Antimalarial – Antiparasitic
Action And Clinical Pharmacology: Chloroquine has been found to be highly active against the erythrocytic forms of Plasmodium vivax, ovale and malariae and many strains of Plasmodium falciparum (but not the gametocytes of Plasmodium falciparum). The precise mechanism of plasmodicidal action of the drug is not known. While the drug can inhibit certain enzymes, its effect is believed to result, in part, from its interaction with DNA.
Chloroquine does not prevent vivax malariae infection when administered prophylactically. It acts on the erythrocytic forms of the parasite, inhibiting parasite development in the red blood cell thus preventing or suppressing clinical symptoms. Chloroquine does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exo-erythrocytic forms of the parasite. 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 a susceptible strain of falciparum malaria, it abolishes the acute attack and effects complete cure of the infection.
In vitro studies with trophozoites of Entamoeba histolytica have demonstrated that chloroquine also possesses amebicidal activity comparable to that of emetine.
Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract. Approximately 55% of the drug in the plasma is bound to nondiffusible plasma constituents. Chloroquine is deposited in 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. Bisdesethylchloroquine, a carboxylic acid derivative, and other uncharacterized metabolites are found in small amounts. Slightly more than half of the urinary drug products can be accounted for as unchanged chloroquine and about one fourth is desethylchloroquine. Excretion is quite slow, but can be increased by acidification of urine.
Indications And Clinical Uses: The 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 treatment of extraintestinal amebiasis.
(Although chloroquine has been used in the treatment of rheumatoid arthritis and discoid lupus erythematosus, it is considered that the potential toxicity of the drug outweighs any anticipated benefits.)
Contra-Indications: 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.
Precautions: In recent years it has been found that certain strains of P. falciparum have become resistant to 4-aminoquinoline compounds (including chloroquine and hydroxychloroquine) as shown by the fact that normally adequate doses have failed to prevent or cure clinical malaria or parasitemia. Treatment with quinine or other specific forms of therapy is therefore advised for patients infected with a resistant strain of parasites.
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 defect 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 skeletal muscle function and tendon reflexes, (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. One case involved the ingestion of a relatively small dose (1 g of chloroquine in a 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 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 possible hazard.
In patients with pre-exisiting auditory damage, chloroquine should be administered with caution. In case of any defect in hearing, chloroquine should be immediately discontinued, and the patient closely observed.
Patients with a history of epilepsy should be advised about the risk of chloroquine provoking seizures.
Pregnancy: Usage of this drug during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the possible hazard. It should be noted that radioactively tagged chloroquine administered i.v. to pregnant pigmented CBA mice passed rapidly across the placenta, accumulated selectively in the melanin structures of the fetal eyes and was retained in the ocular tissues for 5 months after the drug had been eliminated from the rest of the body.
Lactation: Chloroquine crosses the placenta and is excreted in human breast milk. Because of the potential of chloroquine to produce serious adverse reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the therapy to the mother.
Since the 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.
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.
Drug Interactions: Antacids and kaolin can reduce the absorption of chloroquine. An interval of at least 4 hours between intake of these agents and chloroqine should be observed.
Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level.
Chloroquine significantly reduces the bioavailability of ampicillin. An interval of at least 2 hours between ingestion of ampicillin and chloroquine should be observed.
Cyclosporine serum level has been reported to suddenly increase following the ingestion of chloroquine. Close monitoring of serum cyclosporine level is recommended following ingestion of chloroquine. Chloroquine should be discontinued if necessary.
Caution should be observed in prescribing chloroquine concomitantly with any known hepatotoxic agent (see Precautions).
Adverse Reactions: Chloroquine is generally well tolerated when given in antimalarial doses. Adverse effects are rare.
Ocular: With long-term therapy, particularly if high doses are used, retinopathy may occur. This is generally irreversible and sometimes progressive. Rarely, it may be delayed.
Retinal changes include narrowing of the arterioles, macular lesions such as areas of edema, atrophy and abnormal pigmentation with loss of foveal reflex, pallor of the optic disk, optic atrophy and patchy retinal pigmentation.
Initially patients with retinal changes may be asymptomatic, or they may complain of nyctalopia and scotomatous vision with paracentral, pericentral ring types and typically temporal scotomas.
Rarely, scotomatous vision may occur without observable retinal changes.
Reversible corneal changes may develop, including transient edema or opaque deposits in the epithelium. These changes may be asymptomatic or cause visual haloes, focusing difficulties or blurred vision.
Transient and reversible blurring of vision or difficulty of focusing or accommodation may also occur.
Cardiovascular: Rarely, electrocardiographic changes, particularly inversion or depression of the T-wave with widening of the QRS complex, have been noted.
Hypotension has also been noted in case of high doses.
There have been rare reports of cardiomyopathy.
Neuromuscular: Skeletal muscle myopathy leading to progressive weakness and atrophy of proximal muscle groups has been noted. Myopathy is reversible after discontinuation of chloroquine, but recovery may take many months.
Associated mild sensory changes, depression of tendon reflexes and abnormal nerve conduction studies suggesting an associated peripheral neuropathy have also been observed.
There have been rare reports of myasthenia gravis-like signs and symptoms.
Auditory: Side effects such as tinnitus, vertigo and hearing loss have been noted. Severe and permanent hearing losses which normally occur following high-dose prolonged therapy have also been reported following the administration of small doses of the drug.
