Chloroquine, a 4-aminoquinoline derivative, is an antimalarial agent.100
Chloroquine is used for the prevention or chemoprophylaxis of malaria caused by Plasmodium malariae , P. ovale , chloroquine-susceptible P. vivax , and chloroquine-susceptible P. falciparum .100, 115, 121, 134
Although chloroquine has historically been considered the drug of choice for prevention of malaria in travelers to areas where chloroquine-resistant malaria has not been reported,121, 134 chloroquine-resistant P. falciparum has now been confirmed in all areas with P. falciparum malaria, except the Caribbean and Central America west of the Panama Canal.115 In addition, P. vivax with resistance or decreased susceptibility to chloroquine has been confirmed in Papua New Guinea and Indonesia.121, 143 Chloroquine should only be used for the prevention of malaria in areas where chloroquine resistance has not been reported.115, 121
Because chloroquine is active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), it cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species.100, 115 Therefore, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) is indicated in addition to chloroquine prophylaxis if travelers were exposed in areas with P. ovale or P. vivax malaria.100, 115
Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention of malaria are available from the US Centers for Disease Control and Prevention (CDC) at [Web] and [Web].115
Treatment of Uncomplicated Malaria
Chloroquine is used for the treatment of uncomplicated malaria caused by P. malariae , P. knowlesi , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum .100, 134, 143, 144
The fact that chloroquine-resistant P. falciparum has now been confirmed in all areas with P. falciparum malaria, except the Caribbean and Central America west of the Panama Canal,115, 134 should be considered when treating malaria.143 The fact that P. vivax with resistance or decreased susceptibility to chloroquine has been confirmed in Papua New Guinea and Indonesia also should be considered.143 Chloroquine should only be used for the treatment of malaria in areas where chloroquine resistance has not been reported.143
Because chloroquine is active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), the drug cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species.100, 115 Therefore, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) is indicated in conjunction with chloroquine for the treatment of P. ovale or P. vivax malaria.100, 115, 143, 144
The most appropriate regimen for the treatment of malaria is selected based on the infecting species of Plasmodium , malaria severity and clinical status of the patient, expected drug susceptibility as determined by the geographic area where malaria was acquired, and prior receipt of antimalarials (e.g., drugs used for malaria chemoprophylaxis).143 Although uncomplicated malaria can be treated with various oral antimalarial regimens, patients with severe malaria require aggressive treatment with a parenteral antimalarial regimen as soon as possible after the diagnosis.143, 144 Chloroquine is used for the treatment of uncomplicated malaria, but is not recommended for the treatment of severe malaria.143, 144
Information on recommended regimens for the treatment of malaria is available from CDC at [Web].143, 144 Assistance with diagnosis or treatment of malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143, 144
Chloroquine has been used in the treatment of extraintestinal amebiasis caused by Entamoeba histolytica .100 However, a nitroimidazole derivative (metronidazole, tinidazole) followed by a luminal amebicide (iodoquinol, paromomycin) is the regimen of choice for the treatment of extraintestinal amebiasis.134 Because chloroquine is almost completely absorbed from the small intestine and only low concentrations of the drug are present in the intestinal wall, chloroquine is not effective in the treatment of intestinal amebiasis.
Chloroquine has been used in the treatment of discoid lupus erythematosus† and the treatment of systemic lupus erythematosus†. However, hydroxychloroquine usually is preferred over chloroquine if a 4-aminoquinoline derivative is used in the treatment of autoimmune diseases.213
Chloroquine therapy may lead to the regression of skin lesions of discoid or systemic lupus erythematosus and may also have a beneficial effect in patients with systemic lupus erythematosus in whom arthritis is a prominent feature. If chloroquine is used for prolonged periods in the treatment of lupus erythematosus, the risk of serious and sometimes irreversible toxicity should be considered.
Chloroquine has been used in the treatment of rheumatoid arthritis†.213 However, hydroxychloroquine usually is preferred over chloroquine if a 4-aminoquinoline derivative is used in the treatment of autoimmune diseases.213 When a conventional disease-modifying antirheumatic drug (DMARD) is appropriate in the treatment of rheumatoid arthritis, the recommended options are hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine.103
If chloroquine is used for prolonged periods in the treatment of rheumatoid arthritis, the risk of severe and sometimes irreversible toxicity should be considered.
