Hydroxychloroquine Tablets

Hydroxychloroquine sulfate is a white or practically white, crystalline powder, freely soluble in water; practically insoluble in alcohol, chloroform, and in ether. The chemical name for hydroxychloroquine sulfate is 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino]ethanol sulfate (1:1). Its structural formula is:

The molecular weight of hydroxychloroquine sulfate is 433.95, and molecular formula is C18H26ClN3O.H2SO4.

Hydroxychloroquine sulfate tablets contain 200 mg hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral administration.

Inactive Ingredients: Dibasic calcium phosphate USP, hypromellose USP, magnesium stearate NF, polyethylene glycol 400 NF, polysorbate 80 NF, corn starch, titanium dioxide USP, carnauba wax NF, shellac NF, black iron oxide NF.

Resistant strains of malaria: Hydroxychloroquine sulfate tablets are not effective against chloroquine-resistant strains of P. falciparum (see CLINICAL PHARMACOLOGY – Microbiology).

Ocular: Irreversible retinal damage has been observed in some patients who had received hydroxychloroquine sulfate. Significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease.

A baseline ocular examination is recommended within the first year of starting Hydroxychloroquine sulfate tablets. The baseline exam should include: 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 individuals with significant risk factors (daily dose of hydroxychloroquine sulfate greater than 5.0 mg/kg base of actual body weight, subnormal glomerular filtration, use of tamoxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SD-OCT. For individuals without significant risk factors, annual exams can usually be deferred until five years of treatment.

In individuals of Asian descent, retinal toxicity may first be noticed outside the macula. 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.

It is recommended that hydroxychloroquine be discontinued if ocular toxicity is suspected and the patient should be closely observed given that retinal changes (and visual disturbances) may progress even after cessation of therapy.

Cardiac Effects, including Cardiomyopathy and QT prolongation: Postmarketing cases of life-threatening and fatal cardiomyopathy have been reported with use of Hydroxychloroquine sulfate tablets as well as with use of chloroquine. Patients may present with atrioventricular block, pulmonary hypertension, sick sinus syndrome or with cardiac complications. ECG findings may include atrioventricular, right or left bundle branch block. Signs or symptoms of cardiac compromise have appeared during acute and chronic treatment. Clinical monitoring for signs and symptoms of cardiomyopathy is advised, including use of appropriate diagnostic tools such as ECG to monitor patients for cardiomyopathy during Hydroxychloroquine sulfate tablets therapy. Chronic toxicity should be considered when conduction disorders (bundle branch block/atrio-ventricular heart block) or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of Hydroxychloroquine sulfate tablets may prevent life-threatening complications.

Hydroxychloroquine sulfate tablets prolong the QT interval. Ventricular arrhythmias and torsades de pointes have been reported in patients taking Hydroxychloroquine sulfate tablets (see OVERDOSAGE). Therefore, Hydroxychloroquine sulfate tablets should not be administered with other drugs that have the potential to prolong the QT interval (see DRUG INTERACTIONS).

Worsening of psoriasis and porphyria: Use of Hydroxychloroquine sulfate tablets in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The preparation should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the possible hazard.

Proximal Myopathy and 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 been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with Hydroxychloroquine sulfate tablets.

Neuropsychiatric events, including suicidality: Suicidal behavior has been rarely reported in patients treated with Hydroxychloroquine sulfate tablets.

Hypoglycemia: Hydroxychloroquine sulfate tablets have been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with or without antidiabetic medications (see DRUG INTERACTIONS and ADVERSE REACTIONS). Patients treated with Hydroxychloroquine sulfate tablets should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with Hydroxychloroquine sulfate tablets should have their blood glucose checked and treatment reviewed as necessary.

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 if 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 doses (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 (see OVERDOSAGE).

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.

The following adverse reactions have been identified during post-approval use of Hydroxychloroquine sulfate tablets or other 4-aminoqunoline compounds. 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 failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Hemolysis reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Cardiac disorders: Cardiomyopathy which may result in cardiac failure and in some cases a fatal outcome (see WARNINGS and OVERDOSAGE). Hydroxychloroquine sulfate tablets prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported in patients taking Hydroxychloroquine sulfate tablets (see OVERDOSAGE and DRUG INTERACTIONS).

Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, nerve deafness, deafness.

Eye disorders: Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance), visual field defects (paracentral scotomas) and visual disturbances (visual acuity), maculopathies (macular degeneration), decreased dark adaptation, color vision abnormalities, corneal changes (edema and opacities) including corneal deposition of drug with or without accompanying symptoms (halo around lights, photophobia, blurred vision).

Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal pain.

General disorders and administration site conditions: Fatigue.

Hepatobiliary disorders: Liver function tests abnormal, hepatic failure acute.

Immune system disorders: Urticaria, angioedema, bronchospasm

Metabolism and nutrition disorders: Decreased appetite, hypoglycemia, porphyria, weight decreased.

Musculoskeletal and connective tissue disorders: Sensorimotor disorder, skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes and abnormal nerve conduction.

Nervous system disorders: Headache, dizziness, seizure, ataxia and extrapyramidal disorders such as dystonia, dyskinesia, and tremor have been reported with this class of drugs.

Psychiatric disorders: Affect/emotional lability, nervousness, irritability, nightmares, psychosis, suicidal behavior.

Skin and subcutaneous tissue disorders: Rash, pruritus, pigmentation disorders in skin and mucous membranes, hair color changes, alopecia. Dermatitis bullous eruptions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), photosensitivity, dermatitis exfoliative, acute generalized exanthematous pustulosis (AGEP). AGEP has to be distinguished from psoriasis, although Hydroxychloroquine sulfate tablets may precipitate attacks of psoriasis. It may be associated with pyrexia and hyperleukocytosis.

To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Hydroxychloroquine sulfate tablets are white, to off-white, film coated tablets imprinted "PLAQUENIL" on one face in black ink. Each tablet contains 200 mg hydroxychloroquine sulfate (equivalent to 155 mg base). Bottles of 100 tablets (NDC 66993-057-02) and 500 tablets (NDC 66993-057-04).

Do not crush or divide hydroxychloroquine sulfate film-coated tablets (see DOSAGE AND ADMINISTRATION).

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

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

Distributed by:
Prasco Laboratories
Mason, OH 45040 USA

Revised 01/2017
©2015 Prasco Laboratories

All rights reserved.

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