HYDROXYCHLOROQUINE SULFATE- hydroxychloroquine sulfate_tablet, film coated

Malaria Hydroxychloroquine is a 4-aminoquinoline antimalarial [see Microbiology (12. 4) Rheumatoid Arthritis, Systemic Lupus Erythematosus and Chronic Discoid Lupus Erythematosus The mechanisms underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine sulfate in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus are not fully known. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of hydroxychloroquine have not been fully characterized. Following oral administration, the whole blood concentration of hydroxychloroquine at steady-state is dose proportional over a dose range from 200 mg daily to 400 mg daily of hydroxychloroquine sulfate in rheumatoid arthritis and lupus patients. Absorption Following a single 200 mg oral dose of hydroxychloroquine sulfate to healthy male volunteers, whole blood hydroxychloroquine C max max max max Peak blood concentrations ranged from 1,161 ng/mL to 2,436 ng/mL (mean 1,918 ng/mL) following a single dose of 155 mg intravenous infusion and from 2,290 ng/mL to 4,211 ng/mL (mean 3,312 ng/mL) following a single dose of 310 mg intravenous infusion in healthy subjects. 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. 30% to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Distribution Hydroxychloroquine sulfate is extensively distributed to tissues and has a large volume of distribution. Approximately 50% of hydroxychloroquine is bound to plasma proteins. 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. In vitro, Elimination/Excretion Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate for at least 6 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 hydroxychloroquine was approximately 16% to 30% of the dose after oral and IV administration. Results following a single oral dose of a 200 mg tablet demonstrated a half-life of hydroxychloroquine about 40 days in whole blood. Following chronic oral administration of hydroxychloroquine, the absorption half-life of hydroxychloroquine was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days in whole blood. The effective half-life of hydroxychloroquine is likely to be shorter and steady-state is achieved by 6 weeks following 400 mg daily oral administration in rheumatoid arthritis patients. Drug Interaction Studies In vitro In vitro In vitro Mechanism of Action in Malaria The precise mechanism by which hydroxychloroquine exhibits activity against Plasmodium Antimicrobial Activity Hydroxychloroquine is active against the erythrocytic forms of chloroquine sensitive strains of P. falciparum, P. malariae, P. ovale Drug Resistance P. falciparum Plasmodium [see Indications and Usage (1.

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 1. 1 Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. 1 Treatment of rheumatoid arthritis in adults. 2 Treatment of systemic lupus erythematosus in adults. 3 Treatment of chronic discoid lupus erythematosus in adults. 4 Limitations of Use (1. 1): Hydroxychloroquine sulfate tablets are not Treatment of complicated malaria. Treatment of chloroquine or hydroxychloroquine-resistant strains of Plasmodium Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium Prophylaxis of malaria in geographic areas where chloroquine resistance occurs. Prevention of relapses of P. ovale Hydroxychloroquine sulfate tablets are indicated in adult and pediatric patients for the: Treatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale. Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use: Hydroxychloroquine sulfate tablets are not Treatment of complicated malaria. Treatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium [see Microbiology (12. 4) Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium Prophylaxis of malaria in geographic areas where chloroquine resistance occurs. ovale [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 Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults. Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults. Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus in adults.

Malaria in Adult and Pediatric Patients 2. 2 Prophylaxis: Begin weekly doses 2 weeks prior to travel to the endemic area, continue weekly doses while in the endemic area, and continue the weekly doses for 4 weeks after leaving the endemic area: - Adults: 400 mg once a week - Pediatric patients >= 31 kg: 6. 5 mg/kg up to 400 mg, once a week Treatment of Uncomplicated Malaria: See Full Prescribing Information (FPI) for complete dosing information. Rheumatoid Arthritis in Adults 2. 3 Initial dosage: 400 mg to 600 mg daily Chronic dosage: 200 mg once daily or 400 mg once daily (or in two divided doses) Systemic Lupus Erythematosus in Adults 2. 4 200 mg once daily or 400 mg once daily (or in two divided doses) Chronic Discoid Lupus Erythematosus in Adults 2. 5 200 mg once daily or 400 mg once daily (or in two divided doses) Administer hydroxychloroquine sulfate tablets orally with food or milk. Do not crush or divide the tablets. Hydroxychloroquine sulfate tablets are not recommended in pediatric patients less than 31 kg because the lowest available strength (200 mg) exceeds the recommended dose for these patients and it cannot be divided. Prophylaxis Treatment must start 2 weeks before travel to an endemic area. Advise the patient to take the prophylaxis dosage once a week, staring 2 weeks prior to travel to the endemic area, on the same day every week, continuing the same weekly dose while in the endemic area, and for 4 weeks after leaving the endemic area. The recommended prophylaxis dosage is: Adult patients: 400 mg once a week Pediatric patients >= 31 kg: 6. 5 mg/kg actual body weight (up to 400 mg) once a week Treatment of Uncomplicated Malaria The dosages for the treatment of uncomplicated malaria are: Adult patients: Administer 800 mg initially; subsequently administer 400 mg at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 2,000 mg). Pediatric patients >= 31 kg: Administer 13 mg/kg (up to 800 mg) initially; subsequently administer 6. 5 mg/kg (up to 400 mg) at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 31 mg/kg - up to 2,000 mg). For radical cure of P. vivax and P. ovale [see Microbiology (12. 4) The recommended dosage is: Initial dosage: 400 mg to 600 mg daily as a single daily dose or two divided doses. The action of hydroxychloroquine is cumulative and may require weeks to months for maximum therapeutic effect. Daily doses exceeding 5 mg/kg (actual weight) of hydroxychloroquine sulfate increase the incidence of retinopathy [see Warnings and Precautions (5. 2) Chronic dosage: 200 mg once daily to 400 mg daily, as a single dose or two divided doses. Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with hydroxychloroquine sulfate tablets. The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses.