Chloroquine has been used in the treatment of porphyria cutanea tarda†.185, 186, 187
Chloroquine has been used in the treatment of sarcoidosis†.188, 189
Coronavirus Disease 2019 (COVID-19)
Chloroquine and hydroxychloroquine were targeted for investigation as potential options for the treatment and prevention of coronavirus disease 2019 (COVID-19)† caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the early stages of the COVID-19 pandemic based on some evidence of in vitro activity against SARS-CoV-2,198, 212, 231 the possibility that the immunomodulatory activity of the drugs might contribute to anti-inflammatory responses in patients with viral infections,193, 198, 213, 215, 216, 231 and initial anecdotal reports and preliminary information from small trials.197, 218 However, safety and efficacy of chloroquine and hydroxychloroquine for the treatment or prevention of COVID-19 have not been established,230 and the National Institutes of Health (NIH)231 and Infectious Diseases Society of America (IDSA)232 recommend against use of the drugs (alone or in conjunction with other antivirals or other drugs) in the treatment or prevention of COVID-19.
During the early stages of the COVID-19 pandemic, FDA made hydroxychloroquine and chloroquine available is the US for a few months (March 28, 2020 to June 15, 2020) under an FDA emergency use authorization (EUA) to facilitate availability of the drugs for treatment of COVID-19,224 and various clinical trials were initiated in the US and other countries to evaluate use of the drugs (alone or in conjunction with other antivirals or other drugs) for the treatment or prevention of COVID-19.194, 200, 221 FDA revoked the EUA for chloroquine and hydroxychloroquine on June 15, 2020 after concluding that, based on the totality of scientific evidence that became available after the EUAs was issued, it is unlikely that the drugs may be effective in treating COVID-19 and, in light of reports of serious cardiac adverse events and several reported cases of methemoglobinemia in COVID-19 patients, the known and potential benefits of chloroquine and hydroxychloroquine do not outweigh the known and potential risks for the use authorized in the EUA.230 FDA also stated that the suggested chloroquine and hydroxychloroquine dosage regimens are unlikely to produce an antiviral effect; earlier observations of decreased viral shedding with hydroxychloroquine or chloroquine treatment were not consistently replicated; and data from a large randomized controlled trial showed no difference between hydroxychloroquine and standard of care alone.230
Chloroquine phosphate is administered orally.100 Adverse GI effects may be minimized by administering oral chloroquine with a meal.121, 134
Chloroquine also has been administered parenterally† as chloroquine hydrochloride,101, 128, 133, 147, 149 but a parenteral dosage form is no longer commercially available in the US.
Extemporaneously Compounded Oral Suspension
An extemporaneously compounded oral suspension of chloroquine has been prepared.104
Standardized concentrations for an extemporaneously compounded oral suspension of chloroquine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252
Concentration Standards |
|---|
10 mg/mLa |
aChloriquine label should state the 10 mg/mL concentration reflects base chloroquine and not the chloroquine salt.
