Chloroquine (chloroquine phosphate 250 mg) Dailymed

Rev. 05/10 Rx Only

Boxed Warning section

For Malaria and Extraintestinal Amebiasis

Description

Chloroquine Phosphate, USP, is a 4-aminoquinoline compound for oral administration. It is a white, odorless, bitter tasting, crystalline substance, freely soluble in water.

Chloroquine Phosphate Tablets are an antimalarial and amebicidal drug.

Each tablet, for oral administration, contains 250 mg chloroquine phosphate (equivalent to 150 mg base) or 500 mg chloroquine phosphate (equivalent to 300 mg base).

Inactive ingredients 250 mg: Calcium Stearate, Colloidal Silicon Dioxide, Dibasic Calcium Phosphate, Microcrystalline Cellulose, and Talc.

Inactive ingredients 500 mg: Colloidal Silicon Dioxide, Corn Starch, Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose, Polyvinylpyrrolidone, Sodium Starch Glycolate, and Titanium Dioxide. Film Coating and Polishing Solution contains: D&C Red #27 Aluminum Lake, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, Hypromellose, Polyethylene Glycol, Polysorbate 80 and Titanium Dioxide.

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

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.

Microbiology

Chloroquine is an antimalarial agent. While the drug can inhibit certain enzymes, its effect is believed to result, at least in part from its interaction with DNA. However, the mechanism of plasmodicidal action of chloroquine is not completely certain.

Chloroquine is active against the erthyrocytic forms of Plasmodium vivax, Plasmodium malariae, and susceptible strains of Plasmodium falciparum (but not the gametocytes of P. falciparum). It is not effective against exoerythrocytic forms of the parasite.

In vitro studies with trophozoites of Entamoeba histolytica have demonstrated that chloroquine also possesses amebicidal activity comparable to that of emetine.

Resistance of Plasmodium falciparum to chloroquine is widespread and cases of Plasmodium vivax have been reported.

Indications And Usage

Chloroquine Phosphate Tablets are indicated for suppressive treatment and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis.

Chloroquine Phosphate Tablets do not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum.

Contraindications

Use of this drug is contraindicated in the presence of retinal or visual field changes either attributable to 4-aminoquinoline compounds or to any other etiology, and in patients with known hypersensitivity to 4-aminoquinoline compounds. However, in the treatment of acute attacks of malaria caused by susceptible strains of plasmodia, the physician may elect to use this drug after carefully weighing the possible benefits and risks to the patient.

Warnings

It has been found that certain strains of P. falciparum have become resistant to 4-aminoquinoline compounds (including chloroquine and hydroxychloroquine). Chloroquine resistance is widespread and, at present, is particularly prominent in various parts of the world including sub-Saharan Africa, Southeast Asia, the Indian subcontinent, and over large portions of South America, including the Amazon basin¹.

Before using chloroquine for prophylaxis, it should be ascertained whether chloroquine is appropriate for use in the region to be visited by the traveler. Chloroquine should not be used for treatment of P. falciparum infections acquired in areas of chloroquine resistance or malaria occurring in patients where Chloroquine prophylaxis has failed.

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 parasliia should be treated with another form of antimalarial therapy.

Irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinoline therapy. Retinopathy has been reported to be dose related.

When prolonged therapy with any antimalarial compound is contemplated, initial (base line) and periodic ophthalmologic examinations (including visual acuity, expert slit-lamp, funduscopic, and visual field tests) should be performed.

If there is any indication (past or present) of abnormality in the visual acuity, visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and streaks) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be discontinued immediately and the patient closely observed for possible progression. Retinal changes (and visual disturbances) may progress even after cessation of therapy.

All patients on long-term therapy with this preparation 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.

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 this drug out of the reach of children because they are especially sensitive to the 4-aminoquinoline compounds.

Use of Chloroquine Phosphate Tablets in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The drug should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the potential risks.

Usage in Pregnancy:

Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice passed rapidly across the placenta and accumulated selectively in the melanin structures of the fetal eyes. It was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body². There are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgement of the physician the benefit outweighs the potential risk to the fetus.

Precautions

Hematological Effects/Laboratory Tests:

Complete blood cell counts should be made periodically if patients are given prolonged therapy. If any severe blood disorder appears which is not attributable to the disease under treatment, discontinuance of the drug should be considered.

The drug should be administered with caution to patients having G-6-PD (glucose-6 phosphate dehydrogenase) deficiency.

Auditory Effects:

In patients with preexisting auditory damage, chloroquine should be administered with caution. In case of any defects in hearing, chloroquine should be immediately discontinued, and the patients closely observed (see ADVERSE REACTIONS).

Hepatic Effects:

Since this drug 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.

Central Nervous System Effects:

Patients with a history of epilepsy should be advised about the risk of chloroquine provoking seizures.

Drug Interactions:

Antacids and kaolin: Antacids and kaolin can reduce the 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. An interval of at least two hours between intake of this agent 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.

Pregnancy:

See WARNINGS, Usage in Pregnancy.

Nursing Mothers:

Because of the potential for serious adverse reactions in nursing infants from chloroquine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential clinical benefit of the drug to the mother.

The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single dose of chloroquine (600 mg base). The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. Separate chemoprophylaxis for the infant is required. See DOSAGE AND ADMINISTRATION.

Pediatric Use:

See WARNINGS and DOSAGE AND ADMINISTRATION.

Geriatric Use:

Clinical studies of Chloroquine Phosphate 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.

Adverse Reactions

Special Senses: Ocular: Irreversible retinal damage in patients receiving long-term or high-dosage 4-aminoquinoline therapy; visual disturbances (blurring of vision and difficulty of focusing or accommodation); nyctalopia; scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomas, e.g., difficulty in reading with words tending to disappear, seeing half an object, misty vision, and fog before the eyes. Reversible corneal opacities have also been reported.

Auditory: Nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory damage.

Musculoskeletal System: Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, which may be associated with mild sensory changes, depression of tendon reflexes and abnormal nerve conduction, have been noted.

Gastrointestinal system: Hepatitis increased liver enzymes, anorexia, nausea, vomiting, diarrhea, abdominal cramps.

Skin and appendages: Rare reports of erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis and similar desquamation-type events. Pleomorphic skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus, urticaria, anaphylactic/anaphylactoid reaction including angioedema, photosensitivity and hair loss and bleaching of hair pigment.

Hematologic system: Rarely, pancytopenia, aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia.

Nervous system: Convulsive seizures, mild and transient headache, polyneuritis. Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes and depression.

Cardiovascular system: Rarely, hypotension, electrocardiographic change (particularly, inversion or depression of the T-wave with widening of the QRS complex), and cardiomyopathy.

To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001, and the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.