1.1 Malaria

SOVUNA is indicated in adult and pediatric patients for the:

• Treatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale.
• Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported.

Limitations of Use:

SOVUNA is not recommended for:

• Treatment of complicated malaria.
• Treatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4)].
• Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.
• Prophylaxis of malaria in geographic areas where chloroquine resistance occurs.
• Prevention of relapses of P. vivax or P. ovale because it is not active against the hypnozoite liver stage forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary [see Microbiology (12.4)].

For the most current information about drug resistance, refer to the latest recommendations from the Center for Disease Control and Prevention.1

1.2 Rheumatoid Arthritis

SOVUNA is indicated for the treatment of acute and chronic rheumatoid arthritis in adults.

1.3 Systemic Lupus Erythematosus

SOVUNA is indicated for the treatment of systemic lupus erythematosus in adults.

1.4 Chronic Discoid Lupus Erythematosus

SOVUNA is indicated for the treatment of chronic discoid lupus erythematosus in adults.

2.1 Important Administration Instructions

Administer SOVUNA orally with food or milk. Do not crush the tablets.

2.2 Dosage for Malaria in Adult and Pediatric Patients

SOVUNA is not recommended in pediatric patients less than 23 kg because the lowest possible dose of 150 mg (half of the scored 300 mg tablet) exceeds the recommended dose for these patients.

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 weighing greater than or equal to 23 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 weighing greater than or equal to 23 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 infections, concomitant therapy with an 8­aminoquinoline drug is necessary [see Microbiology (12.4)].

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 [see Warnings and Precautions (5.2)].
• Chronic dosage: 200 mg, 300 mg or 400 mg daily, as a single dose or two divided doses.

Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with SOVUNA.

2.4 Dosage for Systemic Lupus Erythematosus in Adults

The recommended dosage is 200 mg, 300 mg or 400 mg daily, as a single dose or two divided doses

2.5 Dosage for Chronic Discoid Lupus Erythematosus in Adults

The recommended dosage is 200 mg or 400 mg daily, as a single dose or two divided doses.

5.1 Cardiomyopathy and Ventricular Arrhythmias

Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with SOVUNA. Signs and symptoms of cardiac compromise have occurred during acute and chronic SOVUNA 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 (5.8, 5.11)].

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.

SOVUNA has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in SOVUNA-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 SOVUNA 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, SOVUNA 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 SOVUNA therapy. Discontinue SOVUNA 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 SOVUNA, a 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 SOVUNA 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 SOVUNA 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 a 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 (5.4,5.5), Adverse Reactions (6)]. Discontinue SOVUNA if these severe reactions occur.

5.4 Worsening of Psoriasis

Administration of SOVUNA to patients with psoriasis may precipitate a severe flare-up of psoriasis. Avoid SOVUNA in patients with psoriasis, unless the benefit to the patient outweighs the possible risk.

5.5 Risks Associated with Use in Porphyria

Administration of SOVUNA to patients with porphyria may exacerbate porphyria. Avoid SOVUNA in patients with porphyria.

Hepatotoxicity Associated with Porphyria Cutanea Tarda

Cases of hepatotoxicity have been reported when hydroxychloroquine was used in patients with porphyria cutanea tarda (PCT). Patients received dosages ranging from 200 mg twice weekly to 400 mg daily. Most of the PCT-related cases presented with marked elevations in transaminases (>20 times upper limit of the reference range) within days to a month of hydroxychloroquine initiation. In some cases, PCT was diagnosed only after the occurrence of treatment-induced liver injury, when hydroxychloroquine was prescribed for an approved indication. Some of the cases were associated with other risk factors for hepatic injury (e.g., alcohol use, concomitant hepatotoxic medications).

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, rash, nausea, dark urine, or jaundice. In this clinical context, if the patient is found to have abnormal serum liver tests (e.g., ALT level greater than three times the upper limit of the reference range, total bilirubin greater than two times the upper limit of the reference range), interrupt treatment with SOVUNA, and investigate further to establish the probable cause.

The safety and effectiveness of SOVUNA for the treatment of PCT have not been established and SOVUNA is not approved for this use.

5.6 Hematologic Toxicity

SOVUNA may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged SOVUNA therapy. If the patient develops myelosuppression which cannot be attributable to the disease, discontinue the drug.

5.7 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.

5.8 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 systems [see Warnings and Precautions

(5.1, 5.11)].

Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with SOVUNA. Discontinue SOVUNA if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy.

5.9 Neuropsychiatric Reactions Including Suicidality

Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse reactions have been reported in patients treated with SOVUNA [see Adverse Reactions (6)].

Neuropsychiatric adverse reactions typically occurred within the first month after the start of treatment with hydroxychloroquine and have been reported in patients with and without a prior history of psychiatric disorders.

The risks and benefits of continued treatment with SOVUNA should be assessed for patients who develop these symptoms. Given the long half-life of the drug, some patients may require several weeks off drug for symptoms to partially or fully abate.

Advise patients to contact their healthcare provider promptly if they experience new or worsening neuropsychiatric symptoms such as depression, suicidal thoughts or behavior, or mood changes.

5.10 Hypoglycemia

SOVUNA 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 SOVUNA-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.

5.11 Renal Toxicity

Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of SOVUNA.

Renal biopsy showed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Physicians should consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders who are receiving SOVUNA. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.8)]. Discontinue SOVUNA if renal toxicity is suspected or demonstrated by tissue biopsy.

7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs

SOVUNA prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if SOVUNA is used concomitantly with other arrhythmogenic drugs. Therefore, SOVUNA 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

SOVUNA 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)].

7.3 Drugs that Lower the Seizure Threshold

SOVUNA can lower the seizure threshold. Co-administration of SOVUNA 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 SOVUNA.

7.5 Methotrexate

Concomitant use of SOVUNA and methotrexate may increase the incidence of adverse reactions.

7.6 Cyclosporine

An increased plasma cyclosporin level was reported when cyclosporin and SOVUNA were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy.

7.7 Digoxin

Concomitant SOVUNA 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 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.

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 4 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 a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Interaction of ampicillin with hydroxychloroquine cannot be ruled out.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SOVUNA 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 SOVUNA use in pregnant women have not identified a 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 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.

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 2500 g) infants, and small for gestational age at birth.

Systemic Lupus Erythematosus: Pregnant women with systemic lupus erythematosus, especially those with increased disease activity, are at increased risk of adverse pregnancy outcomes, including spontaneous abortion, fetal death, preeclampsia, preterm birth, and intrauterine growth restriction. Passage of maternal auto-antibodies across the placenta may result in neonatal illness, including neonatal lupus and congenital heart block.

Data

Human Data

Data from published epidemiologic and clinical studies have not established an association with SOVUNA 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 mother’s clinical need for SOVUNA and any potential adverse effects on the breastfed child from SOVUNA or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of SOVUNA 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 23 kg because the lowest possible dose of 150 mg (half of the scored 300 mg tablet) exceeds the recommended dose for these patients [see Dosage and Administration (2.2)].

The safety and effectiveness of SOVUNA 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 SOVUNA 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 or Hepatic Disease

A reduction in the dosage of SOVUNA may be necessary in patients with hepatic or renal disease.

12.1 Mechanism of Action

Malaria

Hydroxychloroquine is a 4-aminoquinoline antimalarial [see Microbiology (12.4)] and antirheumatic agent.

Rheumatoid Arthritis, Systemic Lupus Erythematosus and Chronic Discoid Lupus Erythematosus

The mechanisms underlying the anti-inflammatory and immunomodulatory effects of SOVUNA 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 SOVUNA in rheumatoid arthritis and lupus patients.

Absorption

Following a single 200 mg oral dose of SOVUNA 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). 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.

Distribution

SOVUNA 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, 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 SOVUNA 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 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.

Antimicrobial Activity

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.

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 (1.1)].

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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

16.1 How Supplied

SOVUNA (hydroxychloroquine sulfate) Tablets are available in the following strengths and packing configurations:

• 200 mg of hydroxychloroquine sulfate: white to off-white, capsule-shaped, film-coated tablets, debossed with "172" on one side and plain on the other side.

         Bottles of 30 tablets with child resistant closure (NDC 70954-804-10)

         Bottles of 100 tablets with child resistant closure (NDC 70954-804-20)

• 300 mg of hydroxychloroquine sulfate: white to off-white, functionally scored, capsule-shaped, film-coated tablets, debossed with "1" on left side of the score and "71" on right side of the score and plain on the other side.

         Bottles of 100 tablets with child resistant closure (NDC 70954-805-10)

16.2 Storage

Dispense in a tight, light-resistant container as defined in the USP/NF. Keep out of the reach of children.

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