Dosage of chloroquine phosphate is expressed in terms of chloroquine phosphate or in terms of the base (chloroquine).100
Each 500-mg tablet of chloroquine phosphate contains 300 mg of the chloroquine.100
Prevention of Malaria in Areas Without Chloroquine-resistant Plasmodium
For the prevention or chemoprophylaxis of malaria in travelers to areas where chloroquine-resistant Plasmodium has not been reported, chloroquine prophylaxis should be initiated 1-2 weeks prior to entering the malarious area and continued during the stay and for 4 weeks after leaving the area.100, 115, 121 Chloroquine prophylaxis is given once weekly and should be administered on the same day each week.100, 115
The usual adult oral dosage for prevention of malaria is 500 mg of chloroquine phosphate (300 mg of chloroquine) once weekly, and the usual pediatric oral dosage 8.3 mg/kg of chloroquine phosphate (5 mg/kg of chloroquine) once weekly.100, 115, 134 Pediatric dosage should not exceed 500 mg of chloroquine phosphate (300 mg of chloroquine) once weekly regardless of weight.100, 115, 134 If chloroquine prophylaxis is not initiated 2 weeks prior to entering a malarious area, the manufacturer recommends that adults receive an oral loading dose of 1 g of chloroquine phosphate (600 mg of chloroquine) and that children receive an oral loading dose of 16.7 mg/kg of chloroquine phosphate (10 mg/kg of chloroquine), given in 2 equally divided doses 6 hours apart followed by the usual dosage regimen.100
Because chloroquine cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) also is indicated if exposure to malaria occurred in areas with P. ovale or P. vivax malaria.100, 115
Treatment of Uncomplicated Chloroquine-susceptible Malaria
For the treatment of uncomplicated malaria caused by P. malariae , P. knowlesi , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum , adults should receive an initial oral dose of 1 g of chloroquine phosphate (600 mg of chloroquine) followed by 500 mg of chloroquine phosphate (300 mg of chloroquine) given at 6, 24, and 48 hours after the initial dose.100, 134, 144
Infants and children with uncomplicated malaria caused by P. malariae , P. knowlesi , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum should receive an initial oral dose of 16.7 mg/kg of chloroquine phosphate (10 mg/kg of chloroquine) followed by 8.3 mg/kg of chloroquine phosphate (5 mg/kg of chloroquine) given at 6, 24, and 48 hours after the initial dose.100, 134, 144
Because chloroquine cannot prevent relapse of P. ovale or P. vivax malaria, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) is indicated to provide a radical cure whenever chloroquine is used for the treatment of malaria caused by these species.134, 143, 144
For the treatment of extraintestinal amebiasis, the manufacturer recommends that adults receive 1 g of chloroquine phosphate (600 mg of chloroquine) once daily for 2 days, followed by 500 mg of chloroquine phosphate (300 mg of chloroquine) once daily for at least 2-3 weeks.100 The drug is administered in conjunction with an intestinal amebicide.100
Dosage in Renal and Hepatic Impairment
The manufacturer makes no specific recommendations regarding the need for dosage adjustment in individuals with renal impairment;136 however, chloroquine is substantially eliminated by the kidneys.136
The manufacturer makes no specific recommendations regarding the need for dosage adjustment in individuals with hepatic impairment;136 however, chloroquine should be used with caution in individuals with hepatic disease.136
In dosages used for prevention and treatment of malaria, adverse effects of chloroquine are usually mild and reversible. However, prolonged or high chloroquine dosage used in the treatment of rheumatoid arthritis† or lupus erythematosus† has been associated with serious and sometimes irreversible toxicity, including retinopathy.100
Cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, has been reported in patients receiving chloroquine.100, 119, 120, 180 Cardiac arrhythmias, conduction disorders such as bundle branch block/atrioventricular block, QT interval prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation have been reported with therapeutic dosages of chloroquine as well as with overdosages.100 Hypotension and ECG changes (particularly inversion or depression of the T wave and widening of the QRS complex) have been reported.100
The risk of adverse cardiovascular effects is increased in patients receiving high chloroquine dosage or long-term therapy with the drug.100 AV block, including complete (third degree) AV block, has occurred during long-term chloroquine therapy in patients with systemic or discoid lupus erythematosus†120 or rheumatoid arthritis†.181 Endomyocardial biopsy in some patients who developed cardiomyopathy during long-term chloroquine therapy revealed vacuolated myocytes, numerous large secondary lysosomes, myeloid bodies, and curvilinear bodies.119, 120 Most reported cases of cardiomyopathy to date have involved patients receiving the drug for the management of systemic or discoid lupus erythematosus.119, 120, 180
Severe hypoglycemia, including loss of consciousness that could be life-threatening, has been reported in patients receiving chloroquine who were or were not receiving treatment with antidiabetic agents.100
Retinopathy and maculopathy, as well as macular degeneration, have been reported in patients receiving chloroquine, especially in those receiving long-term treatment or high chloroquine dosage.136 Ocular effects may be irreversible in some patients.136
Visual disturbances in patients receiving chloroquine include blurred vision and difficulty in focusing or accommodation.136 Nyctalopia,136 scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomas (e.g., difficulty reading with words tending to disappear, seeing half an object, misty vision, fog before the eyes),136 and reversible corneal136 opacities have been reported.
