CHLOROQUINE Drug Interactions: What You Need to Know

Drug Interactions 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. 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. Ampicillin: In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. An interval of at least two hours between intake of ampicillin and chloroquine should be observed. Cyclosporine: After introduction of chloroquine (oral form), a sudden increase in serum cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is recommended and, if necessary, chloroquine should be discontinued. Mefloquine: Co-administration of chloroquine and mefloquine may increase the risk of convulsions. The blood concentrations of chloroquine and desethylchloroquine (the major metabolite of chloroquine, which also has antimalarial properties) were negatively associated with log antibody titers. Chloroquine taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine. 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 (see WARNINGS ).

CONTRAINDICATIONS Use of Chloroquine phosphate tablets for indications other than acute malaria is contraindicated in the presence of retinal or visual field changes of any etiology. Use of Chloroquine phosphate tablets is contraindicated in patients with known hypersensitivity to 4- aminoquinoline compounds.

WARNINGS Chloroquine-Resistant Malaria Chloroquine phosphate tablets are not effective against chloroquine- or hydroxychloroquine-resistant strains of Plasmodium species (see CLINICAL PHARMACOLOGY , Microbiology ). Chloroquine resistance is widespread in P. falciparum and is reported in P. vivax. Before using chloroquine for prophylaxis, it should be ascertained whether chloroquine is appropriate for use in the region to be visited by the traveler. Information regarding the geographic areas where resistance to chloroquine occurs, is available at the Centers for Disease Control and Prevention (www.cdc.gov\malaria). Patients infected with a resistant strain of plasmodia as shown by the fact that normally adequate doses have failed to prevent or cure clinical malaria or parasitemia should be treated with another form of antimalarial therapy. Treatment of Exo-Erythrocytic 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 including Cardiomyopathy and QT prolongation Fatal and life-threatening cardiotoxicity, including cardiomyopathy and arrhythmias, have been reported with the use of chloroquine (see ADVERSE REACTIONS and OVERDOSAGE ). In multiple cases, endomyocardial biopsy showed association of the cardiomyopathy with phospholipidosis in the absence of inflammation, infiltration, or necrosis. Patients may present with ventricular hypertrophy and conduction disorders. ECG findings include atrioventricular, right or left bundle branch block. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) are diagnosed. QT interval prolongation, torsades de pointes, and ventricular arrhythmias have been reported with the use of chloroquine. The risk is greater if chloroquine is administered at high doses. 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 (see WARNINGS , PRECAUTIONS , Drug Interactions , ADVERSE REACTIONS and OVERDOSAGE ). Monitor for signs and symptoms of cardiotoxicity during chloroquine therapy. Discontinue chloroquine if cardiotoxicity is suspected or demonstrated by tissue biopsy.

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 chloroquine phosphate 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 chloroquine should have their blood glucose level checked and treatment reviewed as necessary.

Retinopathy

1 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 (see PRECAUTIONS ), and concurrent macular disease. A baseline ophthalmological examination should be performed within the first year of starting chloroquine phosphate 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 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.

Central Nervous System Effects

Acute extrapyramidal disorders may occur with chloroquine (see PRECAUTIONS , ADVERSE REACTIONS and OVERDOSAGE ). These adverse reactions usually resolve after treatment discontinuation and/or symptomatic treatment.

Neuropsychiatric Reactions Including Suicidality

Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse reactions have been reported in patients treated with chloroquine (see ADVERSE REACTIONS ). Neuropsychiatric adverse reactions typically occur within the first month after the start of treatment with chloroquine and have been reported in patients with and without a prior history of psychiatric disorders. The risks and benefits of continued treatment with chloroquine should be assessed for patients who develop these symptoms. Given the long half-life of the drug, some patients may require several weeks off drug for symptoms to partially or fully abate. Advise patients to contact their healthcare provider promptly if they experience new or worsening neuropsychiatric symptoms such as depression, suicidal thoughts or behavior, or mood changes.

Skeletal Muscle

Myopathy and Neuropathy Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, and abnormal nerve conduction, have been reported. Muscle and nerve biopsies have shown associated phospholipidosis. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with chloroquine. Discontinue chloroquine if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy.

Renal Toxicity

Proteinuria with or without a moderate reduction in glomerular filtration rate have been reported with the use of chloroquine. 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 chloroquine. Discontinue chloroquine if renal toxicity is suspected or demonstrated by tissue biopsy.

Pediatric Accidental

Ingestion A number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3-year-old child). Patients should be strongly warned to keep chloroquine phosphate tablets out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds (see OVERDOSAGE and ADVERSE REACTIONS ). Worsening of Psoriasis Use of chloroquine phosphate tablets in patients with psoriasis may precipitate a severe attack of psoriasis. Chloroquine phosphate tablets should not be used in psoriasis unless the benefit to the patient outweighs the potential risks.

Risks

Associated with Use in Porphyria Administration of chloroquine to patients with porphyria may exacerbate porphyria. Avoid chloroquine in patients with porphyria.

Hepatotoxicity

Associated with Porphyria Cutanea Tarda Cases of hepatotoxicity have been reported when chloroquine was used in patients with porphyria cutanea tarda (PCT). Patients received dosages up to 500 mg per day. Most of the PCT-related cases presented with marked elevations in transaminases (> 20 times the upper limit of the reference range) within days to a month of chloroquine initiation. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, rash, nausea, dark urine, or jaundice. In this clinical context, if the patient is found to have abnormal serum liver tests, interrupt chloroquine treatment and investigate further to establish the probable cause. The safety and effectiveness of chloroquine for the treatment of PCT have not been established and chloroquine is not approved for this use.

Potential Carcinogenic Risk

Experimental data showed a potential risk of inducing gene mutations. There is insufficient evidence regarding the carcinogenicity of chloroquine in experimental animals (see PRECAUTIONS , Carcinogenesis, Mutagenesis, Impairment of Fertility ). In humans, there are insufficient data to rule out an increased risk of cancer in patients receiving long-term treatment. Usage in Pregnancy In animal studies, embryo-fetal developmental toxicity was shown at doses ranging from 250 mg/kg to 1,500 mg/kg body weight; approximately 3 to 16 times the maximum recommended therapeutic dose based on a body surface area comparison (see PRECAUTIONS , Animal Pharmacology and/or Animal Toxicology ). Preclinical data showed a potential risk of genotoxicity in some test systems ( PRECAUTIONS , Carcinogenesis, Mutagenesis, Impairment of Fertility ). 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 chloroquine exposure during pregnancy, have shown no increase in the rate of birth defects or spontaneous abortions. The individual benefit-risk balance should be reviewed before prescribing chloroquine in pregnant women.