ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: oCardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions (5.1)] oRetinal Toxicity [see Warnings and Precautions (5.2)] oSerious Skin Reactions [see Warnings and Precautions (5.3)] oWorsening of Psoriasis and Porphyria [see Warnings and Precautions (5.4)] oHematologic Toxicity [see Warnings and Precautions (5.5)] oHemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.6)] oSkeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.7)] oNeuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.8)] oHypoglycemia [see Warnings and Precautions (5.9)] The following adverse reactions have been identified during post-approval use of 4-aminoquinoline drugs, including hydroxychloroquine sulfate tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 bulls 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)-Psychiatric Disorders: Affect/emotional lability, irritability, nervousness, nightmares, psychosis, suicidal ideation, suicidal behavior -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). oCardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions (5.1)] oRetinal Toxicity [see Warnings and Precautions (5.2)] oSerious Skin Reactions [see Warnings and Precautions (5.3)] oWorsening of Psoriasis and Porphyria [see Warnings and Precautions (5.4)] oHematologic Toxicity [see Warnings and Precautions (5.5)] oHemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.6)] oSkeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.7)] oNeuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.8)] oHypoglycemia [see Warnings and Precautions (5.9)] -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 bulls 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). -Psychiatric Disorders: Affect/emotional lability, irritability, nervousness, nightmares, psychosis, suicidal ideation, suicidal behavior -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 Mylan at 1-877-446-3679 (1-877-4-INFO) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Malaria. Hydroxychloroquine is 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. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of hydroxychloroquine have not been fully characterized.. 12.3 Pharmacokinetics Absorption. Following single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy male volunteers, whole blood hydroxychloroquine Cmax was 129.6 ng/mL (plasma Cmax was 50.3 ng/mL) with Tmax of 3.3 hours (plasma Tmax 3.7 hours). Following single oral hydroxychloroquine sulfate tablets dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e., 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Distribution. Hydroxychloroquine sulfate is extensively distributed to tissues.. Elimination. half-life of 123.5 days in plasma were observed following single 200 mg oral hydroxychloroquine sulfate tablets dose to healthy male volunteers. Urine hydroxychloroquine levels were still detectable after months with approximately 10% of the dose excreted as the parent drug. Results following single dose of 200 mg tablet versus i.v. infusion (155 mg), demonstrated half-life of about 40 days and large volume of distribution. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately to hours and the terminal half-life ranged from 40 to 50 days. Metabolism Significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) were found in plasma and blood, with DHCQ being the major metabolite. Excretion Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate tablets for at least months was similar to that in single dose studies in healthy volunteers, suggesting that no change in clearance occurred with chronic dosing. Renal clearance of unchanged drug was approximately 16% to 30%. 12.4Microbiology Mechanism of Action in Malaria. The precise mechanism by which hydroxychloroquine exhibits activity against Plasmodium is not known. Hydroxychloroquine is weak base and may exert its effect by concentrating in the acid vesicles of the parasite and inhibiting polymerization of heme. It can also inhibit certain enzymes by its interaction with DNA. Antimicrobial Activity. Hydroxychloroquine is active against the erythrocytic forms of chloroquine sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale. Drug Resistance. P. falciparum strains exhibiting reduced susceptibility to chloroquine also show reduced susceptibility to hydroxychloroquine. Resistance of Plasmodium parasites to chloroquine is widespread [see Indications and Usage (1.1)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Malaria in Adult and Pediatric Patients (2.2): oProphylaxis: Begin weekly doses weeks prior to travel to the endemic area, continue weekly doses while in the endemic area, and continue the weekly doses for weeks after leaving the endemic area: -Adults: 400 mg once week-Pediatric patients >= 31 kg: 6.5 mg/kg up to 400 mg, once week oTreatment of Uncomplicated Malaria: See Full Prescribing Information (FPI) for complete dosing information.Rheumatoid Arthritis in Adults (2.3): oInitial dosage: 400 mg to 600 mg daily oChronic dosage: 200 mg once daily or 400 mg once daily (or in two divided doses) Systemic Lupus Erythematosus in Adults (2.4): o200 mg once daily or 400 mg once