Prolonged or high chloroquine dosage has resulted in keratopathy, including transient edema or opaque deposits in the corneal epithelium, which is usually reversible following discontinuance of the drug. Corneal inclusions or deposits have been reported in 30-70% of patients receiving the drug. Keratopathy may be asymptomatic in up to 50% of patients; however, it may cause visual halos, focusing difficulties, photophobia, or blurred vision.
The most serious adverse effect of prolonged or high chloroquine dosage is dose-related retinopathy which may progress even after the drug is discontinued. Occasionally, retinal changes may be reversible if detected early, but they are usually permanent and may rarely result in blindness. Narrowing of the arterioles, pallor of the optic disc, optic atrophy, patchy retinal pigmentation, and macular lesions such as areas of edema, atrophy, abnormal pigmentation, and loss of foveal reflex have been reported. The earliest sign of retinopathy is a generalized increase in granularity and edema of the retina. The lesion progresses to a central area of patchy depigmentation of the macula surrounded by a concentric ring of pigmentation. Narrowing of the retinal vessels, optic atrophy, and diffuse depigmentation of the peripheral retina are later, more advanced changes.
Risk factors for development of retinopathy during chloroquine treatment include age, duration of treatment, and high daily and/or cumulated dosage.136
Neuropsychiatric and Nervous System Effects
Mild and transient headache,136 polyneuritis,136 anxiety,136 agitation,136 confusion,136 insomnia,136 delirium,136 hallucinations,136 and seizures136 have occurred during chloroquine therapy.
Acute extrapyramidal disorders (e.g., dystonia, dyskinesia, tongue protrusion, torticollis) may occur with chloroquine.136 These adverse reactions usually resolve after the drug is discontinued and/or the patient receives symptomatic treatment.136
Neuropsychiatric events, including psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, depression, and suicidal behavior, have been reported in patients receiving chloroquine.100
Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups has been reported with chloroquine.136 Neuromyopathy is manifested as slowly progressing weakness which first affects the proximal muscles of the lower extremities and then progresses to other muscle groups.136 These effects may be associated with mild sensory changes, depression of tendon reflexes, and abnormal nerve conduction.136
Neuromyopathy occurs most frequently when chloroquine dosages of 250 mg or more daily are administered for several weeks or years and is generally reversible when the drug is discontinued.
Adverse GI effects reported with oral chloroquine include epigastric discomfort, anorexia,136 nausea,136 vomiting,136 abdominal cramps,136 diarrhea, and slight weight loss. Stomatitis, which may involve buccal ulceration, has been reported rarely. GI effects may be minimized by administering chloroquine with meals.121, 134
Dermatologic and Sensitivity Reactions
Adverse dermatologic effects including pruritus,136 pigmentary changes of the skin and mucous membranes,136 skin eruptions resembling lichen planus,136 pleomorphic skin eruptions,136 and various dermatoses which may be aggravated by exposure to ultraviolet light have been reported with chloroquine. Pruritus reportedly occurred in 8-28% of Nigerians receiving chloroquine for prophylaxis of malaria. When pruritus occurs, it generally begins 6-48 hours after ingestion of the drug and affects the entire body, but particularly the palms, soles, and scalp; rash is not usually present and antihistamines are generally ineffective in relieving the pruritus. Adverse dermatologic effects have been reported most frequently during prolonged therapy.
Chloroquine may exacerbate psoriasis and may precipitate a severe attack in patients with the disease.
There have been rare reports of erythema multiforme,136 Stevens-Johnson syndrome,136 toxic epidermal necrolysis,136 exfoliative dermatitis,136 and similar desquamation-type adverse events136 in patients receiving chloroquine. Urticaria,136 anaphylactic/anaphylactoid reaction including angioedema,136 and drug rash with eosinophilia and systemic symptoms (DRESS syndrome)136 have also been reported.
