Hydroxychloroquine: uses, appearance and warnings

PLAQUENIL is 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. (1.1) • Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. (1.1) • Treatment of rheumatoid arthritis in adults. (1.2) • Treatment of systemic lupus erythematosus in adults. (1.3) • Treatment of chronic discoid lupus erythematosus in adults. (1.4) Limitations of Use (1.1): PLAQUENIL is 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 PLAQUENIL 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: PLAQUENIL 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 PLAQUENIL is indicated for the treatment of acute and chronic rheumatoid arthritis in adults. 1.3 Systemic Lupus Erythematosus PLAQUENIL is indicated for the treatment of systemic lupus erythematosus in adults. 1.4 Chronic Discoid Lupus Erythematosus PLAQUENIL is indicated for the treatment of chronic discoid lupus erythematosus in adults.

Tablets: 200 mg of hydroxychloroquine sulfate, white to off-white, film-coated tablet imprinted with “PLAQUENIL” on one face in black ink. Tablets: 200 mg of hydroxychloroquine sulfate

16.1 How Supplied PLAQUENIL tablets contain 200 mg hydroxychloroquine sulfate (equivalent to 155 mg base). White to off-white film coated, no score, tablet imprinted with “PLAQUENIL” on one face in black ink. The tablets are available in bottles of: • 60 tablets - NDC 59212-562-60 • 100 tablets - NDC 59212-562-10 and NDC 59212-562-11 16.2 Storage Dispense in a tight, light-resistant container as defined in the USP/NF. Store at room temperature up to 30°C (86°F) and allow for excursions between 15°C and 30°C (59°F and 86°F).

PLAQUENIL is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds. • Patients with hypersensitivity to 4-aminoquinoline compounds ( 4 )

• 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 : Avoid in patients with psoriasis. (5.4) • Risks Associated with Use in Porphyria : Avoid in patients with porphyria. Hepatotoxicity was reported in patients with porphyria cutanea tarda. (5.5) • Hematologic Toxicity: Discontinue if myelosuppression occurs. (5.6) • Renal Toxicity: Consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders. Discontinue PLAQUENIL if renal toxicity is suspected or demonstrated by tissue biopsy in any organ system. ( 5.1 , 5.8 , 5.11 ) 5.1 Cardiomyopathy and Ventricular Arrhythmias Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with PLAQUENIL. Signs and symptoms of cardiac compromise have occurred during acute and chronic PLAQUENIL 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. PLAQUENIL has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in PLAQUENIL-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 PLAQUENIL 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, PLAQUENIL 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 PLAQUENIL therapy. Discontinue PLAQUENIL 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 PLAQUENIL, 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 PLAQUENIL 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 PLAQUENIL 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 PLAQUENIL if these severe reactions occur. 5.4 Worsening of Psoriasis Administration of PLAQUENIL to patients with psoriasis may precipitate a severe flare-up of psoriasis. Avoid PLAQUENIL in patients with psoriasis, unless the benefit to the patient outweighs the possible risk. 5.5 Risks Associated with Use in Porphyria Administration of PLAQUENIL to patients with porphyria may exacerbate porphyria. Avoid PLAQUENIL 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. …

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 [see Warnings and Precautions (5.4) ] • Risks Associated with Use in Porphyria [see Warnings and Precautions (5.5) ] • Hematologic Toxicity [see Warnings and Precautions (5.6) ] • Hemolytic Anemia Associated with G6PD [see Warnings and Precautions (5.7)] • Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions (5.8) ] • Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions (5.9) ] • Hypoglycemia [see Warnings and Precautions (5.10)] • Renal Toxicity [see Warnings and Precautions (5.11) ] The following adverse reactions have been identified duri …

• Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. ( 7.1 ) • See FPI for more important drug interactions.( 7 ) 7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs PLAQUENIL prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if PLAQUENIL is used concomitantly with other arrhythmogenic drugs. Therefore, PLAQUENIL 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 PLAQUENIL 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) ]. …