daily (or in two divided doses) Chronic Discoid Lupus Erythematosus in Adults (2.5): o200 mg once daily or 400 mg once daily (or in two divided doses) oProphylaxis: Begin weekly doses weeks prior to travel to the endemic area, continue weekly doses while in the endemic area, and continue the weekly doses for weeks after leaving the endemic area: -Adults: 400 mg once week-Pediatric patients >= 31 kg: 6.5 mg/kg up to 400 mg, once week -Adults: 400 mg once week. -Pediatric patients >= 31 kg: 6.5 mg/kg up to 400 mg, once week oTreatment of Uncomplicated Malaria: See Full Prescribing Information (FPI) for complete dosing information.. oInitial dosage: 400 mg to 600 mg daily oChronic dosage: 200 mg once daily or 400 mg once daily (or in two divided doses) o200 mg once daily or 400 mg once daily (or in two divided doses) o200 mg once daily or 400 mg once daily (or in two divided doses) 2.1Important Administration Instructions Administer hydroxychloroquine sulfate tablets orally with food or milk. Do not crush or divide the tablets.. 2.2Dosage 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 weeks before travel to an endemic area. Advise the patient to take the prophylaxis dosage once week, staring 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 weeks after leaving the endemic area. The recommended prophylaxis dosage is:oAdult patients: 400 mg once week oPediatric patients >= 31kg: 6.5 mg/kg actual body weight (up to 400 mg) once week oAdult patients: 400 mg once week oPediatric patients >= 31kg: 6.5 mg/kg actual body weight (up to 400 mg) once week Treatment of Uncomplicated Malaria. The dosages for the treatment of uncomplicated malaria are: oAdult patients: Administer 800 mg initially; subsequently administer 400 mg at hours, 24 hours, and 48 hours after the initial dose (total dosage 2000 mg). oPediatric patients >= 31 kg: Administer 13 mg/kg (up to 800 mg) initially; subsequently administer 6.5 mg/kg (up to 400 mg) at hours, 24 hours, and 48 hours after the initial dose (total dosage 31 mg/kg -up to 2000 mg). For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary [see Microbiology (12.4)].. oAdult patients: Administer 800 mg initially; subsequently administer 400 mg at hours, 24 hours, and 48 hours after the initial dose (total dosage 2000 mg). oPediatric patients >= 31 kg: Administer 13 mg/kg (up to 800 mg) initially; subsequently administer 6.5 mg/kg (up to 400 mg) at hours, 24 hours, and 48 hours after the initial dose (total dosage 31 mg/kg -up to 2000 mg). 2.3Dosage for Rheumatoid Arthritis in Adults The recommended dosage is: oInitial dosage: 400 mg to 600 mg daily as 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 mg/kg (actual weight) of hydroxychloroquine sulfate increase the incidence of retinopathy [see Warnings and Precautions (5.2)].oChronic dosage: 200 mg once daily to 400 mg daily, as single dose or two divided doses. Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with hydroxychloroquine sulfate tablets. oInitial dosage: 400 mg to 600 mg daily as 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 mg/kg (actual weight) of hydroxychloroquine sulfate increase the incidence of retinopathy [see Warnings and Precautions (5.2)].. oChronic dosage: 200 mg once daily to 400 mg daily, as single dose or two divided doses. 2.4Dosage 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. 2.5Dosage 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oDrugs Prolonging QT Interval and Other Arrhythmogenic Drugs. (7.1) oSee FPI for more important drug interactions. (7) oDrugs Prolonging QT Interval and Other Arrhythmogenic Drugs. (7.1) oSee FPI for more important drug interactions. (7) 7.1Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs Hydroxychloroquine sulfate tablets prolong the QT interval. There may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine hydroxychloroquine 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) ]. 7.2Insulin or Other Antidiabetic Drugs Hydroxychloroquine sulfate tablets may enhance the effects of insulin and antidiabetic drugs, and consequently increase the hypoglycemic risk. Therefore, decrease in dosage of insulin and other antidiabetic drugs may be necessary [see Warnings and Precautions (5.8)]. 7.3Drugs that Lower the Seizure Threshold Hydroxychloroquine sulfate tablets can lower the seizure threshold. Co-administration of hydroxychloroquine sulfate tablets with other antimalarials known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures.. 7.4Antiepileptics The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine sulfate tablets. 7.5Methotrexate Concomitant use of hydroxychloroquine sulfate tablets and methotrexate may increase the incidence of adverse reactions. 7.6Cyclosporine An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate tablets were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy. 7.7Digoxin Concomitant hydroxychloroquine sulfate tablets and digoxin therapy may result in increased serum digoxin levels. Monitor serum digoxin levels closely in patients receiving combined therapy.. 7.8Cimetidine Concomitant use of cimetidine resulted in 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. 