Photosensitivity has been reported with chloroquine.136
Bleaching of hair has been reported occasionally with chloroquine136 and occurs most frequently in light-haired individuals. Hair bleaching may affect eyelashes and axillary, pubic, scalp, and body hair and is usually evident after 2-5 months of therapy with chloroquine. Hair loss has also been reported.136
Nerve-type deafness,136 which is usually irreversible, has been reported after prolonged therapy with high chloroquine dosa deafness may not become apparent until several weeks after chloroquine therapy. Tinnitus136 and reduced hearing in patients with preexisting auditory damage136 have been reported.
Adverse hematologic effects, including neutropenia,136 agranulocytosis,136 and thrombocytopenia,136 have been reported rarely with chloroquine. Pancytopenia136 and aplastic anemia136 also have been reported.
Hemolysis and acute renal failure reportedly occurred in a few patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency receiving chloroquine.
Hepatitis and increased liver enzymes have been reported with chloroquine.136
Precautions and Contraindications
Chloroquine is contraindicated in patients with known hypersensitivity to 4-aminoquinoline derivatives.100 Use of chloroquine for indications other than acute malaria is contraindicated in patients with retinal or visual field changes attributable to any etiology.100
CDC issued a health advisory concerning the inappropriate use of chloroquine and hydroxychloroquine, including inappropriate use of non-pharmaceutical preparations of the drugs.222 Clinicians should advise patients and the public to not ingest aquarium products or any other chemical products that contain chloroquine since these products are not intended for human consumption and can lead to serious health consequences, including death.222 Chloroquine and hydroxychloroquine should be used only under the supervision of a healthcare provider.222 Inappropriate uses of chloroquine and hydroxychloroquine include taking any commercially available non-pharmaceutical preparations of the drugs, taking the drugs without a prescription or without supervision by a healthcare provider, and taking additional doses of the drugs not recommended by a healthcare provider.222
Because cardiovascular adverse effects, including fatal cardiomyopathy, have been reported with use of chloroquine, the drug should be used with caution in patients with cardiac disease, history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (less than 50 beats per minute), and in those receiving concomitant therapy with other drugs with potential to prolong the QT interval.100 Patients receiving chloroquine should be monitored for signs and symptoms of cardiomyopathy and the drug should be discontinued if cardiomyopathy develops.100 Chronic toxicity should be considered when conduction disorders (bundle branch block/atrioventricular heart block) or biventricular hypertrophy are diagnosed.100 If cardiotoxicity is suspected, prompt discontinuance of chloroquine may prevent life-threatening complications.100
Because severe, potentially life-threatening hypoglycemia has been reported in patients receiving chloroquine (including those who were or were not receiving treatment with antidiabetic agents), patients should be advised about the risk of hypoglycemia and associated clinical signs and symptoms.100 If clinical symptoms suggestive of hypoglycemia occur during treatment with chloroquine, blood glucose should be assessed and treatment reviewed as clinically indicated.100 In patients already receiving insulin or other antidiabetic agents, consider that decreased dosage of these drugs may be required.100
Because retinopathy and maculopathy have been reported, ophthalmologic examinations, including visual acuity, slit-lamp, funduscopic, and visual field tests, should be performed prior to initiation of chloroquine therapy and periodically during therapy whenever long-term use of the drug is contemplated.136 Chloroquine should be discontinued immediately and the patient closely observed for possible progression if there is any indication of abnormalities in visual acuity or visual field, abnormalities in the retinal macular area such as pigmentary changes or loss of foveal reflex, or if any other visual symptoms (e.g., light flashes and streaks) occur that are not fully explainable by difficulties of accommodation or corneal opacities.136 Retinal changes and visual disturbances may continue to progress even after the drug is discontinued.136 (See Cautions: Ocular Effects.)
