SOVUNA

1 INDICATIONS & USAGE SOVUNA is an antimalarial and antirheumatic indicated for the: Treatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax in adult and pediatric patients. (1.1) Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. (1.1) Treatment of rheumatoid arthritis in adults. (1.2) Treatment of systemic lupus erythematosus in adults. (1.3) Treatment of chronic discoid lupus erythematosus in adults. (1.4) Limitations of Use (1.1): SOVUNA is not recommended for the: Treatment of complicated malaria. Treatment of chloroquine or hydroxychloroquine-resistant strains of Plasmodium species. Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. Prophylaxis of malaria in geographic areas where chloroquine resistance occurs. Prevention of relapses of P. vivax or P. ovale because it is not active against the hypnozoite liver stage forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary. 1.1 Malaria SOVUNA is indicated in adult and pediatric patients for the: Treatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale. Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use: SOVUNA is not recommended for: Treatment of complicated malaria. Treatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4)]. Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. Prophylaxis of malaria in geographic areas where chloroquine resistance occurs. Prevention of relapses of P. vivax or P. ovale because it is not active against the hypnozoite liver stage forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary [see Microbiology (12.4)]. For the most current information about drug resistance, refer to the latest recommendations from the Center for Disease Control and Prevention. 1 1.2 Rheumatoid Arthritis SOVUNA is indicated for the treatment of acute and chronic rheumatoid arthritis in adults. 1.3 Systemic Lupus Erythematosus SOVUNA is indicated for the treatment of systemic lupus erythematosus in adults. 1.4 Chronic Discoid Lupus Erythematosus SOVUNA is indicated for the treatment of chronic discoid lupus erythematosus in adults.

2 DOSAGE & ADMINISTRATION Malaria in Adult and Pediatric Patients (2.2): Prophylaxis: Begin weekly doses 2 weeks prior to travel to the endemic area, continue weekly doses while in the endemic area, and continue the weekly doses for 4 weeks after leaving the endemic area: Adults: 400 mg once a week Pediatric patients weighing greater than or equal to 23 kg: 6.5 mg/kg actual body weight up to 400 mg, once a week Treatment of Uncomplicated Malaria: See Full Prescribing Information (FPI) for complete dosing information. Rheumatoid Arthritis in Adults (2.3): Initial dosage: 400 mg to 600 mg daily Chronic dosage: 200 mg, 300 mg or 400 mg once daily (or in two divided doses) Systemic Lupus Erythematosus in Adults (2.4): 200 mg, 300 mg or 400 mg once daily (or in two divided doses) Chronic Discoid Lupus Erythematosus in Adults (2.5): 200 mg or 400 mg once daily (or in two divided doses) 2.1 Important Administration Instructions Administer SOVUNA orally with food or milk. Do not crush the tablets. 2.2 Dosage for Malaria in Adult and Pediatric Patients SOVUNA is not recommended in pediatric patients less than 23 kg because the lowest possible dose of 150 mg (half of the scored 300 mg tablet) exceeds the recommended dose for these patients. Prophylaxis Treatment must start 2 weeks before travel to an endemic area. Advise the patient to take the prophylaxis dosage once a week, staring 2 weeks prior to travel to the endemic area, on the same day every week, continuing the same weekly dose while in the endemic area, and for 4 weeks after leaving the endemic area. The recommended prophylaxis dosage is: Adult patients: 400 mg once a week Pediatric patients weighing greater than or equal to 23 kg: 6.5 mg/kg actual body weight (up to 400 mg) once a week Treatment of Uncomplicated Malaria The dosages for the treatment of uncomplicated malaria are: Adult patients: Administer 800 mg initially; subsequently administer 400 mg at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 2,000 mg). Pediatric patients weighing greater than or equal to 23 kg: Administer 13 mg/kg (up to 800 mg) initially; subsequently administer 6.5 mg/kg (up to 400 mg) at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 31 mg/kg - up to 2,000 mg). For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8­aminoquinoline drug is necessary [see Microbiology (12.4)]. 2.3 Dosage for Rheumatoid Arthritis in Adults The recommended dosage is: Initial dosage: 400 mg to 600 mg daily as a single daily dose or two divided doses. The action of hydroxychloroquine is cumulative and may require weeks to months for maximum therapeutic effect. Daily doses exceeding 5 mg/kg (actual weight) of hydroxychloroquine sulfate increase the incidence of retinopathy [see Warnings and Precautions (5.2)]. Chronic dosage: 200 mg, 300 mg or 400 mg daily, as a single dose or two divided doses. Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with SOVUNA. 2.4 Dosage for Systemic Lupus Erythematosus in Adults The recommended dosage is 200 mg, 300 mg or 400 mg daily, as a single dose or two divided doses 2.5 Dosage for Chronic Discoid Lupus Erythematosus in Adults The recommended dosage is 200 mg or 400 mg daily, as a single dose or two divided doses.