7.9Rifampicin Lack of efficacy of hydroxychloroquine was reported when rifampicin was concomitantly administered. Avoid concomitant use of rifampicin. 7.10Praziquantel Chloroquine has been reported to reduce the bioavailability of praziquantel. Interaction of praziquantel with hydroxychloroquine cannot be ruled out. 7.11Antacids and Kaolin Antacids and kaolin can reduce absorption of chloroquine; an interval of at least hours between intake of these agents and chloroquine should be observed. Interaction of antacids and kaolin with hydroxychloroquine cannot be ruled out. 7.12Ampicillin In study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Interaction of ampicillin with hydroxychloroquine cannot be ruled out.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Hydroxychloroquine sulfate tablets are an antimalarial and antirheumatic indicated for the: oTreatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax in adult and pediatric patients. (1.1) oProphylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. (1.1) oTreatment of rheumatoid arthritis in adults. (1.2) oTreatment of systemic lupus erythematosus in adults. (1.3) oTreatment of chronic discoid lupus erythematosus in adults. (1.4) Limitations of Use (1.1): Hydroxychloroquine sulfate tablets are not recommended for the: oTreatment of complicated malaria. oTreatment of chloroquine or hydroxychloroquine-resistant strains of Plasmodium species. oTreatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. oProphylaxis of malaria in geographic areas where chloroquine resistance occurs. oPrevention 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. oTreatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax in adult and pediatric patients. (1.1) oProphylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. (1.1) oTreatment of rheumatoid arthritis in adults. (1.2) oTreatment of systemic lupus erythematosus in adults. (1.3) oTreatment of chronic discoid lupus erythematosus in adults. (1.4) oTreatment of complicated malaria. oTreatment of chloroquine or hydroxychloroquine-resistant strains of Plasmodium species. oTreatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. oProphylaxis of malaria in geographic areas where chloroquine resistance occurs. oPrevention 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. 1.1Malaria Hydroxychloroquine sulfate tablets are indicated in adult and pediatric patients for the: oTreatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale. oProphylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use:Hydroxychloroquine sulfate tablets are not recommended for: oTreatment of complicated malaria. oTreatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4)].oTreatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. oProphylaxis of malaria in geographic areas where chloroquine resistance occurs. oPrevention 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.. oTreatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale. oProphylaxis of malaria in geographic areas where chloroquine resistance is not reported. oTreatment of complicated malaria. oTreatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4)].. oTreatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. oProphylaxis of malaria in geographic areas where chloroquine resistance occurs. oPrevention 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)].. 1.2Rheumatoid Arthritis Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults. 1.3Systemic Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults. 1.4Chronic Discoid Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus in adults.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Important Administration Instructions: Advise the patient to take hydroxychloroquine sulfate tablets with food or milk and not to crush or divide the tablet. Cardiomyopathy and Ventricular Arrhythmias: Inform the patient that serious cardiac effects, life-threatening and fatal cases have been reported with use of hydroxychloroquine sulfate tablets Advise patients to seek medical attention immediately if they experience any symptoms of heart rhythm changes including fast or irregular heartbeat, lightheadedness, dizziness, or syncope [see Warnings and Precautions (5.1)]. Retinal Toxicity: Inform the patient that irreversible retinal damage has been observed in some patients with the use of hydroxychloroquine sulfate tablets. Advise patients of the importance of the ophthalmology visits for monitoring their eyes. Instruct patients to seek medical attention promptly if they experience decreased vision or decreased dark adaptation [see Warnings and Precautions (5.2)]. Serious Skin Reactions: Inform the patient that severe, life-threatening skin reactions have been reported with the use of hydroxychloroquine sulfate tablets. Advise the patient to seek medical attention immediately if experiencing any of the following signs and symptoms: blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever [see Warnings and Precautions (5.3)]. Skeletal Muscle Myopathy or Neuropathy: Inform the patient that muscle weakness and atrophy has been reported with hydroxychloroquine sulfate tablets use Advise patients to report to the physician symptoms of