DOSAGE AND ADMINISTRATION

One hydroxychloroquine sulfate tablet, USP contains 200 mg of hydroxychloroquine sulfate, USP which is equivalent to 155 mg base.

Take hydroxychloroquine sulfate tablets with a meal or a glass of milk.

Malaria

Prophylaxis

Adults: 400 mg (310 mg base) once weekly on the same day of each week starting 2 weeks prior to exposure, and continued for4 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 2 weeks prior to

exposure, and continued for 4 weeks after leaving the endemic area.

Treatment of Uncomplicated Malaria

Adults: 800 mg (620 mg base) followed by 400 mg (310 mg base) at 6 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 6 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 a

single daily dose or in two divided doses. Doses above 400 mg a 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 a single daily dose or in two divided doses. In a small percentage of patients, side effects may require temporary reduction of the initial dosage.

Maintenance adult dosage: When a good response is obtained, the dosage may be reduced by

50 percent and continued at a maintenance level of 200 mg to 400 mg (155 to 310 mg base) daily, administered as a 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 tablets, and they can generally be decreased gradually in dosage or eliminated after a maintenance dose of hydroxychloroquine sulfate tablets has been achieved.

PRECAUTIONS

General

Use with caution in patients with gastrointestinal, neurological, or blood disorders, and in those with a 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. A 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 tt 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 tablets.

Hydroxychloroquine sulfate tablets should be administered with caution in patients having

glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

**Dermatologic Effects:**Dermatologic reactions to hydroxychloroquine sulfate tablets may occur

and, therefore, proper care should be exercised when it is administered to any patient receiving a

drug with a significant tendency to produce dermatitis.

Drug Interactions

Digoxin: Concomitant hydroxychloroquine sulfate tablets 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 tablets may enhance the effects of a

hypoglycemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

Drugs that prolong QT interval and other arrhythmogenic drugs: Hydroxychloroquine sulfate tablets prolong 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 tablets are used concomitantly with other arrhythmogenic drugs.

Mefloquine and other drugs known to lower the convulsive threshold: Hydroxychloroquine sulfate tablets can lower the convulsive threshold. Co- administration of hydroxychloroquine sulfate tablets 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 tablets.

Methotrexate: Combined use of methotrexate with hydroxychloroquine sulfate tablets 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 tablets 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 4 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 a 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 tablets, 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 tablets.

The mutagenic potential of hydroxychloroquine was not evaluated. However, chloroquine has been shown to be a catalytic inhibitor of DNA repair enzymes (topoisomerase II) and to produce weak genotoxic effects through this mode of action.

Pregnancy

**Teratogenic 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

tablets 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 tablets 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 dose (0.75 g or 1 g in one 3-year-old child). Patients should be strongly warned to keep these drugs out of the reach of children (seeOVERDOSAGE****).

**Geriatric Use:**Clinical studies of hydroxychloroquine sulfate tablets 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.

CLINICAL PHARMACOLOGY

Pharmacokinetics: Following a single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy males, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached In 3.26 hours with a 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 a half-life of 2963 hours (123.5 days). Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a 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 6 months following the 31 O mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating II near 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 3 to 4 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 3 to 4 hours. Renal clearance in rheumatoid arthritis (RA) patients taking hydroxychloroquine sulfate tablets 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, a dosage adjustment is not required for patients with renal impairment. In rheumatoid arthritis (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 a 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 againstthe erythrocytic forms of chloroquine sensitive strains of Plasmodium falclparum, Plasmodlum malarlae, Plasmodlum 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 parasitemia, or patients who acquired malaria in a 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 tablets are unknown.