4 CONTRAINDICATIONS SOVUNA is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds. Patients with hypersensitivity to 4-aminoquinoline compounds (4)

5 WARNINGS AND PRECAUTIONS Cardiomyopathy and Ventricular Arrhythmias : Fatal or life-threatening cardiomyopathy and ventricular arrhythmias were reported. (5.1) Retinal Toxicity : Irreversible retinal damage is related to cumulative dosage and treatment duration. Baseline retinal exam and exams during treatment are recommended. (5.2) Serious Skin Reactions: Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis have been reported. (5.3) Worsening of Psoriasis: Avoid in patients with psoriasis. (5.4) Risks Associated with Use in Porphyria: Avoid in patients with porphyria. Hepatotoxicity was reported in patients with porphyria cutanea tarda (5.5) Hematologic Toxicity : Discontinue if myelosuppression occurs. (5.6) Renal Toxicity: Consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders. Discontinue SOVUNA if renal toxicity is suspected or demonstrated by tissue biopsy in any organ system. (5.1, 5.8, 5.11) 5.1 Cardiomyopathy and Ventricular Arrhythmias Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with SOVUNA. Signs and symptoms of cardiac compromise have occurred during acute and chronic SOVUNA treatment. In multiple cases, endomyocardial biopsy showed association of the cardiomyopathy with phospholipidosis in the absence of inflammation, infiltration, or necrosis. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.8, 5.11)]. Patients may present with ventricular hypertrophy, pulmonary hypertension and conduction disorders including sick sinus syndrome. ECG findings include atrioventricular, right or left bundle branch block. SOVUNA has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in SOVUNA-treated patients. The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded [see Adverse Reactions (6) , Overdosage (10)]. Avoid SOVUNA administration in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as: Cardiac disease, e.g., heart failure, myocardial infarction. Proarrhythmic conditions, e.g., bradycardia (< 50 bpm). History of ventricular dysrhythmias. Uncorrected hypokalemia and/or hypomagnesemia. Concomitant administration with QT interval prolonging agents as this may lead to an increased risk for ventricular arrhythmias [see Drug Interactions (7.1)]. Therefore, SOVUNA is not recommended in patients taking other drugs that have the potential to prolong the QT interval. Correct electrolyte imbalances prior to use. Monitor cardiac function as clinically indicated during SOVUNA therapy. Discontinue SOVUNA if cardiotoxicity is suspected or demonstrated by tissue biopsy. 5.2 Retinal Toxicity Irreversible retinal damage was observed in some patients treated with hydroxychloroquine sulfate and it is related to cumulative dosage and treatment duration. In patients of Asian descent, retinal toxicity may first be noticed outside the macula. Risk factors for retinal damage include daily hydroxychloroquine sulfate dosages ≥5 mg/kg of actual body weight, durations of use greater than five years, renal impairment, use of concomitant drug products such as tamoxifen citrate, and concurrent macular disease. Within the first year of starting SOVUNA, a baseline ocular examination is recommended including best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT). For patients at higher risk of retinal damage, monitoring should include annual examinations which include BCVA, VF and SD-OCT. For patients without significant risk factors, annual retinal exams can usually be deferred until five years of treatment. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees. If ocular toxicity is suspected, discontinue SOVUNA and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy. 5.3 Serious Skin Reactions Serious adverse reactions have been reported with the use of SOVUNA including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP). Monitor for serious skin reactions, especially in patients receiving a drug that may also induce dermatitis. Advise patients to seek medical attention promptly if they experience signs and symptoms of serious skin reactions such as blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever [see Warnings and Precautions (5.4,5.5), Adverse Reactions (6)]. Discontinue SOVUNA if these severe reactions occur. 