muscle weakness [see Warnings and Precautions (5.7)]. Neuropsychiatric Reactions Including Suicidality: Alert patients to seek medical attention immediately if they experience new or worsening depression, suicidal thoughts, or other mood changes [see Warnings and Precautions (5.8)]. Hypoglycemia: Inform the patient that hydroxychloroquine sulfate tablets have been associated with severe hypoglycemia. Advise the patient to monitor blood sugar levels if possible and to seek medical attention if experiencing any of the signs and symptoms of hypoglycemia such as sweating, shakiness, weakness, dizziness, tachycardia, nausea, blurred vision, confusion, fainting, or loss of consciousness [see Warnings and Precautions (5.9)].Pregnancy: Inform the patient that there is pregnancy registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine sulfate tablets during pregnancy. Encourage patients to register by contacting 1-877-311-8972 [see Use in Specific Populations (8.1)]. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 1/2022HXCQ:RX2.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption. Following single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy male volunteers, whole blood hydroxychloroquine Cmax was 129.6 ng/mL (plasma Cmax was 50.3 ng/mL) with Tmax of 3.3 hours (plasma Tmax 3.7 hours). Following single oral hydroxychloroquine sulfate tablets dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e., 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Distribution. Hydroxychloroquine sulfate is extensively distributed to tissues.. Elimination. half-life of 123.5 days in plasma were observed following single 200 mg oral hydroxychloroquine sulfate tablets dose to healthy male volunteers. Urine hydroxychloroquine levels were still detectable after months with approximately 10% of the dose excreted as the parent drug. Results following single dose of 200 mg tablet versus i.v. infusion (155 mg), demonstrated half-life of about 40 days and large volume of distribution. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately to hours and the terminal half-life ranged from 40 to 50 days. Metabolism Significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) were found in plasma and blood, with DHCQ being the major metabolite. Excretion Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate tablets for at least months was similar to that in single dose studies in healthy volunteers, suggesting that no change in clearance occurred with chronic dosing. Renal clearance of unchanged drug was approximately 16% to 30%.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure Registry. There is 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 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 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 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.

SPL UNCLASSIFIED SECTION.

1.1Malaria Hydroxychloroquine sulfate tablets are indicated in adult and pediatric patients for the: oTreatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale. oProphylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use:Hydroxychloroquine sulfate tablets are not recommended for: oTreatment of complicated malaria. oTreatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4)].oTreatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. oProphylaxis of malaria in geographic areas where chloroquine resistance occurs. oPrevention 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.. oTreatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale. oProphylaxis of malaria in geographic areas where chloroquine resistance is not reported. oTreatment of complicated malaria. oTreatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4)].. oTreatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. oProphylaxis of malaria in geographic areas where chloroquine resistance occurs. oPrevention 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)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry. There is 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 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 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 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 mothers 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 is not reported. However, this product cannot be directly administered to pediatric patients weighing less than 31 kg because the film-coated tablets cannot be crushed or divided [see Dosage and Administration (2.1, 2.2)]. The safety and effectiveness of hydroxychloroquine sulfate tablets have not been established in pediatric patients for the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus, or systemic lupus erythematosus.. 8.5 Geriatric Use Clinical trials of hydroxychloroquine sulfate tablets did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. Nevertheless, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. In general, dose selection in geriatric patients should start with the lowest recommended dose, taking into consideration the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. 8.6Patients with Renal or Hepatic Disease A reduction in the dosage of hydroxychloroquine sulfate tablets may be necessary in patients with hepatic or renal disease.