Chloroquine-induced hearing loss may progress or even develop after discontinuation.
CNS: Mild and transient headache has been reported. The occurrence of headache is usually reversible upon withdrawal of chloroquine.
Mental changes including psychic stimulation, psychosis, anxiety and personality changes although uncommon have been observed.
Convulsions have also been reported.
Hematological: Blood dyscrasias are rare and include aplastic anemia, reversible agranulocytosis, thrombocytopenia and neutropenia.
Chloroquine may exacerbate porphyria.
Patients with G-6-PD deficiency may present with severe hemolysis in case of treatment with chloroquine.
Dermatologic: Pruritus and rashes are usually reversible upon withdrawal of chloroquine.
Other uncommon adverse effects from prolonged use include: skin and mucosal pigment changes (bluish-black), photosensitivity, lichen planus-like eruptions, exfoliative dermatitis, hair loss and bleaching of hair pigment.
Chloroquine may precipitate attacks of psoriasis.
Gastrointestinal: Gastrointestinal disturbances which are usually reversible upon withdrawal of chloroquine therapy include: anorexia, nausea, vomiting, diarrhea and abdominal cramps.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: As chloroquine is rapidly and completely absorbed after ingestion, and in accidental overdosage, or rarely with lower doses in hypersensitive patients, toxic doses may be fatal. As little as 1 g may be fatal in children. Toxic symptoms may occur within minutes. These consist of headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, and convulsions followed by sudden and early respiratory and cardiac arrest. The ECG may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest. Treatment with early gastric lavage is indicated if ingestion has occurred recently. In order to avoid sudden cardiac arrest and lung aspiration lavage should be preceded by appropriate symptomatic treatment and intubation with artificial respiration.
Symptomatic and prompt measures which may be taken include immediate evacuation of the stomach by emesis (at home, before transportation to the hospital) and/or gastric lavage until the stomach is completely emptied. Finely-powdered, activated charcoal, if introduced by the stomach tube after lavage within 30 minutes after ingestion of the antimalarial, may inhibit further intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at least 5 times the estimated dose of chloroquine ingested.
Convulsions, if present, should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an ultra short-acting barbiturate may be tried but, if due to anoxia it should be corrected by oxygen administration and artificial respiration. In shock with hypotension, vasopressor therapy such as phenylephrine and other means of circulatory support may also be indicated.
Diazepam also may be used to treat convulsions. It may decrease the cardiotoxicity of chloroquine. Because of the importance of supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, may also be necessary.
A patient who survives the acute phase and is asymptomatic should be closely observed for at least 6 hours. Fluids may be forced, and ammonium chloride (8 g daily in divided doses for adults) may be administered for a few days to acidify the urine to help promote urinary excretion in cases of both overdosage or sensitivity.
Dosage And Administration: The dosage of chloroquine phosphate is often expressed or calculated as the base. Each 250 mg tablet of Aralen is equivalent to 150 mg base. In infants and children the dosage is preferably calculated by body weight.
Malaria: Suppression: In adults, 500 mg (300 mg base) on exactly the same day of each week. In infants and children the weekly suppressive dosage is 5 mg/kg (calculated as base), but should not exceed the adult dose regardless of weight.
If circumstances permit, suppressive therapy should begin 2 weeks prior to exposure. However, failing this in adults, an initial double (loading) dose of 1 g (600 mg base) may be taken; or in children 10 mg base/kg may be given in 2 divided doses, 6 hours apart. The suppressive therapy should be continued for 8 weeks after leaving the endemic area.
Treatment of the acute attack: In adults, an initial dose of 1 g (600 mg base) followed by an additional 500 mg (300 mg base) after 6 to 8 hours and then a single dose of 500 mg (300 mg base) on each of 2 consecutive days. This represents a total dose of 2.5 g chloroquine phosphate or 1.5 g base in 3 days.
The dosage for adults may also be calculated on the basis of body weight; this method is preferred for infants and children. In children, a total dose representing 25 mg/kg (calculated as base) is administered in 3 days, as follows:
First dose: 10 mg base/kg (but not exceeding a single dose of 600 mg base).
Second dose: 5 mg base/kg (but not exceeding a single dose of 300 mg base) 6 hours after 1st dose.
Third dose: 5 mg base/kg 18 hours after 2nd dose.
Fourth dose: 5 mg base/kg 24 hours after 3rd dose.
For radical cure of vivax and malariae concomitant therapy with an 8-aminoquinoline compound is necessary.
Extraintestinal amebiasis: Adults, 1 g (600 mg base) daily for 2 days, followed by 500 mg (300 mg base) daily for at least 2 to 3 weeks. Treatment is usually combined with an effective intestinal amebicide.
Availability And Storage: Each white, round tablet, W on one side, scored on other, contains: chloroquine phosphate USP 250 mg (equivalent to 150 mg chloroquine base). Nonmedicinal ingredients: calcium phosphate (dibasic, dihydrate), cornstarch, magnesium stearate and talc. Energy: 0.4 kJ (0.10 kcal). Gluten-, lactose-, sucrose- and tartrazine-free. Bottles of 100. (Shown in Product Recognition Section)
ARALEN® Sanofi Chloroquine Phosphate Antimalarial – Antiparasitic