Hydroxychloroquine sulfate

Warnings and Precautions, Risks Associated with Use in Porphyria ( 5.5 ) ...............................................................................................................7/2023 Warnings and Precautions, Neuropsychiatric Reactions Including Suicidality ( 5.9 )................................................................................7/2023

1 INDICATIONS AND USAGE Hydroxychloroquine sulfate tablets are 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 ): Hydroxychloroquine sulfate tablets are 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 Hydroxychloroquine sulfate tablets are 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: Hydroxychloroquine sulfate tablets are 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 Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults. 1.3 Systemic Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults. 1.4 Chronic Discoid Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus in adults.

2 DOSAGE AND 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 ≥ 31 kg: 6.5 mg/kg 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 once daily or 400 mg once daily (or in two divided doses) Systemic Lupus Erythematosus in Adults ( 2.4 ): • 200 mg once daily or 400 mg once daily (or in two divided doses) Chronic Discoid Lupus Erythematosus in Adults ( 2.5 ): • 200 mg once daily or 400 mg once daily (or in two divided doses) 2.1 Important Administration Instructions Administer hydroxychloroquine sulfate tablets orally with food or milk. Do not crush or divide the tablets. 2.2 Dosage for Malaria in Adult and Pediatric Patients Hydroxychloroquine sulfate tablets are not recommended in pediatric patients less than 31 kg because the lowest available strength (200 mg) exceeds the recommended dose for these patients and it cannot be divided. 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 ≥ 31kg: 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 ≥ 31 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 8­-aminoquinoline 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 once daily to 400 mg daily, as a single dose or two divided doses. Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with hydroxychloroquine sulfate tablets. 2.4 Dosage for Systemic Lupus Erythematosus in Adults The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses. 2.5 Dosage for Chronic Discoid Lupus Erythematosus in Adults The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses.

3 DOSAGE FORMS AND STRENGTHS 100 mg: Hydroxychloroquine Sulfate Tablets, USP are white to off-white, capsule shaped film-coated tablets debossed with “A1” on one side and plain on the other side. 200 mg: Hydroxychloroquine Sulfate Tablets, USP are white to off-white capsule shaped film-coated tablets debossed with “AC 384” on one side and plain on the other side. 300 mg: Hydroxychloroquine Sulfate Tablets, USP are yellow to pale yellow colored, capsule shaped, film-coated tablets debossed with “A3” on one side and plain on the other side. 400 mg: Hydroxychloroquine Sulfate Tablets, USP are white to off-white, capsule shaped, film-coated tablets debossed with “A4” on one side and plain on the other side. Tablets: 100 mg, 200 mg, 300 mg and 400 mg of hydroxychloroquine sulfate (3)

4 CONTRAINDICATIONS Hydroxychloroquine sulfate tablets are contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds. • Patients with hypersensitivity to 4-aminoquinoline compounds ( 4 )

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 hydroxychloroquine sulfate. 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. () To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Hydroxychloroquine sulfate tablets prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine sulfate tablets are used concomitantly with other arrhythmogenic drugs. Therefore, hydroxychloroquine sulfate tablets are 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 Hydroxychloroquine sulfate tablets 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 Hydroxychloroquine sulfate tablets can lower the seizure threshold. Coadministration of hydroxychloroquine sulfate tablets 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 coadministered with hydroxychloroquine sulfate tablets. 7.5 Methotrexate Concomitant use of hydroxychloroquine sulfate tablets and methotrexate may increase the incidence of adverse reactions. 7.6 Cyclosporine An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate tablets were coadministered. Monitor serum cyclosporine levels closely in patients receiving combined therapy. 7.7 Digoxin Concomitant hydroxychloroquine sulfate tablets 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine sulfate tablets 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 sulfate tablets 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 to 4% and 15 to 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 hydroxychloroquine sulfate tablets 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. 8.2 Lactation Risk Summary Published lactation data report that hydroxychloroquine is present in human milk at low levels. No adverse reactions have been reported in breastfed infants. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine through breastmilk. There is no information on the effect of hydroxychloroquine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for hydroxychloroquine sulfate tablets and any potential adverse effects on the breastfed child from hydroxychloroquine sulfate tablets or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of hydroxychloroquine sulfate tablets have been established in pediatric patients for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. vivax, and P. ovale , as well as for the prophylaxis of malaria in geographic areas where chloroquine resistance …

12.1 Mechanism of Action Malaria Hydroxychloroquine is a 4-aminoquinoline antimalarial [ see Microbiology (12.4) ] and antirheumatic agent. Rheumatoid Arthritis, Systemic Lupus Erythematosus and Chronic Discoid Lupus Erythematosus The mechanisms underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine sulfate tablets in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus are not fully known.

