XARIA

Hydroxychloroquine sulfate tablets, USP is an antimalarial and antirheumatic drug, chemically described as 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate (1:1) with the molecular formula C 18 H 26 ClN 3 O•H 2 SO 4.

The molecular weight of hydroxychloroquine sulfate is 433.95.

Its structural formula is

Hydroxychloroquine sulfate, USP is a white or practically white crystalline powder, freely soluble in water; practically insoluble in alcohol, chloroform and ether.

Hydroxychloroquine sulfate tablets, USP 200 mg for oral administration contain 200 mg hydroxychloroquine sulfate (equivalent to 155 mg of hydroxychloroquine) and the following inactive ingredients: corn starch, pregelatinized starch, anhydrous dibasic calcium phosphate, magnesium stearate, hypromellose 2910(3 mPas), hydroxypropyl cellulose, titanium dioxide, polyethylene glycol 400, hypromellose 2910(50 mPas).

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.

Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients.

Treatment of rheumatoid arthritis in adults.

Treatment of systemic lupus erythematosus in adults.

Treatment of chronic discoid lupus erythematosus in adults.

Hydroxychloroquine sulfate tablets are not recommended for the: Treatment of complicated malaria.

Treatment of chloroquine or hydroxychloroquine-resistant strains of Plasmodium species.

Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.

Prophylaxis of malaria in geographic areas where chloroquine resistance occurs.

Prevention of relapses of

P. vivax or P. ovale because it is not active against the hypnozoite liver stage forms of these parasites.

For radical cure of

P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary. 1.1 Malaria Hydroxychloroquine sulfate tablets are indicated in adult and pediatric patient 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.

Hydroxychloroquine sulfate tablets are not recommended for: Treatment of complicated malaria.

Treatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species.

P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary.

For the most current information about drug resistance, refer to the latest recommendations from the Center for Disease Control and Prevention1. 1.2 Rheumatoid Arthritis Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults. 1.3 Systemic Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults. 1.4 Chronic Discoid Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus in adults.

Hydroxychloroquine is a 4-aminoquinoline antimalarial and antirheumatic agent.

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 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 tablets in rheumatoid arthritis and lupus patients.

Following a single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy male volunteers, whole blood hydroxychloroquine Cmax was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours).

Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine.

Mean absolute oral bioavailability is 79% (SD: 12%) in fasting conditions.

Peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following a single dose of 155 mg intravenous infusion and from 2290 ng/mL to 4211 ng/mL (mean 3312 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.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity.

Hydroxychloroquine sulfate tablets are extensively distributed to tissues and has a large volume of distribution.

Approximately 50% of hydroxychloroquine is bound to plasma proteins.

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, hydroxychloroquine is metabolized mainly by CYP2C8, CYP3A4 and CYP2D6 as well as by FMO-1 and MAO-A Elimination / Excretion Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate tablets 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 to 4 hours and the terminal half-life ranged from 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.

In vitro study suggested that hydroxychloroquine has a potential to inhibit CYP2D6, CYP3A4, P-glycoproteins (P-gp), MATE1 and MATE2-K. In vitro study suggested that hydroxychloroquine has no significant potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and the main transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2.

In vitro, hydroxychloroquine has no significant potential to induce CYP1A2, CYP2B6 and CYP3A4. 12.4 Microbiology Mechanism of Action in Malaria The precise mechanism by which hydroxychloroquine exhibits activity against Plasmodium is not known.

Hydroxychloroquine is a 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.

Hydroxychloroquine is active against the erythrocytic forms of chloroquine sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale.

Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale.

P. falciparum strains exhibiting reduced susceptibility to chloroquine also show reduced susceptibility to hydroxychloroquine.

Resistance of

Plasmodium parasites to chloroquine is widespread.

