ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The following adverse reactions have been identified during post-approval use of hydroxychloroquine sulfate or other 4-aminoquinoline compounds. 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 failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Hemolysis reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Cardiac disorders: Cardiomyopathy which may result in cardiac failure and in some cases fatal outcome (see WARNINGS and OVERDOSAGE). Hydroxychloroquine sulfate prolongs the QT interval. Ventricular arrhythmias and torsade de pointes have been reported in patients taking hydroxychloroquine sulfate (see OVERDOSAGE and DRUG INTERACTIONS ). Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, nerve deafness, deafness. Eye disorders: Irreversible retinopathy with retinal pigmentation changes (bulls eye appearance), visual field defects (paracentral scotomas) and visual disturbances (visual acuity), maculopathies (macular degeneration), decreased dark adaptation, color vision abnormalities, corneal changes (edema and opacities) including corneal deposition of drug with or without accompanying symptoms (halo around lights, photophobia, blurred vision). Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal pain. General disorders and administration site conditions: Fatigue. Hepatobiliary disorders: Liver function tests abnormal, hepatic failure acute. Immune system disorders: Urticaria, angioedema, bronchospasm Metabolism and nutrition disorders: Decreased appetite, hypoglycemia, porphyria, weight decreased. Musculoskeletal and connective tissue disorders: Sensorimotor disorder, skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes and abnormal nerve conduction. Nervous system disorders: Headache, dizziness, seizure, ataxia and extrapyramidal disorders such as dystonia, dyskinesia, and tremor have been reported with this class of drugs. Psychiatric disorders: Affect/emotional lability, nervousness, irritability, nightmares, psychosis, suicidal behavior. Skin and subcutaneous tissue disorders: Rash, pruritus, pigmentation disorders in skin and mucous membranes, hair color changes, alopecia. Dermatitis bullous eruptions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), photosensitivity, dermatitis exfoliative, acute generalized exanthematous pustulosis (AGEP). AGEP has to be distinguished from psoriasis, although hydroxychloroquine sulfate may precipitate attacks of psoriasis. It may be associated with pyrexia and hyperleukocytosis. To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacokinetics: Following single 200 mg oral dose of hydroxychloroquine sulfate to healthy males, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with half-life of 537 hours (22.4 days). In the same study, the plasma peak concentration was 50.3 ng/mL reached in 3.74 hours with half-life of 2963 hours (123.5 days). 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. Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. The mean fraction of the dose absorbed was 0.74. 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. Following chronic oral administration of hydroxychloroquine, significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) have been found in plasma and blood, with DHCQ being the major metabolite. The absorption half-life was approximately to hours and the terminal half-life ranged from 40 to 50 days. The long half-life can be attributed to extensive tissue uptake rather than through decreased excretion. Peak plasma levels of hydroxychloroquine were seen in about to hours. Renal clearance in rheumatoid arthritis (RA) patients taking hydroxychloroquine sulfate for at least six months seemed to be similar to that of the single dose studies in volunteers, suggesting that no change occurs with chronic dosing. Range for renal clearance of unchanged drug was approximately 16 to 30% and did not correlate with creatinine clearance; therefore, dosage adjustment is not required for patients with renal impairment. In RA patients, 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. Cellular levels of patients on daily hydroxychloroquine have been shown to be higher in mononuclear cells than polymorphonuclear leucocytes. Microbiology Malaria Mechanism of action: The precise mechanism by which hydroxychloroquine exhibits activity against Plasmodium is not known. Hydroxychloroquine, like chloroquine, is weak base and may exert its effect by concentrating in the acid vesicles of the parasite and by inhibiting polymerization of heme. It can also inhibit certain enzymes by its interaction with DNA. Activity in vitro and in Clinical Infections: Hydroxychloroquine is active against the erythrocytic forms of chloroquine sensitive strains of Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite stage (P. vivax and P. ovale) of the Plasmodium parasites. 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 Malaria). Patients in whom chloroquine or hydroxychloroquine have failed to prevent or cure clinical malaria or parastextia, or patients who acquired malaria in geographic area where chloroquine resistance is known to occur should be treated with another form of antimalarial therapy (see INDICATIONS AND USAGE Malaria and WARNINGS). Rheumatoid Arthritis and Systemic Lupus Erythematosus Mechanism of action: The mechanisms underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine sulfate are unknown.