Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

ARALEN (NDA-006002)

(CHLOROQUINE PHOSPHATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/24/2018 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility

Extensive new information added; please refer to label for complete information

WARNINGS

…In humans, at recommended doses for prophylaxis and treatment of malaria, observational studies as well as a meta-analysis, including a small number of prospective studies with large exposure to chloroquine during pregnancy have shown no increase in the rate of birth defects or spontaneous abortions.

07/13/2017 (SUPPL-44)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

Use of ARALEN for indications other than acute malaria is contraindicated in the presence of retinal or visual field changes of any etiology.

Use of ARALEN is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.

5 Warnings and Precautions

PRECAUTIONS

(Additions and/or revisions are underlined)

Hematological Effects/Laboratory Tests

Complete blood cell counts should be checked periodically if patients are given prolonged therapy.

Chloroquine may cause hemolysis in glucose-6 phosphate dehydrogenase (G-6-PD) deficiency. Blood monitoring may be needed as hemolytic anemia may occur, in particular in association with other drugs that cause hemolysis.

Central Nervous System Effects

Chloroquine may increase the risk of convulsions in patients with a history of epilepsy.

WARNINGS

(Additions and/or revisions are underlined)

Chloroquine-Resistant Malaria

ARALEN is not effective against chloroquine- or hydroxychloroquine-resistant strains of Plasmodium species. Chloroquine resistance is widespread in P. falciparum and is reported in P. vivax… Information regarding the geographic areas where resistance to chloroquine occurs, is available at the Centers for Disease Control and Prevention (www.cdc.gov\malaria).

Treatment of Exo-Erythocytic Forms of Malaria

Chloroquine does not treat the hypnozoite liver stage forms of Plasmodium and will therefore not prevent relapses of malaria due to P. vivax or P. ovale. Additional treatment with an anti-malarial agent active against these forms, such as an 8-aminoquinoline, is required for the treatment of infections with P. vivax and P. ovale.

Cardiac Effects

Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated during long term therapy at high doses with chloroquine. Monitor for signs and symptoms of cardiomyopathy and discontinue chloroquine if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of chloroquine may prevent life-threatening complications. QT interval prolongation, torsades de pointes, and ventricular arrhythmias have been reported. The risk is greater if chloroquine is administered at high doses. Fatal cases have been reported. Chloroquine should be used with caution in patients with cardiac disease, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (?50 bpm), and during concomitant administration with QT interval prolonging agents due to potential for QT interval prolongation.

Hypoglycemia

Chloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life-threatening in patients treated with or without antidiabetic medications (see PRECAUTIONS, Drug Interactions). Patients treated with ARALEN 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 chloroquine should have their blood glucose level checked and treatment reviewed as necessary.

Retinopathy

Irreversible retinal damage has been observed in some patients who had received chloroquine. Significant risk factors for retinal damage include daily doses of chloroquine phosphate greater than 2.3 mg/kg 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 ophthalmological examination should be performed within the first year of starting ARALEN. 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 optical coherence tomography (SD-OCT).

For individuals with significant risk factors (daily dose of chloroquine phosphate greater than 2.3 mg/kg 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 (including BCVA, VF and SD-OCT) 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 chloroquine 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.

Muscular Weakness

All patients on long-term therapy with chloroquine should be questioned and examined periodically, including testing knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs, discontinue the drug.

Pediatric Accidental Ingestion

…Patients should be strongly warned to keep ARALEN out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds.

Worsening of Psoriasis and Porphyria

…ARALEN should not be used in these conditions unless the benefit to the patient outweighs the potential risks.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post-approval use of chloroquine 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.

Ocular disorders: Maculopathy and macular degeneration have been reported and may be irreversible. Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance) and visual field defects (paracentral scotomas) in patients receiving long-term or high-dosage 4- aminoquinoline therapy have been reported.

Immune system disorders: Urticaria, anaphylactic reaction including angioedema.

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

Blood and lymphatic system disorders: Pancytopenia, aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia. Hemolytic anemia in G6PD deficient patients.

Neuropsychiatric disorders: Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, depression, and suicidal behavior.

Cardiac disorders: Hypotension, electrocardiographic changes (particularly, inversion or depression of the T-wave with widening of the QRS complex), and cardiomyopathy (which may result in cardiac failure and in some cases a fatal outcome).

Cardiac arrhythmias, conduction disorders such as bundle branch block / atrio-ventricular block, QT interval prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation have been reported with therapeutic doses of chloroquine as well as with overdose. The risk is greater if chloroquine is administered at high doses. Fatal cases have been reported.

Metabolic and Nutritional disorders: Hypoglycemia

7 Drug Interactions

(Additions and/or revisions are underlined)

Insulin and other antidiabetic drugs: As chloroquine may enhance the effects of a hypoglycemic treatment, a decrease in doses of insulin or other antidiabetic drugs may be required.

Arrhythmogenic drugs: There may be an increased risk of inducing ventricular arrhythmias if chloroquine is used concomitantly with other arrhythmogenic drugs, such as amiodarone or moxifloxacin.

Praziquantel: In a single-dose interaction study, chloroquine has been reported to reduce the bioavailability of praziquantel.

Tamoxifen: Concomitant use of chloroquine with drugs known to induce retinal toxicity such as tamoxifen is not recommended.

8 Use in Specific Populations

(Additions and/or revisions are underlined)

Usage in Pregnancy

Usage of chloroquine during pregnancy should be avoided except in the prophylaxis or treatment of malaria when the benefit outweighs the potential risk to the fetus.

Use in Patients with Hepatic Impairment

Since ARALEN is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs.