ± 8 hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 ± 9 hours. Following a single oral dose of extended-release carbamazepine (200–800 mg) the AUC and C max of carbamazepine-10,11-epoxide were less than 10% of carbamazepine. Following multiple dosing of extended-release carbamazepine (800–1600 mg daily for 14 days), the AUC and C max of carbamazepine-10,11-epoxide were dose-related, ranging from 15.7 mcg.hr/mL and 1.5 mcg/mL at 800 mg/day to 32.6 mcg.hr/mL and 3.2 mcg/mL at 1600 mg/day, respectively, and were less than 30% those of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins. Food Effect: A high-fat meal diet increased the rate of absorption of a single 400 mg dose (mean T max was reduced from 24 hours, in the fasting state, to 14 hours, and C max increased from 3.2 to 4.3 mcg/mL) but not the extent (AUC) of absorption. The elimination half-life remained unchanged between fed and fasting state. The multiple-dose study conducted in the fed state showed that the steady-state C max values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling the beads over applesauce compared to the intact capsule administered in the fasted state. Elimination: After oral administration of 14 C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% was found in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. Metabolism: In vitro data indicate carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the transdiol by epoxide hydrolase. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide. Renal Impairment: The effect of renal impairment on the pharmacokinetics of carbamazepine is not known. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Consider reducing the dosage in patients with hepatic impairment. Effect of Age: Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age. The safety and effectiveness of EQUETRO have not been established in pediatric patients for indications other than Epilepsy [see Indications and Usage ( 1.3 )]. Effect of Gender: No difference in the mean AUC and C max of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

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 2.3 Pharmacokinetics Carbamazepine (CBZ) Absorption: Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 mcg/mL and the time to reach the peak was 19 ± 7 hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 mcg/mL and the time to reach the peak was 5.9 ± 1.8 hours. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200–800 mg. Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. The average half-life ranged from 35 to 40 hours following a single extended-release dose of carbamazepine and from 12 to 17 hours following repeated dosing. The apparent oral clearance was 25 ± 5 mL/min following a single dose and 80 ± 30 mL/min following multiple dosing. Carbamazepine-10,11-epoxide (CBZ-E): Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following a single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was 0.11 ± 0.012 mcg/mL and the time to reach the peak was 36 ± 6 hours. Following chronic administration of an extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 ± 0.9 mcg/mL and the time to reach the peak was 14 ± 8 hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 ± 9 hours. Following a single oral dose of extended-release carbamazepine (200–800 mg) the AUC and C max of carbamazepine-10,11-epoxide were less than 10% of carbamazepine. Following multiple dosing of extended-release carbamazepine (800–1600 mg daily for 14 days), the AUC and C max of carbamazepine-10,11-epoxide were dose-related, ranging from 15.7 mcg.hr/mL and 1.5 mcg/mL at 800 mg/day to 32.6 mcg.hr/mL and 3.2 mcg/mL at 1600 mg/day, respectively, and were less than 30% those of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins. Food Effect: A high-fat meal diet increased the rate of absorption of a single 400 mg dose (mean T max was reduced from 24 hours, in the fasting state, to 14 hours, and C max increased from 3.2 to 4.3 mcg/mL) but not the extent (AUC) of absorption. The elimination half-life remained unchanged between fed and fasting state. The multiple-dose study conducted in the fed state showed that the steady-state C max values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling the beads over applesauce compared to the intact capsule administered in the fasted state. Elimination: After oral administration of 14 C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% was found in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. Metabolism: In vitro data indicate carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the transdiol by epoxide hydrolase. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide. Renal Impairment: The effect of renal impairment on the pharmacokinetics of carbamazepine is not known. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Consider reducing the dosage in patients with hepatic impairment. Effect of Age: Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age. The safety and effectiveness of EQUETRO have not been established in pediatric patients for indications other than Epilepsy [see Indications and Usage ( 1.3 )]. Effect of Gender: No difference in the mean AUC and C max of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

20221013

9

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 )