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. One hydroxychloroquine sulfate tablet contains 200 mg of hydroxychloroquine sulfate, which is equivalent to 155 mg base. Take hydroxychloroquine sulfate tablet with meal or glass of milk. Malaria Prophylaxis Adults: 400 mg (310 mg base) once weekly on the same day of each week starting weeks prior to exposure, and continued for weeks after leaving the endemic area. Weight-based dosing in adults and pediatric patients: 6.5 mg/kg (5 mg/kg base), not to exceed 400 mg (310 mg base), once weekly on the same day of the week starting weeks prior to exposure, and continued for weeks after leaving the endemic area. Treatment of Uncomplicated Malaria Adults: 800 mg (620 mg base) followed by 400 mg (310 mg base) at hours, 24 hours and 48 hours after the initial dose (total 2000 mg hydroxychloroquine sulfate or 1550 mg base). Weight based dosage in adults and pediatric patients: 13 mg/kg (10 mg/kg base), not to exceed 800 mg (620 mg base) followed by 6.5 mg/kg (5 mg/kg base), not to exceed 400 mg (310 mg base), at hours, 24 hours and 48 hours after the initial dose. Hydroxychloroquine sulfate film-coated tablets cannot be divided, therefore they should not be used to treat patients who weigh less than 31 kg. For radical cure of P. vivax and P. malariae infections, concomitant therapy with an 8--aminoquinoline compound is necessary. Lupus Erythematosus The recommended adult dosage is 200 to 400 mg (155 to 310 mg base) daily, administered as single daily dose or in two divided doses. Doses above 400 mg day are not recommended. The incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded. Rheumatoid Arthritis The action of hydroxychloroquine is cumulative and may require weeks to months to achieve the maximum therapeutic effect (see CLINICAL PHARMACOLOGY). Initial adult dosage: 400 mg to 600 mg (310 to 465 mg base) daily, administered as single daily dose or in two divided doses. In small percentage of patients, side effects may require temporary reduction of the initial dosage. Maintenance adult dosage: When good response is obtained, the dosage may be reduced by 50 percent and continued at maintenance level of 200 mg to 400 mg (155 to 310 mg base) daily, administered as single daily dose or in two divided doses. Do not exceed 600 mg or 6.5 mg/kg (5 mg/kg base) per day, whichever is lower, as the incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded. Corticosteroids and salicylates may be used in conjunction with hydroxychloroquine sulfate, and they can generally be decreased gradually in dosage or eliminated after maintenance dose of hydroxychloroquine sulfate has been achieved.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Malaria Hydroxychloroquine sulfate tablets are indicated for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. ovale, and P. vivax. Hydroxychloroquine sulfate tablets are indicated for the prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use in Malaria Hydroxychloroquine sulfate tablets are not recommended for the treatment of complicated malaria.Hydroxychloroquine sulfate tablets are not effective against chloroquine or hydroxychloroquine-resistant strains of Plasmodium species (see CLINICAL PHARMACOLOGY Microbiology ). Hydroxychloroquine sulfate tablets are not recommended for the treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.Hydroxychloroquine sulfate tablets are not recommended for malaria prophylaxis in geographic areas where chloroquine resistance occurs.Hydroxychloroquine sulfate tablets do not prevent relapses of P. vivax or P. ovale because it is not active against the hypnozoite forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline compound is necessary (see CLINICAL PHARMACOLOGY Microbiology). Prior to prescribing hydroxychloroquine sulfate tablets for the treatment or prophylaxis of malaria, consult the Centers for Disease Control and Prevention (CDC) Malaria website (http://www.cdc.gov/malaria). Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus and systemic lupus erythematosus in adults. Rheumatoid Arthritis Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults.. Hydroxychloroquine sulfate tablets are not recommended for the treatment of complicated malaria.. Hydroxychloroquine sulfate tablets are not effective against chloroquine or hydroxychloroquine-resistant strains of Plasmodium species (see CLINICAL PHARMACOLOGY Microbiology ). Hydroxychloroquine sulfate tablets are not recommended for the treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.. Hydroxychloroquine sulfate tablets are not recommended for malaria prophylaxis in geographic areas where chloroquine resistance occurs.. Hydroxychloroquine sulfate tablets do not prevent relapses of P. vivax or P. ovale because it is not active against the hypnozoite forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline compound is necessary (see CLINICAL PHARMACOLOGY Microbiology).