5.4 Worsening of Psoriasis Administration of SOVUNA to patients with psoriasis may precipitate a severe flare-up of psoriasis. Avoid SOVUNA in patients with psoriasis, unless the benefit to the patient outweighs the possible risk. 5.5 Risks Associated with Use in Porphyria Administration of SOVUNA to patients with porphyria may exacerbate porphyria. Avoid SOVUNA in patients with porphyria. Hepatotoxicity Associated with Porphyria Cutanea Tarda Cases of hepatotoxicity have been reported when hydroxychloroquine was used in patients with porphyria cutanea tarda (PCT). Patients received dosages ranging from 200 mg twice weekly to 400 mg daily. Most of the PCT-related cases presented with marked elevations in transaminases (>20 times upper limit of the reference range) within days to a month of hydroxychloroquine initiation. In some cases, PCT was diagnosed only after the occurrence of treatment-induced liver injury, when hydroxychloroquine was prescribed for an approved indication. Some of the cases were associated with other risk factors for hepatic injury (e.g., alcohol use, concomitant hepatotoxic medications). Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, rash, nausea, dark urine, or jaundice. In this clinical context, if the patient is found to have abnormal serum liver tests (e.g., ALT level greater than three times the upper limit of the reference range, total bilirubin greater than two times the upper limit of the reference range), interrupt treatment with SOVUNA, and investigate further to establish the probable cause. The safety and effectiveness of SOVUNA for the treatment of PCT have not been established and SOVUNA is not approved for this use. 5.6 Hematologic Toxicity SOVUNA may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged SOVUNA therapy. If the patient develops myelosuppression which cannot be attributable to the disease, discontinue the drug. 5.7 Hemolytic Anemia Associated with G6PD Deficiency Hemolysis has been reported in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor for hemolytic anemia as this can occur, particularly in association with other drugs that cause hemolysis. 5.8 Skeletal Muscle Myopathy or Neuropathy Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction, have been reported. Muscle and nerve biopsies have shown associated phospholipidosis. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.11)]. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with SOVUNA. Discontinue SOVUNA if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy. 5.9 Neuropsychiatric Reactions Including Suicidality Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse reactions have been reported in patients treated with SOVUNA [see Adverse Reactions (6)]. Neuropsychiatric adverse reactions typically occurred within the first month after the start of treatment with hydroxychloroquine and have been reported in patients with and without a prior history of psychiatric disorders. The risks and benefits of continued treatment with SOVUNA should be assessed for patients who develop these symptoms. Given the long half-life of the drug, some patients may require several weeks off drug for symptoms to partially or fully abate. Advise patients to contact their healthcare provider promptly if they experience new or worsening neuropsychiatric symptoms such as depression, suicidal thoughts or behavior, or mood changes. 5.10 Hypoglycemia SOVUNA can cause severe and potentially life-threatening hypoglycemia, in the presence or absence of antidiabetic agents [see Drug Interactions (7)]. Measure blood glucose in patients presenting with clinical symptoms suggestive of hypoglycemia and as adjust the antidiabetic treatment as necessary. Warn SOVUNA-treated patients about the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia; diabetic patients should monitor their blood sugar levels. Advise patients to seek medical attention if they develop any signs and symptoms of hypoglycemia. 5.11 Renal Toxicity Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of SOVUNA. Renal biopsy showed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Physicians should consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders who are receiving SOVUNA. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.8)] . Discontinue SOVUNA if renal toxicity is suspected or demonstrated by tissue biopsy.