The following adverse reactions are described in greater detail in other sections: Cardiomyopathy and Ventricular Arrhythmias Retinal Toxicity Serious Skin Reactions Worsening of Psoriasis Risks Associated with Use in Porphyria Hematologic Toxicity Hemolytic Anemia Associated with G6PD Skeletal Muscle Myopathy or Neuropathy Neuropsychiatric Reactions Including Suicidality Hypoglycemia Renal Toxicity 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders: Bone marrow depression, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia Cardiac disorders: Cardiomyopathy, cardiac failure, QT-interval prolongation, ventricular tachycardia, torsades de pointes, atrioventricular block, bundle branch block, sick sinus syndrome, pulmonary hypertension Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, sensorineural hearing loss Eye disorders: Retinopathy, retinal pigmentation changes (typically bull's eye appearance), visual field defects (paracentral scotomas), macular degeneration, corneal edema, corneal opacities, decreased dark adaptation Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain General disorders: Fatigue Hepatobiliary disorders: Abnormal liver function tests, fulminant hepatic failure Immune system disorders: Urticaria, angioedema, bronchospasm Metabolism and nutrition disorders: Anorexia, hypoglycemia, weight loss Musculoskeletal and connective tissue disorders: Proximal myopathy, depressed tendon reflexes, abnormal nerve conduction Nervous system disorders: Ataxia, dizziness, headache, seizure, extrapyramidal disorders (dystonia, dyskinesia, tremor) Neuropsychiatric disorders: Affect/emotional lability, irritability, nervousness, psychosis, suicidal ideation, suicidal behavior, depression, hallucinations, anxiety, agitation, confusion, delusions, paranoia, mania and sleep disorders (insomnia, night terrors, nightmares) Skin and subcutaneous tissue disorders: Alopecia, hair color changes, rash, pruritus, photosensitivity, psoriasis exacerbation, hyperpigmentation, exfoliative dermatitis, erythema multiforme, acute generalized exanthematous pustulosis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) The most common adverse reactions reported are: nausea, vomiting, diarrhea, and abdominal pain.

To report SUSPECTED ADVERSE

REACTIONS, contact Creekwood Pharmaceuticals LLC.fda.gov/medwatch.

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 a poison center or a medical toxicologist for overdosage management recommendations.

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

Patients with hypersensitivity to 4-aminoquinoline compounds.

Patients: ● 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.

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: 200 mg once daily or 400 mg once daily (or in two divided doses) Chronic Discoid Lupus Erythematosus in Adults: 200 mg once daily or 400 mg once daily (or in two divided doses) 2.1 Important Administration Instructions Administer hydroxychloroquine sulfate tablets orally with food or milk.

Do not crush or divide the tablets. 2.2 Dosage for Malaria in Adult and Pediatric Patients Hydroxychloroquine sulfate tablets are not recommended in pediatric patients less than 31 kg because the lowest available strength (200 mg) exceeds the recommended dose for these patients and it cannot be divided.

Treatment must start 2 weeks before travel to an endemic area.

Advise the patient to take the prophylaxis dosage once a week, staring 2 weeks prior to travel to the endemic area, on the same day every week, continuing the same weekly dose while in the endemic area, and for 4 weeks after leaving the endemic area.

The recommended prophylaxis dosage is

Adult patients: 400 mg once a week Pediatric patients ≥ 31kg: 6.5 mg/kg actual body weight (up to 400 mg) once a week Treatment of Uncomplicated Malaria The dosages for the treatment of uncomplicated malaria are: Adult patients: Administer 800 mg initially; subsequently administer 400 mg at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 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 6 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. 2.3 Dosage for Rheumatoid Arthritis in Adults The recommended dosage is: Initial dosage: 400 mg to 600 mg daily as a single daily dose or two divided doses.

The action of hydroxychloroquine is cumulative and may require weeks to months for maximum therapeutic effect.

Daily doses exceeding 5 mg/kg (actual weight) of hydroxychloroquine sulfate increase the incidence of retinopathy.

Chronic dosage: 200 mg once daily to 400 mg daily, as a single dose or two divided doses.

Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with hydroxychloroquine sulfate tablets. 2.4 Dosage for Systemic Lupus Erythematosus in Adults The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses. 2.5 Dosage for Chronic Discoid Lupus Erythematosus in Adults The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses.

Hydroxychloroquine sulfate tablets, USP 200 mg is white, capsule shaped film-coated tablets debossed with "ꓲꓲꓲ" on one side and plain on other side.

The tablets are available in bottles of: 100 tablets.

• NDC 82619-131-01 500 tablets.

• NDC 82619-131-02 1000 tablets.

• NDC 82619-131-03 16.2 Storage Dispense in a tight, light-resistant container as defined in the USP/NF.

Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F) .

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine sulfate tablets during pregnancy.

Encourage patients to register by contacting 1-877-311-8972.

Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine sulfate tablets use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal, or fetal outcomes.

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.

Animal reproduction studies were not conducted with hydroxychloroquine.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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.

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.

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 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.

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.

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.

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.