PRECAUTIONS SECTION.

PRECAUTIONS. General: Use with caution in patients with gastrointestinal, neurological, or blood disorders, and in those with sensitivity to quinine. Hepatic/Renal Disease: Antimalarial compounds should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. reduction in dosage may be necessary in patients with hepatic or renal disease, as well as in those taking medicines known to affect these organs. Hematologic Effects/Laboratory Tests: Antimalarial compounds should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. Periodic blood cell counts should be performed if patients are given prolonged therapy. If any severe blood disorder such as aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia, appears which is not attributable to the disease under treatment, consider discontinuation of hydroxychloroquine sulfate. Hydroxychloroquine sulfate should be administered with caution in patients having glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Dermatologic Effects: Dermatologic reactions to hydroxychloroquine sulfate may occur and, therefore, proper care should be exercised when it is administered to any patient receiving drug with significant tendency to produce dermatitis. Drug Interactions Digoxin: Concomitant hydroxychloroquine sulfate and digoxin therapy may result in increased serum digoxin levels: serum digoxin levels should be closely monitored in patients receiving combined therapy. Insulin or antidiabetic drugs: As hydroxychloroquine sulfate may enhance the effects of hypoglycemic treatment, decrease in doses of insulin or antidiabetic drugs may be required. Drugs that prolong QT interval and other arrhythmogenic drugs: Hydroxychloroquine sulfate prolongs the QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias. Also, there may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine sulfate is used concomitantly with other arrhythmogenic drugs. Mefloquine and other drugs known to lower the convulsive threshold: Hydroxychloroquine sulfate can lower the convulsive threshold. Co-administration of hydroxychloroquine sulfate with other antimalarials known to lower the convulsion threshold (e.g., mefloquine) may increase the risk of convulsions. Antiepileptics: The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine sulfate. Methotrexate: Combined use of methotrexate with hydroxychloroquine sulfate has not been studied and may increase the incidence of adverse effects. Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate were co-administered. The following interactions have been observed on treatment with the structurally related substance chloroquine phosphate, and therefore cannot be ruled out for hydroxychloroquine. Praziquantel: Chloroquine has been reported to reduce the bioavailability of praziquantel. 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. Cimetidine: Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. Concomitant use of cimetidine should be avoided. Ampicillin: In study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Information for Patients: Patients should be informed of the early signs and symptoms of toxicity such as rash or visual changes. Patients must see their physicians promptly in case of the appearance of these or of any unusual effects. Periodic laboratory tests may be recommended in some patients. Patients should be fully informed of the potential risks of the use of hydroxychloroquine sulfate, especially in pregnancy and in children. Carcinogenesis, mutagenesis, impairment of fertility: Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of hydroxychloroquine sulfate. The mutagenic potential of hydroxychloroquine was not evaluated. However, chloroquine has been shown to be catalytic inhibitor of DNA repair enzymes (topoisomerase II) and to produce weak genotoxic effects through this mode of action.PregnancyTeratogenic Effects: Human pregnancies resulting in live births have been reported in the literature and no increase in the rate of birth defects has been demonstrated. Embryonic deaths and malformations of anophthalmia and microphthalmia in the offspring have been reported when pregnant rats received large doses of chloroquine.Nursing Mothers: Caution should be exercised when administering hydroxychloroquine sulfate to nursing women. It has been demonstrated that hydroxychloroquine administered to nursing women is excreted in human milk and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.Pediatric Use: Safety and efficacy have not been established in the chronic use of hydroxychloroquine sulfate for systemic lupus erythematosus and juvenile idiopathic arthritis in children. Children are especially sensitive to the 4-aminoquinoline compounds. Most reported fatalities followed the accidental ingestion of chloroquine, sometimes in small doses (0.75 or g in one 3-year-old child). Patients should be strongly warned to keep these drugs out of the reach of children (see OVERDOSAGE).Geriatric Use: Clinical studies of hydroxychloroquine sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, 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. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

WARNINGS SECTION.