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oCardiomyopathy and Ventricular Arrhythmias: Fatal or life-threatening cardiomyopathy and ventricular arrhythmias were reported. (5.1) oRetinal Toxicity: Irreversible retinal damage is related to cumulative dosage and treatment duration. Baseline retinal exam and exams during treatment are recommended. (5.2) oSerious Skin Reactions: Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis have been reported. (5.3) oWorsening of Psoriasis and Porphyria: Avoid in patients with psoriasis or porphyria. (5.4) oHematologic Toxicity: Discontinue if myelosuppression occurs. (5.5) oCardiomyopathy and Ventricular Arrhythmias: Fatal or life-threatening cardiomyopathy and ventricular arrhythmias were reported. (5.1) oRetinal Toxicity: Irreversible retinal damage is related to cumulative dosage and treatment duration. Baseline retinal exam and exams during treatment are recommended. (5.2) oSerious Skin Reactions: Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis have been reported. (5.3) oWorsening of Psoriasis and Porphyria: Avoid in patients with psoriasis or porphyria. (5.4) oHematologic Toxicity: Discontinue if myelosuppression occurs. (5.5) 5.1Cardiomyopathy and Ventricular Arrhythmias Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine sulfate tablets. Signs and symptoms of cardiac compromise have occurred during acute and chronic hydroxychloroquine sulfate tablets treatment. 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. Hydroxychloroquine sulfate tablets have potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in hydroxychloroquine sulfate tablets-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 hydroxychloroquine sulfate tablets administration in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as:oCardiac disease, e.g., heart failure, myocardial infarction. oProarrhythmic conditions, e.g., bradycardia (< 50 bpm). oHistory of ventricular dysrhythmias. oUncorrected hypokalemia and/or hypomagnesemia. oConcomitant administration with QT interval prolonging agents [see Drug Interactions (7.1)] as this may lead to an increased risk for ventricular arrhythmias. Therefore, hydroxychloroquine sulfate tablets are not recommended in patients taking other drugs that have the potential to prolong the QT interval. Monitor cardiac function as clinically indicated during hydroxychloroquine sulfate tablets therapy. Correct electrolyte imbalances prior to use. Discontinue hydroxychloroquine sulfate tablets if cardiotoxicity is suspected.. oCardiac disease, e.g., heart failure, myocardial infarction. oProarrhythmic conditions, e.g., bradycardia (< 50 bpm). oHistory of ventricular dysrhythmias. oUncorrected hypokalemia and/or hypomagnesemia. oConcomitant administration with QT interval prolonging agents [see Drug Interactions (7.1)] as this may lead to an increased risk for ventricular arrhythmias. 5.2Retinal 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 >= 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 hydroxychloroquine sulfate tablets, 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 hydroxychloroquine sulfate tablets and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy. 5.3Serious Skin Reactions Serious adverse reactions have been reported with the use of hydroxychloroquine sulfate tablets 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 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), Adverse Reactions (6)]. Discontinue hydroxychloroquine sulfate tablets if these severe reactions occur.. 5.4Worsening of Psoriasis and Porphyria Administration of hydroxychloroquine sulfate tablets in patients with psoriasis may precipitate severe flare-up of psoriasis. Administration of hydroxychloroquine sulfate tablets in patients with porphyria may exacerbate porphyria. Avoid hydroxychloroquine sulfate tablets in patients with psoriasis or porphyria, unless the benefit to the patient outweighs the possible risk. 5.5Hematologic Toxicity Hydroxychloroquine sulfate tablets may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged hydroxychloroquine sulfate tablets therapy. If the patient develops myelosuppression which cannot be attributable to the disease, discontinue the drug. 5.6Hemolytic 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.. 5.7Skeletal 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 demonstrated bodies and muscle fiber atrophy with vacuolar changes. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine sulfate tablets. If weakness occurs, discontinue the drug. 5.8Neuropsychiatric Reactions Including Suicidality Suicidal behavior has been reported in patients treated with hydroxychloroquine sulfate tablets [see Adverse Reactions (6)]. Alert patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or mood changes. The risk and benefit of continued treatment with hydroxychloroquine sulfate tablets should be assessed for patients who develop these symptoms. 5.9Hypoglycemia Hydroxychloroquine sulfate tablets 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 hydroxychloroquine sulfate tablets-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.