NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with hydroxychloroquine. No animal studies have been performed to evaluate the potential effects of hydroxychloroquine on reproduction or development, or to determine potential effects on fertility in males or females.

DESCRIPTION SECTION.

11 DESCRIPTION. Hydroxychloroquine sulfate, USP is an antimalarial and antirheumatic drug, chemically described as (+-)-2-[[4-[(7-Chloro-4- quinolyl) amino]pentyl] ethylamino] ethanol sulfate (1:1) (salt). Its structural formula is:C18H26ClN3OoH2SO4 Molecular Weight: 433.95Hydroxychloroquine sulfate, USP is white to almost white, crystalline powder, freely soluble in water; practically insoluble in alcohol, chloroform, and ether.Hydroxychloroquine sulfate tablets, USP for oral administration contain 200 mg hydroxychloroquine sulfate, USP (equivalent to 155 mg of hydroxychloroquine) and the following inactive ingredients: dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polydextrose, polyethylene glycol, starch 1500 partially pregelatinized maize starch, titanium dioxide, and triacetin. 2.

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

12.1 Mechanismof Action. MalariaHydroxychloroquine 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.

ADVERSE REACTIONS SECTION.

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 and Porphyria [see Warnings and Precautions (5.4)] Hematologic Toxicity [see Warnings and Precautions (5.5)] Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.6)] Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.7)] Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.8)] Hypoglycemia [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). 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 and Porphyria [see Warnings and Precautions (5.4)] Hematologic Toxicity [see Warnings and Precautions (5.5)] Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.6)] Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.7)] Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.8)] Hypoglycemia [see Warnings and Precautions (5.9)] The most common adverse reactions reported are: nausea, vomiting, diarrhea, and abdominal pain. (6)To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with hydroxychloroquine. No animal studies have been performed to evaluate the potential effects of hydroxychloroquine on reproduction or development, or to determine potential effects on fertility in males or females.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanismof Action. MalariaHydroxychloroquine 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. AbsorptionFollowing single 200 mg oral dose of hydroxychloroquine sulfate tablet 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 tablet 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. DistributionHydroxychloroquine sulfate is extensively distributed to tissues.EliminationA half-life of 123.5 days in plasma were observed following single 200 mg oral hydroxychloroquine sulfate tablet 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.MetabolismSignificant 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%. 12.4 Microbiology. Mechanism of Action in MalariaThe 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 ActivityHydroxychloroquine 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 ResistanceP. 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)].

CONTRAINDICATIONS SECTION.

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

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Malaria in Adult and Pediatric Patients (2.2):Prophylaxis: 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 weekTreatment 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 dailyChronic 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). Prophylaxis: 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. Treatment of Uncomplicated Malaria: See Full Prescribing Information (FPI) for complete dosing information.. Initial dosage: 400 mg to 600 mg daily. Chronic dosage: 200 mg once daily or 400 mg once daily (or in two divided doses). 200 mg once daily or 400 mg once daily (or in two divided doses). 200 mg once daily or 400 mg once daily (or in two divided doses). 2.1 ImportantAdministration Instructions. Administer hydroxychloroquine sulfate tablets orally with food or milk. Do not crush or divide the tablets. 2.2 Dosage forMalaria 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.ProphylaxisTreatment 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:Adult patients: 400 mg once weekPediatric patients >= 31kg: 6.5 mg/kg actual body weight (up to 400 mg) once weekTreatment of Uncomplicated MalariaThe dosages for the treatment of uncomplicated malaria are: Adult patients: Administer 800 mg initially; subsequently administer 400 mg at hours, 24 hours, and 48 hours after the initial dose (total dosage 2000 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 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)]. Adult patients: 400 mg once week. Pediatric patients >= 31kg: 6.5 mg/kg actual body weight (up to 400 mg) once week. Adult patients: Administer 800 mg initially; subsequently administer 400 mg at hours, 24 hours, and 48 hours after the initial dose (total dosage 2000 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 hours, 24 hours, and 48 hours after the initial dose (total dosage 31 mg/kg up to 2000 mg).. 2.3 Dosage forRheumatoid Arthritis in Adults. The recommended dosage is:Initial 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)]. Chronic 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.. Initial 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)]. Chronic dosage: 200 mg once daily to 400 mg daily, as single dose or two divided doses.. 2.4 Dosage forSystemic 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 forChronic 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 200 mg of hydroxychloroquine sulfate, white, unscored, film-coated, capsule-shaped tablets debossed TV and 2401 on one side and plain on the other side. Tablets: 200 mg of hydroxychloroquine sulfate (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. (7.1)See FPI for more important drug interactions. (7). Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. (7.1). See FPI for more important drug interactions. (7). 7.1 DrugsProlonging 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 orOther 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 )]. 7.3 Drugs thatLower 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 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 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 study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Interaction of ampicillin with hydroxychloroquine cannot be ruled out.

