Chloroquine Phosphate

CHLOROQUINE PHOSPHATE- chloroquine phosphate tablet
Amneal Pharmaceuticals of New York LLC

DESCRIPTION

Chloroquine phosphate tablet, USP, is a 4-aminoquinoline compound for oral administration. It is a white, crystalline powder, freely soluble in water, practically insoluble in alcohol (ethanol 96%), in chloroform and in ether.

Chloroquine phosphate tablet is an antimalarial and amebicidal drug.

Chemically, it is 7-chloro-4-[[4- (diethylamino)-1-methylbutyl]amino] quinoline phosphate (1:2) and has the following structural formula:

1

Each tablet contains 250 mg of chloroquine phosphate USP, equivalent to 150 mg chloroquine base.

Inactive Ingredients: Anhydrous citric acid, hydrogenated vegetable oil, lactose monohydrate, magnesium stearate, corn starch, pregelatinized starch and starch.

CLINICAL PHARMACOLOGY

Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract, and only a small proportion of the administered dose is found in the stools. Approximately 55% of the drug in the plasma is bound to nondiffusible plasma constituents. Excretion of chloroquine is quite slow but is increased by acidification of the urine. Chloroquine is deposited in the tissues in considerable amounts. In animals, from 200 to 700 times the plasma concentration may be found in the liver, spleen, kidney, and lung; leukocytes also concentrate the drug. The brain and spinal cord, in contrast, contain only 10 to 30 times the amount present in plasma.

Chloroquine undergoes appreciable degradation in the body. The main metabolite is desethylchloroquine, which accounts for one fourth of the total material appearing in the urine; bisdesethylchloroquine, a carboxylic acid derivative, and other metabolic products as yet uncharacterized are found in small amounts. Slightly more than half of the urinary drug products can be accounted for as unchanged chloroquine.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with oral azithromycin (500 mg, 1,000 mg, and 1,500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1,000 mg and 1,500 mg azithromycin, respectively.

Microbiology

Mechanism of Action: Chloroquine, a 4-aminoquinoline, is an anti-protozoal agent. The precise mechanism by which chloroquine exhibits activity is not known. Chloroquine, may exert its effect against Plasmodium species by concentrating in the acid vesicles of the parasite and by inhibiting polymerization of heme. It can also inhibit certain enzymes by its interaction with DNA.

Activity in Vitro and in Clinical Infections: Chloroquine is active against the erythrocytic forms of susceptible strains of Plasmodium falciparum, Plasmodium malariae , Plasmodium ovale, and Plasmodium vivax. Chloroquine is not active against the gametocytes and the exoerythrocytic forms including the hypnozoite stage (P. vivax and P. ovale) of the Plasmodium parasites.

In vitro studies with Chloroquine demonstrated that it is active against the trophozoites of Entamoeba histolytica.

Drug Resistance: Resistance of Plasmodium parasites to chloroquine is widespread (see INDICATIONS AND USAGE,Limitations of Use in Malaria and WARNINGS).

Plasmodium parasites exhibiting reduced susceptibility to hydroxychloroquine also show reduced susceptibility to chloroquine.

Patients in whom chloroquine or hydroxychloroquine have failed to prevent or cure clinical malaria or parasitemia, or patients who acquired malaria in a geographic area where chloroquine resistance is known to occur should be treated with another form of antimalarial therapy (see WARNINGS and INDICATIONS AND USAGE, Limitations of Use).

INDICATIONS AND USAGE

Chloroquine phosphate tablets are indicated for the:

  • Treatment of uncomplicated malaria due to susceptible strains of P. falciparum, P.malariae, P. ovale , and P.vivax.
  • Prophylaxis of malaria in geographic areas where resistance to chloroquine is not present.
  • Treatment of extraintestinal amebiasis.

Chloroquine phosphate tablets do not prevent relapses in patients with vivax or ovale malaria because it is not effective against exoerythrocytic forms of the parasites.

Limitations of Use in Malaria:

  • Do not use chloroquine phosphate tablets for the treatment of complicated malaria (high-grade parasitemia and/or complications e.g., cerebral malaria or acute renal failure).
  • Do not use chloroquine phosphate tablets for malaria prophylaxis in areas where chloroquine resistance occurs, Resistance to chloroquine phosphate tablets are widespread in P. falciparum, and is reported in P.vivax (see WARNINGS).
  • Concomitant therapy with an 8-aminoquinoline drug is necessary for treatment of the hypnozoite liver stage forms of P.vivax and P.ovale (see DOSAGE AND ADMINISTRATION).

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 are 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.

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