The following adverse reactions are described in greater detail in other sections: Cardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions (5. 1) Retinal Toxicity [see Warnings and Precautions (5. 2) Serious Skin Reactions [see Warnings and Precautions (5. 3) Worsening of Psoriasis [see Warnings and Precautions (5. 4) Risks Associated with Use in Porphyria [see Warnings and Precautions (5. 5) Hematologic Toxicity [see Warnings and Precautions (5. 6) Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5. 7) Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5. 8) Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5. 9) Hypoglycemia [see Warnings and Precautions (5. 10) Renal Toxicity [see Warnings and Precautions (5. 11) The following adverse reactions have been identified during post-approval use of 4-aminoquinoline drugs, including hydroxychloroquine sulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders Cardiac disorders: Ear and labyrinth disorders Eye disorders: Gastrointestinal disorders: General disorders Hepatobiliary disorders Immune system disorders Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders: Nervous system disorders: Neuropsychiatric disorders: Skin and subcutaneous tissue disorders: The most common adverse reactions reported are: nausea, vomiting, diarrhea, and abdominal pain. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

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

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine sulfate 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 use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal, or fetal outcomes (see Data) (see Clinical Considerations). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Malaria Rheumatoid Arthritis: Systemic Lupus Erythematosus Data Human Data Data from published epidemiologic and clinical studies have not established an association with hydroxychloroquine sulfate 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 Risk Summary Published lactation data report that hydroxychloroquine is present in human milk at low levels. No adverse reactions have been reported in breastfed infants. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine through breastmilk. There is no information on the effect of hydroxychloroquine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for hydroxychloroquine sulfate and any potential adverse effects on the breastfed child from hydroxychloroquine sulfate or from the underlying maternal condition. The safety and effectiveness of hydroxychloroquine sulfate have been established in pediatric patients for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. ovale, [see Dosage and Administration (2. 2) The safety and effectiveness of hydroxychloroquine sulfate have not been established in pediatric patients for the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus, or systemic lupus erythematosus. Clinical trials of hydroxychloroquine sulfate 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. A reduction in the dosage of hydroxychloroquine sulfate may be necessary in patients with hepatic or renal disease.

Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. 1 See FPI for more important drug interactions. ( 7 Hydroxychloroquine sulfate prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine sulfate is used concomitantly with other arrhythmogenic drugs. Therefore, hydroxychloroquine sulfate is not recommended in patients taking other drugs that have the potential to prolong the QT interval or are arrhythmogenic [see Warnings and Precautions (5. 1) Hydroxychloroquine sulfate may enhance the effects of insulin and antidiabetic drugs, and consequently increase the hypoglycemic risk. Therefore, a decrease in dosage of insulin and other antidiabetic drugs may be necessary [see Warnings and Precautions (5. 10 ) Hydroxychloroquine sulfate can lower the seizure threshold. Co-administration of hydroxychloroquine sulfate with other antimalarials known to lower the seizure threshold (e. , mefloquine) may increase the risk of seizures. The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine sulfate. Concomitant use of hydroxychloroquine sulfate and methotrexate may increase the incidence of adverse reactions. An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy. Concomitant hydroxychloroquine sulfate and digoxin therapy may result in increased serum digoxin levels. Monitor serum digoxin levels closely in patients receiving combined therapy. Concomitant use of cimetidine resulted in a 2-fold increase of exposure of chloroquine, which is structurally related to hydroxychloroquine. Interaction of cimetidine with hydroxychloroquine cannot be ruled out. Avoid concomitant use of cimetidine. Lack of efficacy of hydroxychloroquine was reported when rifampicin was concomitantly administered. Avoid concomitant use of rifampicin. Chloroquine has been reported to reduce the bioavailability of praziquantel. Interaction of praziquantel with hydroxychloroquine cannot be ruled out. Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed. Interaction of antacids and kaolin with hydroxychloroquine cannot be ruled out. In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Interaction of ampicillin with hydroxychloroquine cannot be ruled out.

OVERDOSAGE
Hydroxychloroquine sulfate overdosage symptoms have an onset within 1 hour to 3 hours of ingestion. The following have been reported with hydroxychloroquine sulfate 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 a poison center (1-800-221-2222) or a medical toxicologist for overdosage management recommendations.
NONCLINICAL TOXICOLOGY
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.
REFERENCES
1 https://www.cdc.gov/parasites/malaria/index.html

Amneal Pharmaceuticals NY LLC

HYDROXYCHLOROQUINE SULFATE- hydroxychloroquine sulfate_tablet, film coated Product manual source documgent