GERIATRIC USE SECTION.

8.5 GeriatricUse. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 HowSupplied. Hydroxychloroquine Sulfate Tablets USP, 200 mg (equivalent to 155 mg of base), are white, unscored, film-coated, capsule-shaped tablets debossed TV and 2401 on one side and plain on the other side in bottles of 100 (NDC 0093-2401-01). 16.2 Storage. Dispense in tight, light-resistant container as defined in the USP, with child-resistant closure (as required).Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].Do not crush or divide hydroxychloroquine sulfate film-coated tablets. KEEP OUT OF THE REACH OF CHILDREN.

INDICATIONS & USAGE SECTION.

1 INDICATIONSAND 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.. 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). 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.. 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.. 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)]. 1.2 RheumatoidArthritis. Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults. 1.3 SystemicLupus Erythematosus. Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults. 1.4 ChronicDiscoid 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 InstructionsAdvise the patient to take hydroxychloroquine sulfate tablets with food or milk and not to crush or divide the tablet.Cardiomyopathy and Ventricular ArrhythmiasInform 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 ToxicityInform 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 ReactionsInform 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 NeuropathyInform 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 SuicidalityAlert 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)]. HypoglycemiaInform 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)]. PregnancyInform 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)].Distributed By: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Rev. 8/2021.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Hydroxychloroquine sulfate tablets overdosage symptoms have an onset within 1-3 hours of ingestion. The following have been reported with hydroxychloroquine sulfate tablets overdosage:Cardiovascular toxicity, including QRS or QTc prolongation, ventricular tachycardia, ventricular fibrillation, torsade de pointes, atrioventricular block, cardiac arrest and death.Life-threatening hypotension is common.Severe hypokalemia secondary to an intracellular shift is common in severe toxicity.Central nervous system (CNS) depression, seizures, visual disturbances, transient blindness, and coma may occur.Gastrointestinal decontamination procedures warrant consideration in patients that present within the first hour post-ingestion. If the level of consciousness rapidly deteriorates in severe poisoning, consider intubation before gastrointestinal decontamination procedures. Monitor plasma potassium levels and manage accordingly. Hemofiltration, hemodialysis, and hemoperfusion are not of benefit.Consider contacting poison center (1-800-221-2222) or medical toxicologist for overdosage management recommendations. Cardiovascular toxicity, including QRS or QTc prolongation, ventricular tachycardia, ventricular fibrillation, torsade de pointes, atrioventricular block, cardiac arrest and death.. Life-threatening hypotension is common.. Severe hypokalemia secondary to an intracellular shift is common in severe toxicity.. Central nervous system (CNS) depression, seizures, visual disturbances, transient blindness, and coma may occur.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. NDC 0093-2401-01Hydroxychloroquine Sulfate Tablets, USP200 mgKEEP OUT OF THE REACH OF CHILDRENRx only100 TABLETS. 1.

PEDIATRIC USE SECTION.

8.4 PediatricUse. 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.

PHARMACODYNAMICS SECTION.

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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing single 200 mg oral dose of hydroxychloroquine sulfate tablet 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 tablet 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. DistributionHydroxychloroquine sulfate is extensively distributed to tissues.EliminationA half-life of 123.5 days in plasma were observed following single 200 mg oral hydroxychloroquine sulfate tablet 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.MetabolismSignificant 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 RegistryThere 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 SummaryProlonged 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 ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskMalaria: 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.DataHuman 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.

REFERENCES SECTION.

15 REFERENCES. Center for Disease Control and Prevention. Malaria.https://www.cdc.gov/parasites/malaria/index.html.

SPL UNCLASSIFIED SECTION.

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.. 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.. 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)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere 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 SummaryProlonged 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 ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskMalaria: 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.DataHuman 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 PediatricUse. 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 GeriatricUse. 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. 8.6 Patientswith Renal or Hepatic Disease. 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. 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 and Porphyria: Avoid in patients with psoriasis or porphyria. (5.4)Hematologic Toxicity: Discontinue if myelosuppression occurs. (5.5). 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 and Porphyria: Avoid in patients with psoriasis or porphyria. (5.4). Hematologic Toxicity: Discontinue if myelosuppression occurs. (5.5). 5.1 Cardiomyopathyand 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 has 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: 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 [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.. 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 [see Drug Interactions (7.1)] as this may lead to an increased risk for ventricular arrhythmias.. 5.2 RetinalToxicity. 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 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. 5.3 SeriousSkin 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. 5.4 Worsening 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. 5.5 HematologicToxicity. 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. 5.6 HemolyticAnemia 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. 5.7 SkeletalMuscle 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. 5.8 NeuropsychiatricReactions 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. 5.9 Hypoglycemia. 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.