WARNINGS. Resistant strains of malaria: Hydroxychloroquine sulfate is not effective against chloroquine-resistant strains of P. falciparum (see CLINICAL PHARMACOLOGY Microbiology). Ocular: Irreversible retinal damage has been observed in some patients who had received hydroxychloroquine sulfate. Significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease. baseline ocular examination is recommended within the first year of starting hydroxychloroquine sulfate. The baseline exam should include: 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 individuals with significant risk factors (daily dose of hydroxychloroquine sulfate greater than mg/kg base of actual body weight, subnormal glomerular filtration, use of tamoxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SD-OCT. For individuals without significant risk factors, annual exams can usually be deferred until five years of treatment. In individuals of Asian descent, retinal toxicity may first be noticed outside the macula. 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. It is recommended that hydroxychloroquine be discontinued if ocular toxicity is suspected and the patient should be closely observed given that retinal changes (and visual disturbances) may progress even after cessation of therapy. Cardiac Effects, including Cardiomyopathy and QT prolongation: Postmarketing cases of life-threatening and fatal cardiomyopathy have been reported with use of hydroxychloroquine sulfate as well as with use of chloroquine. Patients may present with atrioventricular block, pulmonary hypertension, sick sinus syndrome or with cardiac complications. ECG findings may include atrioventricular, right or left bundle branch block. Signs or symptoms of cardiac compromise have appeared during acute and chronic treatment. Clinical monitoring for signs and symptoms of cardiomyopathy is advised, including use of appropriate diagnostic tools such as ECG to monitor patients for cardiomyopathy during hydroxychloroquine sulfate therapy. Chronic toxicity should be considered when conduction disorders (bundle branch block/atrio-ventricular heart block) or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of hydroxychloroquine sulfate may prevent life-threatening complications. Hydroxychloroquine sulfate prolongs the QT interval. Ventricular arrhythmias and torsades de pointes have been reported in patients taking hydroxychloroquine sulfate (see OVERDOSAGE). Therefore, hydroxychloroquine sulfate should not be administered with other drugs that have the potential to prolong the QT interval (see DRUG INTERACTIONS ). Worsening of psoriasis and porphyria: Use of hydroxychloroquine sulfate in patients with psoriasis may precipitate severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The preparation should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the possible hazard. Proximal Myopathy and 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 been associated with curvilinear 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. Neuropsychiatric events, including suicidality: Suicidal behavior has been rarely reported in patients treated with hydroxychloroquine sulfate. Hypoglycemia: Hydroxychloroquine sulfate has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with or without antidiabetic medications (see DRUG INTERACTIONS and ADVERSE REACTIONS ). Patients treated with hydroxychloroquine sulfate should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with hydroxychloroquine sulfate should have their blood glucose checked and treatment reviewed as necessary.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. (7.1)o See FPI for more important drug interactions.(7). 7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. Hydroxychloroquine prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine is used concomitantly with other arrhythmogenic drugs. Therefore, hydroxychloroquine is not recommended in patients taking other drugs that have the potential to prolong the QT interval or are arrhythmogenic [see Warnings and Precautions (5.1)]. 7.2 Insulin or Other Antidiabetic Drugs. Hydroxychloroquine 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 that Lower the Seizure Threshold. Hydroxychloroquine can lower the seizure threshold. Co-administration of hydroxychloroquine with other antimalarials known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures.. 7.4 Antiepileptics. The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine.. 7.5 Methotrexate. Concomitant use of hydroxychloroquine and methotrexate may increase the incidence of adverse reactions.. 7.6 Cyclosporine. An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy.. 7.7 Digoxin. Concomitant hydroxychloroquine 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.

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 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)]. Distributed by: Rising Pharma Holdings, Inc. East Brunswick, NJ 08816Manufactured by:Laurus Labs LimitedVisakhapatnam-531011M. L. No.: 16/VSP/AP/2015/F B/CCRevised: 08/2022.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing single 200 mg oral dose of hydroxychloroquine 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 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 1,161 ng/mL to 2,436 ng/mL (mean 1,918 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 is extensively distributed to tissues. Elimination half-life of 123.5 days in plasma were observed following single 200 mg oral hydroxychloroquine 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 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 during pregnancy. Encourage patients to register by contacting 1-877-311-8972. Risk Summary Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine use in pregnant women have not identified 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 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Malaria: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Rheumatoid Arthritis: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 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 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.