11 DESCRIPTION Hydroxychloroquine sulfate is a white or practically white, crystalline powder, freely soluble in water; practically insoluble in alcohol, chloroform, and in ether. The chemical name for hydroxychloroquine sulfate is 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate (1:1). Its structural formula is The molecular weight of hydroxychloroquine sulfate is 433.95, and molecular formula is C 18 H 26 CIN 3 O•H 2 SO 4 . Hydroxychloroquine Sulfate Tablets, USP contains 100 mg hydroxychloroquine sulfate, equivalent to 77.5 mg base, and are for oral administration. Inactive Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Hydroxychloroquine Sulfate Tablets, USP contain 200 mg hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral administration. Inactive Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Hydroxychloroquine Sulfate Tablets, USP contains 300 mg hydroxychloroquine sulfate, equivalent to 232.5 mg base, and are for oral administration. Inactive Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow iron oxide. Hydroxychloroquine Sulfate Tablets, USP contain 400 mg hydroxychloroquine sulfate, equivalent to 310 mg base, and are for oral administration. Inactive Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Meets USP Dissolution Test 1 Chemical Structure

OVERDOSAGE The 4-aminoquinoline compounds are very rapidly and completely absorbed after ingestion, and in accidental overdosage, or rarely with lower doses in hypersensitive patients, toxic symptoms may occur within 30 minutes. The symptoms of overdosage may include headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia and ventricular fibrillation, followed by sudden potentially fatal respiratory and cardiac arrest. Treatment is symptomatic and must be prompt. Immediate gastric lavage until the stomach is completely emptied is indicated. After lavage, activated charcoal is introduced by the stomach tube within 30 minutes of ingestion of the drug may inhibit further intestinal absorption. To be effective, the dose of activated charcoal should be at least five times the estimated dose of hydroxychloroquine ingested. Consideration should be given to administering diazepam parenterally since studies suggest that it may be beneficial in reversing chloroquine and hydroxychloroquine cardiotoxicity. Respiratory support and shock management should be instituted as necessary. Exchange transfusions are used to reduce the level of 4-aminoquinoline drug in the blood. A patient who survives the acute phase and is asymptomatic should be closely observed for at least six hours. Fluids may be forced and sufficient ammonium chloride (8 g daily in divided doses for adults) may be administered for a few days to acidify the urine. This will promote urinary excretion in cases of both overdosage and sensitivity. However, caution must be exercised in patients with impaired renal function and/or metabolic acidosis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Hydroxychloroquine Sulfate Tablets, USP contain 200 mg of hydroxychloroquine sulfate, USP (equivalent to 155 mg base). White to off-white, capsule-shaped, biconvex, film-coated tablets debossed with "ZC38" on one side and plain on other side, and are supplied as follows: NDC 76420-850-30 in bottles of 30 tablets (repackaged from NDC 16714-110-XX) NDC 76420-850-60 in bottles of 60 tablets (repackaged from NDC 16714-110-XX) NDC 76420-850-90 in bottles of 90 tablets (repackaged from NDC 16714-110-XX) NDC 76420-850-01 in bottles of 100 tablets (relabeled from NDC 16714-110-01) NDC 76420-850-05 in bottles of 500 tablets (relabeled from NDC 16714-110-02) 16.2 Storage Store at 20° to 25°C (68° to 77°F) and allow for excursions between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP/NF. Keep out of the reach of children.

16.1 How Supplied Hydroxychloroquine Sulfate Tablets, USP contain 200 mg of hydroxychloroquine sulfate, USP (equivalent to 155 mg base). White to off-white, capsule-shaped, biconvex, film-coated tablets debossed with "ZC38" on one side and plain on other side, and are supplied as follows: NDC 76420-850-30 in bottles of 30 tablets (repackaged from NDC 16714-110-XX) NDC 76420-850-60 in bottles of 60 tablets (repackaged from NDC 16714-110-XX) NDC 76420-850-90 in bottles of 90 tablets (repackaged from NDC 16714-110-XX) NDC 76420-850-01 in bottles of 100 tablets (relabeled from NDC 16714-110-01) NDC 76420-850-05 in bottles of 500 tablets (relabeled from NDC 16714-110-02)