HYDROXYCHLOROQUINE SULFATE- hydroxychloroquine sulfate tablet, film coated
Amneal Pharmaceuticals NY LLC
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use HYDROXYCHLOROQUINE SULFATE TABLETS safely and effectively. See full prescribing information for HYDROXYCHLOROQUINE SULFATE TABLETS.
HYDROXYCHLOROQUINE SULFATE tablets, for oral use
Initial U.S. Approval: 1955
INDICATIONS AND USAGE
Hydroxychloroquine sulfate tablets are an antimalarial and antirheumatic indicated for the:
Limitations of Use (1.1):
Hydroxychloroquine sulfate tablets are not recommended for the:
DOSAGE AND ADMINISTRATION
Malaria in Adult and Pediatric Patients (2.2):
- Adults: 400 mg once a week
- Pediatric patients ≥ 31 kg: 6.5 mg/kg up to 400 mg, once a week
Rheumatoid Arthritis in Adults (2.3):
Systemic Lupus Erythematosus in Adults (2.4):
Chronic Discoid Lupus Erythematosus in Adults (2.5):
DOSAGE FORMS AND STRENGTHS
Tablets: 200 mg of hydroxychloroquine sulfate. (3)
WARNINGS AND PRECAUTIONS
The most common adverse reactions reported are: nausea, vomiting, diarrhea, and abdominal pain. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
Hydroxychloroquine sulfate tablets are indicated in adult and pediatric patients for the:
Limitations of Use:
Hydroxychloroquine sulfate tablets are not recommended for:
For the most current information about drug resistance, refer to the latest recommendations from the Center for Disease Control and Prevention1.
Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults.
Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults.
Administer hydroxychloroquine sulfate tablets orally with food or milk. Do not crush or divide the tablets.
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.
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:
Treatment of Uncomplicated Malaria
The dosages for the treatment of uncomplicated malaria are:
For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary [see Microbiology (12.4)].
The recommended dosage is:
Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with hydroxychloroquine sulfate tablets.
The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses.
Hydroxychloroquine Sulfate Tablets USP, 200 mg are white to off-white, film-coated tablets debossed “AC54” on one side and plain on the other side. Each tablet contains 200 mg of hydroxychloroquine sulfate, USP equivalent to 155 mg base.
Hydroxychloroquine sulfate tablets are contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.
Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine sulfate. Signs and symptoms of cardiac compromise have occurred during acute and chronic hydroxychloroquine sulfate 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 sulfate has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in hydroxychloroquine sulfate-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 sulfate administration in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as:
Therefore, hydroxychloroquine sulfate is not recommended in patients taking other drugs that have the potential to prolong the QT interval. Monitor cardiac function as clinically indicated during hydroxychloroquine sulfate therapy. Correct electrolyte imbalances prior to use. Discontinue hydroxychloroquine sulfate if cardiotoxicity is suspected or demonstrated by tissue biopsy.
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 sulfate, 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 sulfate and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy.
Serious adverse reactions have been reported with the use of hydroxychloroquine sulfate 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 sulfate if these severe reactions occur.
Administration of hydroxychloroquine sulfate in patients with psoriasis may precipitate a severe flare-up of psoriasis. Administration of hydroxychloroquine sulfate in patients with porphyria may exacerbate porphyria. Avoid hydroxychloroquine sulfate in patients with psoriasis or porphyria, unless the benefit to the patient outweighs the possible risk.
Hydroxychloroquine sulfate may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged hydroxychloroquine sulfate therapy. If the patient develops myelosuppression which cannot be attributable to the disease, discontinue the drug.
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.
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, 5.10)].
Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine sulfate. Discontinue hydroxychloroquine sulfate if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy.
Suicidal behavior has been reported in patients treated with hydroxychloroquine sulfate [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 sulfate should be assessed for patients who develop these symptoms.
Hydroxychloroquine sulfate 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 sulfate-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.
Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of hydroxychloroquine sulfate.
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 sulfate. Drug-induced phospholipidosis may occur in other organ systems [see Warnings and Precautions (5.1, 5.7)]. Discontinue hydroxychloroquine sulfate if renal toxicity is suspected or demonstrated by tissue biopsy.
The following adverse reactions are described in greater detail in other sections:
The following adverse reactions have been identified during post-approval use of 4-aminoquinoline drugs, including hydroxychloroquine sulfate. 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:
Hydroxychloroquine sulfate prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine sulfate is used concomitantly with other arrhythmogenic drugs. Therefore, hydroxychloroquine sulfate 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)].
Hydroxychloroquine sulfate 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)].
Hydroxychloroquine sulfate can lower the seizure threshold. Co-administration of hydroxychloroquine sulfate with other antimalarials known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures.
The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine sulfate.
Concomitant use of hydroxychloroquine sulfate and methotrexate may increase the incidence of adverse reactions.
An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy.
Concomitant hydroxychloroquine sulfate and digoxin therapy may result in increased serum digoxin levels. Monitor serum digoxin levels closely in patients receiving combined therapy.
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.
Lack of efficacy of hydroxychloroquine was reported when rifampicin was concomitantly administered. Avoid concomitant use of rifampicin.
Chloroquine has been reported to reduce the bioavailability of praziquantel. Interaction of praziquantel with hydroxychloroquine cannot be ruled out.
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.
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine sulfate during pregnancy. Encourage patients to register by contacting 1-877-311-8972.
Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine sulfate 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% to 4% and 15% to 20%, respectively.
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 2,500 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 from published epidemiologic and clinical studies have not established an association with hydroxychloroquine sulfate 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.