EQUETRO Carbamazepine CARBAMAZEPINE CARBAMAZEPINE CITRIC ACID MONOHYDRATE SILICON DIOXIDE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE SODIUM LAURYL SULFATE TALC TRIETHYL CITRATE GELATIN FD&C BLUE NO. 2 FERRIC OXIDE YELLOW TITANIUM DIOXIDE yellow cap bluish green opaque body SPD417;SPD417;100;mg EQUETRO Carbamazepine CARBAMAZEPINE CARBAMAZEPINE CITRIC ACID MONOHYDRATE SILICON DIOXIDE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE SODIUM LAURYL SULFATE TALC TRIETHYL CITRATE GELATIN FD&C BLUE NO. 2 FERRIC OXIDE YELLOW TITANIUM DIOXIDE yellow opaque cap blue opaque body SPD417;SPD417;200;mg EQUETRO Carbamazepine CARBAMAZEPINE CARBAMAZEPINE CITRIC ACID MONOHYDRATE SILICON DIOXIDE LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE SODIUM LAURYL SULFATE TALC TRIETHYL CITRATE GELATIN FD&C BLUE NO. 2 FERRIC OXIDE YELLOW TITANIUM DIOXIDE yellow opaque cap blue body SPD417;SPD417;300;mg

13 NONCLINICAL TOXICOLOGY 1 3 .1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity Oral administration of carbamazepine to rats for 2 years at doses of 25, 75, and 250 mg/kg/day resulted in a dose-related increase in the incidence of hepatocellular tumors (females) and of benign interstitial cell adenomas in the testes. Mutagenicity Carbamazepine was negative in in vitro bacterial and mammalian genotoxicity. Impairment of Fertility The effects of carbamazepine on male and female fertility have not been adequately studied in animals. However, testicular atrophy and/or aspermatogenesis were observed in rats with repeat oral administration of carbamazepine at clinically relevant doses.

NDA021710

EQUETRO

Carbamazepine

30698-421

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 30698-419-12 Equetro ® Extended - Release Capsules (carbamazepine) 100 mg 120 Capsules Rx Only NDC 30698-419-12 Equetro® Extended - Release Capsules (carbamazepine) 100 mg 120 Capsules Rx Only

Warnings and Precautions ( 5.5 ) 10/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Serious Dermatologic Reactions Inform patients and caregivers about the risk of potentially fatal, serious skin reactions and the signs and symptoms that may signal a serious skin reaction. Instruct patients to consult with their healthcare provider immediately if a skin reaction occurs during treatment with EQUETRO [ s ee Warnings and Precautions ( 5.1 )] . Agranulocytosis and Aplastic Anemia Inform patients and caregivers about the risk of potentially fatal agranulocytosis and aplastic anemia and the signs and symptoms that may signal these reactions. Instruct them to contact their healthcare provider immediately if symptoms occur [ s ee Warnings and Precautions ( 5.2 )] . Drug Reaction with Eosinophilia and Systemic Symptoms Inform patients of the early toxic signs and symptoms of a potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. Advise patients that these signs and symptoms may signal a serious reaction and to report any occurrence immediately to their healthcare provider [ s ee Warnings and Precautions ( 5.3 )] . Suicidal Ideation and Behavior Counsel patients, their caregivers, and families that AEDs, including EQUETRO, may increase the risk of suicidal thinking and behavior and advise them of the need 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, behavior, or thoughts about self-harm. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions ( 5.4 )] . Abrupt Discontinuation and Risk of Seizure Inform patients that abrupt discontinuation of EQUETRO can cause seizures or an increase in seizure frequency. Advise patients that the drug should be tapered when discontinued [ s ee Warning s and Precautions ( 5.6 )] . Hyponatremia Advise patients that EQUETRO may reduce serum sodium concentrations especially if they are taking other medications that can lower sodium. Advise patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, seizures, or more frequent or more severe seizures [see Warnings and Precautions ( 5.7 ) ] . Potential for Cognitive and Motor Impairment Advise patients not to drive or operate machinery until they have gained sufficient experience on EQUETRO to gauge whether it adversely affects their ability to drive or operate machinery. Advise patients to exercise caution if alcohol is taken in combination with EQUETRO therapy, due to a possible additive sedative effect [ s ee Warnings and Precautions ( 5.8 )]. Concomitant Use with other Carbamazepine Products Inform patients that EQUETRO contains carbamazepine and should not be used in combination with any other medications containing carbamazepine. Embryofetal Toxicity EQUETRO may cause fetal harm. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. [see Warning and Precautions ( 5.5 ) and Use in Specific Populations ( 8.1 )] . Pregnancy Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to EQUETRO during pregnancy [see Use in Specific Populations ( 8.1 )] . Decreased Effectiveness of Hormonal Contraceptives Inform patients that EQUETRO can significantly decrease the effectiveness of hormonal contraceptives, such as oral contraceptives and subdermal implants. This can cause contraceptive failure or breakthrough bleeding [see Drug Interactions ( 7.2 ) and Use in Specific Populations ( 8.3 ) ] . Infertility Advise males of reproductive potential that EQUETRO may impair fertility [see Use in Specific Populations ( 8.3 )]. Manufactured for and Distributed by: Validus Pharmaceuticals LLC Parsippany, NJ 07054 info@validuspharma.com http://www.equetro.com 1-866-982-5438 Product of India © 2022 Validus Pharmaceuticals LLC 60079-04 October 2022