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 during pregnancy. Encourage patients to register by contacting 1-877-311-8972. Risk Summary Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine use in pregnant women have not identified 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 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Malaria: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Rheumatoid Arthritis: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 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 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 and any potential adverse effects on the breastfed child from hydroxychloroquine or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of hydroxychloroquine 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 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 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 Patients with Renal and Hepatic Disease. reduction in the dosage of hydroxychloroquine 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) Renal Toxicity: Consider phospholipidosis as possible cause of renal injury in patients with underlying connective tissue disorders. Discontinue hydroxychloroquine if renal toxicity is suspected or demonstrated by tissue biopsy in any organ system. (5.1, 5.7, 5.10). 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) Renal Toxicity: Consider phospholipidosis as possible cause of renal injury in patients with underlying connective tissue disorders. Discontinue hydroxychloroquine if renal toxicity is suspected or demonstrated by tissue biopsy in any organ system. (5.1, 5.7, 5.10). 5.1 Cardiomyopathy and Ventricular Arrhythmias. Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine. Signs and symptoms of cardiac compromise have occurred during acute and chronic hydroxychloroquine treatment. In multiple cases, endomyocardial biopsy showed association of the cardiomyopathy with phospholipidosis in the absence of inflammation, infiltration, or necrosis. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.7, 5.10)]. 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 has potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in hydroxychloroquine-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 administration in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as: Cardiac disease, e.g., heart failure, myocardial infarction. Proarrhythmic conditions, e.g., bradycardia (< 50 bpm). History of ventricular dysrhythmias. Uncorrected hypokalemia and/or hypomagnesemia. Concomitant administration with QT interval prolonging agents as this may lead to an increased risk for ventricular arrhythmias [see Drug Interactions (7.1)]. Therefore, hydroxychloroquine is not recommended in patients taking other drugs that have the potential to prolong the QT interval. Correct electrolyte imbalances prior to use. Monitor cardiac function as clinically indicated during hydroxychloroquine therapy. Discontinue hydroxychloroquine if cardiotoxicity is suspected or demonstrated by tissue biopsy.. 5.2 Retinal Toxicity. Irreversible retinal damage was observed in some patients treated with hydroxychloroquine sulfate and it is related to cumulative dosage and treatment duration. In patients of Asian descent, retinal toxicity may first be noticed outside the macula. Risk factors for retinal damage include daily hydroxychloroquine sulfate dosages >=5 mg/kg of actual body weight, durations of use greater than five years, renal impairment, use of concomitant drug products such as tamoxifen citrate, and concurrent macular disease. Within the first year of starting hydroxychloroquine, 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 and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy.. 5.3 Serious Skin Reactions. Serious adverse reactions have been reported with the use of hydroxychloroquine 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 if these severe reactions occur.. 5.4 Worsening of Psoriasis and Porphyria. Administration of hydroxychloroquine in patients with psoriasis may precipitate severe flare-up of psoriasis. Administration of hydroxychloroquine in patients with porphyria may exacerbate porphyria. Avoid hydroxychloroquine in patients with psoriasis or porphyria, unless the benefit to the patient outweighs the possible risk.. 5.5 Hematologic Toxicity. Hydroxychloroquine may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged hydroxychloroquine therapy. If the patient develops myelosuppression which cannot be attributable to the disease, discontinue the drug. 5.6 Hemolytic Anemia Associated with G6PD Deficiency. Hemolysis has been reported in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor for hemolytic anemia as this can occur, particularly in association with other drugs that cause hemolysis. 5.7 Skeletal Muscle Myopathy or Neuropathy. Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction, have been reported. Muscle and nerve biopsies have shown associated phospholipidosis. Drug-induced phospholipidosis may occur in other organ system see Warnings and Precautions (5.1, 5.10)]. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine. Discontinue hydroxychloroquine if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy.. 5.8 Neuropsychiatric Reactions Including Suicidality. Suicidal behavior has been reported in patients treated with hydroxychloroquine [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 should be assessed for patients who develop these symptoms. 5.9 Hypoglycemia. Hydroxychloroquine 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-treated patients about the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia; diabetic patients should monitor their blood sugar levels. Advise patients to seek medical attention if they develop any signs and symptoms of hypoglycemia.. 5.10 Renal Toxicity. Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of hydroxychloroquine.Renal biopsy showed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Physicians should consider phospholipidosis as possible cause of renal injury in patients with underlying connective tissue disorders who are receiving hydroxychloroquine. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.7)]. Discontinue hydroxychloroquine if renal toxicity is suspected or demonstrated by tissue biopsy.