7 DRUG INTERACTIONS Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. (7.1) See FPI for more important drug interactions. (7) 7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs SOVUNA prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if SOVUNA is used concomitantly with other arrhythmogenic drugs. Therefore, SOVUNA is not recommended in patients taking other drugs that have the potential to prolong the QT interval or are arrhythmogenic [see Warnings and Precautions (5.1)]. 7.2 Insulin or Other Antidiabetic Drugs SOVUNA may enhance the effects of insulin and antidiabetic drugs, and consequently increase the hypoglycemic risk. Therefore, a decrease in dosage of insulin and other antidiabetic drugs may be necessary [see Warnings and Precautions (5.10 ) ] . 7.3 Drugs that Lower the Seizure Threshold SOVUNA can lower the seizure threshold. Co-administration of SOVUNA with other antimalarials known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures. 7.4 Antiepileptics The activity of antiepileptic drugs might be impaired if co-administered with SOVUNA. 7.5 Methotrexate Concomitant use of SOVUNA and methotrexate may increase the incidence of adverse reactions. 7.6 Cyclosporine An increased plasma cyclosporin level was reported when cyclosporin and SOVUNA were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy. 7.7 Digoxin Concomitant SOVUNA and digoxin therapy may result in increased serum digoxin levels. Monitor serum digoxin levels closely in patients receiving combined therapy. 7.8 Cimetidine Concomitant use of cimetidine resulted in a 2-fold increase of exposure of chloroquine, which is structurally related to hydroxychloroquine. Interaction of cimetidine with hydroxychloroquine cannot be ruled out. Avoid concomitant use of cimetidine. 7.9 Rifampicin Lack of efficacy of hydroxychloroquine was reported when rifampicin was concomitantly administered. Avoid concomitant use of rifampicin. 7.10 Praziquantel Chloroquine has been reported to reduce the bioavailability of praziquantel. Interaction of praziquantel with hydroxychloroquine cannot be ruled out. 7.11 Antacids and kaolin Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed. Interaction of antacids and kaolin with hydroxychloroquine cannot be ruled out. 7.12 Ampicillin In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Interaction of ampicillin with hydroxychloroquine cannot be ruled out.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Cardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions (5.1)] Retinal Toxicity [see Warnings and Precautions (5.2)] Serious Skin Reactions [see Warnings and Precautions (5.3)] Worsening of Psoriasis [see Warnings and Precautions (5.4)] Risks Associated with Use in Porphyria [see Warnings and Precautions (5.5)] Hematologic Toxicity [see Warnings and Precautions (5.6)] Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.7)] Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.8)] Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.9)] Hypoglycemia [see Warnings and Precautions (5.10)] Renal Toxicity [see Warnings and Precautions (5.11)] The following adverse reactions have been identified during post-approval use of 4­ aminoquinoline drugs, including SOVUNA. 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: Blood and lymphatic system disorders : Bone marrow depression, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia Cardiac disorders: Cardiomyopathy, cardiac failure, QT-interval prolongation, ventricular tachycardia, torsades de pointes, atrioventricular block, bundle branch block, sick sinus syndrome, pulmonary hypertension Ear and labyrinth disorders : Vertigo, tinnitus, nystagmus, sensorineural hearing loss Eye disorders: Retinopathy, retinal pigmentation changes (typically bull’s eye appearance), visual field defects (paracentral scotomas), macular degeneration, corneal edema, corneal opacities, decreased dark adaptation Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain General disorders : Fatigue Hepatobiliary disorders : Abnormal liver function tests, fulminant hepatic failure Immune system disorders : Urticaria, angioedema, bronchospasm Metabolism and nutrition disorders : Anorexia, hypoglycemia, weight loss Musculoskeletal and connective tissue disorders: Proximal myopathy, depressed tendon reflexes, abnormal nerve conduction Nervous system disorders: Ataxia, dizziness, headache, seizure, extrapyramidal disorders (dystonia, dyskinesia, tremor) Neuropsychiatric disorders: Affect/emotional lability, irritability, nervousness, psychosis, suicidal ideation, suicidal behavior, depression, hallucinations, anxiety, agitation, confusion, delusions, paranoia, mania and sleep disorders (insomnia, night terrors, nightmares) Skin and subcutaneous tissue disorders: Alopecia, hair color changes, rash, pruritus, photosensitivity, psoriasis exacerbation, hyperpigmentation, exfoliative dermatitis, erythema multiforme, acute generalized exanthematous pustulosis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) The most common adverse reactions reported are: nausea, vomiting, diarrhea, and abdominal pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SOVUNA during pregnancy. Encourage patients to register by contacting 1-877-311-8972. Risk Summary Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal, or fetal outcomes (see Data) . There are risks to the mother and fetus associated with untreated or increased disease activity from malaria, rheumatoid arthritis, and systemic lupus erythematosus in pregnancy (see Clinical Considerations). Animal reproduction studies were not conducted with hydroxychloroquine. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Malaria : Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Rheumatoid Arthritis: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Systemic Lupus Erythematosus : Pregnant women with systemic lupus erythematosus, especially those with increased disease activity, are at increased risk of adverse pregnancy outcomes, including spontaneous abortion, fetal death, preeclampsia, preterm birth, and intrauterine growth restriction. Passage of maternal auto-antibodies across the placenta may result in neonatal illness, including neonatal lupus and congenital heart block. Data Human Data Data from published epidemiologic and clinical studies have not established an association with SOVUNA use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Hydroxychloroquine readily crosses the placenta with cord blood levels corresponding to maternal plasma levels. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine in utero . Available epidemiologic and clinical studies have methodological limitations including small sample size and study design.