Medication Guide EQUETRO (ē-kwĕ-trō) (carbamazepine) Extended-Release Capsules Read this Medication Guide before you start taking EQUETRO and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about EQUETRO? Do not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems. If you have any of the problems listed below call your healthcare provider right away. EQUETRO can cause serious side effects, including: 1. EQUETRO may cause rare but serious rashes that may lead to death. These serious skin reactions are more likely to happen within the first four months after you start taking EQUETRO, but may occur at later times. These reactions can happen to anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic blood test before you take EQUETRO to see if you are at higher risk for serious skin reactions with this medicine. Symptoms may include: skin rash hives sores in your mouth blistering or peeling of the skin 2. EQUETRO may cause rare but serious blood problems. Symptoms may include: fever shortness of breath fatigue easy bruising red or purple spots on your body unusual bleeding such as bleeding gums, nose bleeds, or heavy menstrual bleeding swollen glands and sore throat 3. EQUETRO may cause a serious or life-threatening allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. You may or may not have rash with these types of reactions. Call a healthcare provider right away if you have any of the following symptoms: skin rash hives fever swollen glands that do not go away swelling of your lips or tongue yellowing of your skin or eyes unusual bruising or bleeding severe fatigue or weakness unexpected, severe muscle pain frequent infections These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking EQUETRO. 4. EQUETRO may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity or talking (mania) other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop EQUETRO without first talking to a healthcare provider. Stopping EQUETRO suddenly can cause serious problems. You should talk to your healthcare provider before stopping. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is EQUETRO? EQUETRO is a prescription medicine used to treat people with: acute manic or mixed episodes that happen with Bipolar I Disorder certain types of nerve pain (trigeminal neuralgia and glossopharyngeal neuralgia) certain types of seizures (partial, tonic-clonic, mixed) EQUETRO is not a regular pain medicine and should not be used for aches or pains. EQUETRO should not be used to treat people with absence seizures (petit mal). It is not known if EQUETRO is safe and effective in children and adolescents for the treatment of Bipolar I Disorder and nerve pain. Who should not take EQUETRO? Do not take EQUETRO if you: have a history of bone marrow depression. are allergic to carbamazepine or any of the ingredients in EQUETRO. See the end of this Medication Guide for a complete list of ingredients in EQUETRO. are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. are taking delaviridine or other medicines called reverse transcriptase inhibitors. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. are taking nefazodone. What should I tell my healthcare provider before taking EQUETRO? Before you take EQUETRO, tell your healthcare provider if you: have or have had suicidal thoughts or actions, depression or mood problems have or ever had heart problems have or ever had blood problems have or ever had liver problems have or ever had kidney problems have or ever had allergic reactions to medicines have or ever had increased pressure in your eye have any other medical conditions drink grapefruit juice or eat grapefruit use birth control. EQUETRO may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and EQUETRO. are pregnant or plan to become pregnant. EQUETRO may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking EQUETRO. You and your healthcare provider will decide if you should take EQUETRO while you are pregnant. ○ If you become pregnant while taking EQUETRO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. are breastfeeding or plan to breastfeed. EQUETRO can pass into breast milk. ○ Talk to your healthcare provider about the best way to feed your baby while you take EQUETRO. Tell your healthcare provider about all the medicines you take , including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking EQUETRO with certain other medicines may cause side effects or affect how well they work. Do not stop or start other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take EQUETRO? Do not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems. Take EQUETRO exactly as prescribed. Your healthcare provider will tell you how much EQUETRO to take. Your healthcare provider may change your dose. Do not change your dose of EQUETRO without talking to your healthcare provider. Swallow EQUETRO capsules whole. Do not crush or chew. ○ If you cannot swallow EQUETRO capsules whole, you may open the EQUETRO capsules and sprinkle the beads over food such as a teaspoon of applesauce and swallow the mixture. Do not crush or chew the beads. Take EQUETRO with or without food. If you take too much EQUETRO, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking EQUETRO? Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking EQUETRO until you talk to your healthcare provider. EQUETRO taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Do not drive, operate heavy machinery, or do other dangerous activities until you know how EQUETRO affects you. EQUETRO can slow your thinking and motor skills. What are the possible side effects of EQUETRO? See “What is the most important information I should know about EQUETRO?” EQUETRO may cause other serious side effects, including: Seizure risk. Stopping EQUTERO suddenly may cause you to have a seizure. The risk of seizures may be higher in people who already have seizures. Do not stop taking EQUETRO without first talking with your healthcare provider. Low level of sodium in your blood (hyponatremia). Symptoms of hyponatremia may include: ○ headache ○ new seizures or an increased number of seizures ○ difficulty concentrating ○ memory problems ○ confusion ○ weakness ○ balance problems Problems with judgment, thinking, and movement. Liver problems. Symptoms of liver problems may include: ○ yellowing of your skin or the whites of your eyes ○ dark urine ○ pain on the right side of your stomach area (abdominal pain) ○ easy bruising ○ loss of appetite ○ nausea or vomiting Get medical help right away if you have any of the symptoms listed above or listed in “What is the most important information I should know about EQUETRO?” The most common side effects of EQUETRO include: dizziness drowsiness nausea vomiting problems with walking and coordination (unsteadiness) constipation itching dry mouth weakness blurred vision problems speaking EQUETRO may cause fertility problems in males. This may affect your ability to father a child while you are taking EQUETRO. Talk to your healthcare provider if this is a concern for you. These are not all the possible side effects of EQUETRO. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 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 . How should I store EQUETRO? Store EQUETRO between 68 0 F to 77 0 F (20 0 C to 25 0 C). Keep EQUETRO capsules out of the light. Keep EQUETRO capsules dry. Keep EQUETRO and all medicines out of the reach of children. General Information about the safe and effective use of EQUETRO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EQUETRO for a condition for which it was not prescribed. Do not give EQUETRO to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about EQUETRO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about EQUETRO that is written for health professionals. For more information, go to www.EQUETRO.com or call 1-866-982-5438. What are the ingredients in EQUETRO? Active ingredient: carbamazepine Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate, and other ingredients. 100mg capsule shell contains: gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink. 200mg capsule shell contains: gelatin-NF, Yellow Iron Oxide, FD&C Blue #2, and Titanium Dioxide, and are imprinted with white ink. 300mg capsule shell contains: gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink. This Medication Guide has been approved by the U. S. Food and Drug Administration. Manufactured for and Distributed by: Validus Pharmaceuticals LLC Parsippany, NJ 07054 info@validuspharma.com http://www.equetro.com 1-866-982-5438 Product of India © 2022 Validus Pharmaceuticals LLC 60080-04 October 2022