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 hydroxychloroquine sulfate and any potential adverse effects on the breastfed child from hydroxychloroquine sulfate or from the underlying maternal condition.
The safety and effectiveness of hydroxychloroquine sulfate 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 31 kg because the film-coated tablets cannot be crushed or divided [see Dosage and Administration (2.1, 2.2)].
The safety and effectiveness of hydroxychloroquine sulfate have not been established in pediatric patients for the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus, or systemic lupus erythematosus.
Clinical trials of hydroxychloroquine sulfate 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.
Hydroxychloroquine sulfate overdosage symptoms have an onset within 1 hour to 3 hours of ingestion. The following have been reported with hydroxychloroquine sulfate overdosage:
Gastrointestinal decontamination procedures warrant consideration in patients that present within the first hour post-ingestion. If the level of consciousness rapidly deteriorates in severe poisoning, consider intubation before gastrointestinal decontamination procedures. Monitor plasma potassium levels and manage accordingly. Hemofiltration, hemodialysis, and hemoperfusion are not of benefit.
Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for overdosage management recommendations.
Hydroxychloroquine sulfate, USP is an antimalarial and antirheumatic drug, chemically described as 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino]ethanol sulfate (1:1) with the molecular formula C18H26ClN3O•H2SO4. The molecular weight of hydroxychloroquine sulfate is 433.95. Its structural formula is:
Hydroxychloroquine sulfate, USP is a white to almost white crystalline powder. It is freely soluble in water; practically insoluble in ethanol (96%) and in ether.
Hydroxychloroquine sulfate tablets, USP, 200 mg for oral administration contain 200 mg hydroxychloroquine sulfate, USP (equivalent to 155 mg base) and the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate dihydrate, maize starch, magnesium stearate, polyvinyl alcohol, polyethylene glycol, sodium lauryl sulfate, talc and titanium dioxide.
Meets USP Dissolution Test 2.
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 hydroxychloroquine sulfate in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus are not fully known.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of hydroxychloroquine have not been fully characterized.
Following a single 200 mg oral dose of hydroxychloroquine sulfate 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). Following a single oral hydroxychloroquine sulfate dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine.
After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1,161 ng/mL to 2,436 ng/mL (mean 1,918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. 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.
Hydroxychloroquine sulfate is extensively distributed to tissues.
A half-life of 123.5 days in plasma were observed following a single 200 mg oral hydroxychloroquine sulfate dose to healthy male volunteers. 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. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days.
Significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) were found in plasma and blood, with DHCQ being the major metabolite.
Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate 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 drug was approximately 16% to 30%.
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.
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.
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)].
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.
1 Center for Disease Control and Prevention. Malaria.
Hydroxychloroquine Sulfate Tablets USP, 200 mg are supplied as white to off-white, film-coated tablets debossed “AC54” on one side and plain on the other side. Each tablet contains 200 mg of hydroxychloroquine sulfate, USP equivalent to 155 mg base.
They are available as:
Bottles of 100: NDC 69238-1544-1
Bottles of 500: NDC 69238-1544-5
Store at 20° to 25ºC (68° to 77ºF); excursions permitted between 15º to 30ºC (59° to 86ºF) [see USP Controlled Room Temperature]. Keep out of the reach of children.
Dispense in a tight, light-resistant container as defined in the USP.
Do not crush or divide hydroxychloroquine sulfate film-coated tablets.
Important Administration Instructions
Advise the patient to take hydroxychloroquine sulfate tablets with food or milk and not to crush or divide the tablet.
Cardiomyopathy and Ventricular Arrhythmias
Inform the patient that serious cardiac effects, life-threatening and fatal cases have been reported with use of hydroxychloroquine sulfate. Advise patients to seek medical attention immediately if they experience any symptoms of heart rhythm changes including fast or irregular heartbeat, lightheadedness, dizziness, or syncope [see Warnings and Precautions (5.1)].
Inform the patient that irreversible retinal damage has been observed in some patients with the use of hydroxychloroquine sulfate. Advise patients of the importance of the ophthalmology visits for monitoring their eyes. Instruct patients to seek medical attention promptly if they experience decreased vision or decreased dark adaptation [see Warnings and Precautions (5.2)].
Serious Skin Reactions
Inform the patient that severe, life-threatening skin reactions have been reported with the use of hydroxychloroquine sulfate. Advise the patient to seek medical attention immediately if experiencing any of the following signs and symptoms: blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever [see Warnings and Precautions (5.3)].
Skeletal Muscle Myopathy or Neuropathy
Inform the patient that muscle weakness and atrophy has been reported with hydroxychloroquine sulfate use. Advise patients to report to the physician symptoms of muscle weakness [see Warnings and Precautions (5.7)].
Neuropsychiatric Reactions Including Suicidality
Alert patients to seek medical attention immediately if they experience new or worsening depression, suicidal thoughts, or other mood changes [see Warnings and Precautions (5.8)].
Inform the patient that hydroxychloroquine sulfate has been associated with severe hypoglycemia. Advise the patient to monitor blood sugar levels if possible and to seek medical attention if experiencing any of the signs and symptoms of hypoglycemia such as sweating, shakiness, weakness, dizziness, tachycardia, nausea, blurred vision, confusion, fainting, or loss of consciousness [see Warnings and Precautions (5.9)].
Inform the patient that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine sulfate during pregnancy. Encourage patients to register by contacting 1-877-311-8972 [see Use in Specific Populations (8.1)].
Amneal Pharmaceuticals Pvt. Ltd.
Oral Solid Dosage Unit
Ahmedabad 382213, INDIA
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807
hydroxychloroquine sulfate tablet, film coated
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