Hydroxychloroquine Sulfate: Package Insert and Label Information

HYDROXYCHLOROQUINE SULFATE- hydroxychloroquine sulfate tablet, film coated
Bryant Ranch Prepack

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1 INDICATIONS & USAGE

1.1 Malaria

Hydroxychloroquine sulfate tablets are 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:
Hydroxychloroquine sulfate tablets are 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 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.

2 DOSAGE & ADMINISTRATION

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.
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 ≥ 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 = 2,000 mg).
• Pediatric patients ≥ 31 kg: Administer 13 mg/kg (up to 800 mg) initially; subsequently administer 6.5 mg/kg (up to 400 mg) at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 31 mg/kg — up to 2,000 mg).
For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline 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 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.

3 DOSAGE FORMS & STRENGTHS

Hydroxychloroquine sulfate tablets, USP are white to off white, capsule shaped, biconvex, film coated tablets debossed with ‘L7’ on one side and plain on the other side.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

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 a 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, 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 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 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), 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 a 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 a 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.

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections:
• Cardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions (5.1)]
• Retinal Toxicity [see Warnings and Precautions (5.2)]
• Serious Skin Reactions [see Warnings and Precautions (5.3)]
• Worsening of Psoriasis and Porphyria [see Warnings and Precautions (5.4)]
• Hematologic Toxicity [see Warnings and Precautions (5.5)]
• Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.6)]
• Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.7)]
• Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.8)]
• Hypoglycemia [see Warnings and Precautions (5.9)]
The following adverse reactions have been identified during post-approval use of 4-aminoquinoline drugs, including hydroxychloroquine. 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)
Psychiatric disorders: Affect/emotional lability, irritability, nervousness, nightmares, psychosis, suicidal ideation, suicidal behavior
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)

7 DRUG INTERACTIONS

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, a decrease in dosage of insulin and other antidiabetic drugs may be necessary [see Warnings and Precautions (5.8)].

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