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%

8.5 Geriatric Use Clinical studies of EQUETRO did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and 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.

8.4 Pediatric Use Bipolar Disorder and Pain of Trigeminal Neuralgia The safety and effectiveness of EQUETRO have not been established in pediatric patients.

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. Published studies have demonstrated that carbamazepine crosses the placenta. Data Human Data 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). These available data suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. The North American Antiepileptic Drug (NAAED) Pregnancy Registry has reported a rate of major congenital malformations of 3.0% (95% CI: 2.1, 4.2) among pregnant females exposed to carbamazepine monotherapy (n=1,033) during the first trimester with a relative risk of 2.7 (95% CI: 1.0, 7.0) compared to pregnant females not taking an epileptic drug. The European Registry of Antiepileptic Drugs and Pregnancy (EURAP), a large international pregnancy registry focused outside of North America, reported major birth defects in 5.5% (95% CI: 4.5, 6.6) of 1,957 exposures to carbamazepine monotherapy in the first trimester. The UK Epilepsy and Pregnancy Register reported major birth defects in 2.6% (95% CI: 1.9-3.5) of 1,657 exposures to carbamazepine during the first three months of pregnancy. Animal Data In studies in which pregnant rats were administered carbamazepine orally during organogenesis, dose-related increases in the rates of fetal structural abnormalities (craniofacial, skeletal, cardiac, and urogenital defects), intrauterine growth retardation, and embryofetal death occurred at clinically relevant doses.

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. Published studies have demonstrated that carbamazepine crosses the placenta. Data Human Data 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). These available data suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. The North American Antiepileptic Drug (NAAED) Pregnancy Registry has reported a rate of major congenital malformations of 3.0% (95% CI: 2.1, 4.2) among pregnant females exposed to carbamazepine monotherapy (n=1,033) during the first trimester with a relative risk of 2.7 (95% CI: 1.0, 7.0) compared to pregnant females not taking an epileptic drug. The European Registry of Antiepileptic Drugs and Pregnancy (EURAP), a large international pregnancy registry focused outside of North America, reported major birth defects in 5.5% (95% CI: 4.5, 6.6) of 1,957 exposures to carbamazepine monotherapy in the first trimester. The UK Epilepsy and Pregnancy Register reported major birth defects in 2.6% (95% CI: 1.9-3.5) of 1,657 exposures to carbamazepine during the first three months of pregnancy. Animal Data In studies in which pregnant rats were administered carbamazepine orally during organogenesis, dose-related increases in the rates of fetal structural abnormalities (craniofacial, skeletal, cardiac, and urogenital defects), intrauterine growth retardation, and embryofetal death occurred at clinically relevant doses. 8.2 Lactation Carbamazepine and its epoxide metabolite are present in human milk. Most infants with reported exposure to carbamazepine through human milk have not had adverse reactions; however, there are a few reported cases of hepatitis, regurgitations, poor weight gain, and vomiting in breastfed infants of females taking carbamazepine. There are no data on the effects of carbamazepine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EQUETRO and any potential adverse effects on the breastfed child from EQUETRO or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential In females currently on EQUETRO who may become pregnant, assess the risks and benefits of continuing on EQUETRO and discuss with the patient if an alternative treatment should be considered. Dietary folic acid supplementation both prior to conception and during pregnancy should be recommended for patients using carbamazepine [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 )]. Contraception EQUETRO can increase metabolism of certain hormonal contraceptives (through CYP3A4 induction) such as oral and subdermal implant contraceptives, leading to significant 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 Drug Interactions ( 7.2 )] . Infertility Based on human and animal findings, EQUETRO may impair male fertility. Published clinical studies have reported a reduction in semen quality in males of reproductive potential with epilepsy that were treated with carbamazepine [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Bipolar Disorder and Pain of Trigeminal Neuralgia The safety and effectiveness of EQUETRO have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of EQUETRO did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and 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.

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.

16.2 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.

WARNING: SERIOUS DERMATOLOGIC REACTIONS AND APLASTIC ANEMIA AND AGRANULOCYTOSIS S erious Dermatologic Reactions and HLA-B*1502 Allele Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have occurred in patients treat ed with carbamazepine. These syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, but the risk in patients of Asian descent is estimat ed to be about 10 times higher. There is a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. Test fo r HLA-B*1502 , prior to initiating EQUETRO in patients with an increased likelihood of carrying this allele . Avoid use of EQUETRO in patients testing positive for the allele unless the benefit clearly outweighs the risk . Discontinue EQ U ETRO if you suspect that the patient has a serious dermatologic reaction [see Warnings and Precautions ( 5.1 )] . A plastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis can occur during treatment with EQUETRO . The risk of developing these reactions with EQUETRO is 5-8 times greater t han in the general population. However, the overall risk in the general population is low (6 cases in a population of one million per year for agranulocytosis and two cases in a population of one million per year for aplastic anemia ) . O btain a complete blood count before beginning treatment with EQUETRO, and monitor CBC periodicall y . Consider discontinuing EQUETRO if significant bone marrow depression develops [see Warnings and Precautions ( 5.2 ) ] . WARNING: SERIOUS DERMATOLOGIC REACTIONS AND APLASTIC ANEMIA AND AGRANULOCYTOSIS See full prescribing information for complete boxed warning. Serious Dermatologic Reactions • Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have occurred with EQUETRO ( 5.1 ) • Patients of Asian ancestry have a 10-fold greater risk of TEN/SJS, compared to other populations. In genetically at-risk patients, test for the HLA-B*1502 allele prior to initiating EQUETRO ( 2.1 , 5.1 ) • Discontinue EQUETRO if these reactions occur ( 5.1 ) Aplastic Anemia and Agranulocytosis • Aplastic anemia and agranulocytosis occurred with EQUETRO ( 5.2 ) • Obtain complete pretreatment hematological testing. Consider discontinuing EQUETRO if significant bone marrow depression develops ( 2.1 , 5.2 )