Because seizures have been reported in patients receiving chloroquine, patients with a history of epilepsy should be advised about the risk.136
Chloroquine should be used with caution in patients with preexisting auditory damage.136 The drug should be discontinued immediately and the patient closely monitored if any hearing defects occur.136
Because chloroquine is substantially eliminated by the kidneys, the risk of serious adverse effects may be greater in patients with impaired renal function.136
Because chloroquine may concentrate in the liver, the drug should be used with caution in patients with hepatic disease or alcoholism and in patients receiving other hepatotoxic drugs.136
Complete blood cell counts (CBCs) should be performed periodically in patients receiving prolonged chloroquine therapy.136 Chloroquine should be discontinued if there is evidence of any severe blood disorder not attributable to the disease being treated.136 The manufacturer states that chloroquine should be administered with caution to patients with G-6-PD deficiency.136
Patients receiving prolonged chloroquine therapy should be questioned and examined periodically for evidence of muscular weakness; knee and ankle reflexes should be tested.136 If muscular weakness occurs during chloroquine therapy, the drug should be discontinued.136
Because chloroquine may precipitate severe attacks of psoriasis in patients with the disease, the drug should not be used in patients with psoriasis unless the potential benefits outweigh the risks.136
Because chloroquine reportedly may exacerbate porphyria in patients with the condition, the drug should not be used in patients with porphyria unless potential benefits outweigh the risks.136
Children are especially sensitive to 4-aminoquinoline derivatives.136 Fatalities have been reported following accidental ingestion of relatively small doses of chloroquine, and severe reactions and fatalities have occurred following administration of parenteral chloroquine (no longer commercially available in the US).
Patients should be strongly warned to keep chloroquine out of the reach of children.136 Regardless of age, when oral chloroquine is indicated for prophylaxis or treatment of malaria in children, they should receive the appropriate dosages.115
Clinical studies of chloroquine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.136 However, the drug is substantially eliminated by the kidneys and the risk of severe adverse reactions may be greater in patients with impaired renal function.136 Because geriatric patients are more likely to have decreased renal function, dosage should be selected carefully and it may be useful to monitor renal function.136
Studies in pregnant mice indicate that chloroquine readily crosses the placenta, accumulates selectively in the melanin structures of the fetal eyes, and is retained in the ocular tissue for 5 months after the drug has been eliminated from the rest of the body.136 Use of chloroquine during pregnancy in a dosage of 250 mg twice daily for the treatment of lupus erythematosus† has resulted in loss of eighth nerve function, posterior column defects, and mental retardation in several children; retinal degeneration has also been reported in 2 children whose mother received chloroquine during both pregnancies.
Although there are no adequate and well-controlled studies evaluating the safety and efficacy of chloroquine in pregnant women,136 the drug has been used for prevention and treatment of malaria in pregnant women without evidence of adverse effects on the fetus.107, 112, 115, 121
The manufacturer states that chloroquine should be avoided during pregnancy, except for prevention or treatment of malaria when the clinician has determined that possible benefits of the drug outweigh potential risks to the fetus.136
CDC states that pregnancy is not a contraindication to use of chloroquine when the drug is indicated for prevention or treatment of malaria.115, 143
Small amounts of chloroquine and desethylchloroquine (major metabolite with antiplasmodial activity) are distributed into breast milk.122, 123, 124, 136 Following single 300- or 600-mg oral doses of chloroquine in lactating women, maximum ingestion of the drug in breastfed infants is estimated to be 0.4-0.7% of a dose daily122, 123, 124, 136 (up to about 4.2% of a single dose during 9 days of nursing).122 Although it is expected that larger amounts of the drug would be ingested from breast milk during long-term chloroquine prophylaxis,122, 123 the resultant amount of drug consumed by nursing infants still is likely to be small.122, 123
The manufacturer states that, because of the potential for serious adverse effects from chloroquine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.136 The risk to nursing infants of women receiving chronic chloroquine therapy (e.g., for rheumatoid arthritis†) is not known.123 Although further study is necessary,122, 123, 124 some clinicians suggest that the risk to nursing infants of maternal use of chloroquine in dosages used for prevention of malaria is thought to be low.122, 123 However, the risk of low concentrations of the drug in nursing infants for promoting Plasmodium resistance is not known.122
The amount of drug transferred in breast milk would be insufficient to provide adequate protection against malaria in nursing infants.115, 122 If prevention of malaria is necessary, such infants should receive recommended dosages of appropriate antimalarial agent(s).115, 136
Drugs that Prolong the QT Interval
Concomitant use of chloroquine and drugs known to prolong the QT interval may increase the risk of QT interval prolongation and ventricular arrhythmias.100 If concomitant use is necessary, caution is advised.100
In a study in healthy individuals, concomitant use of chloroquine and ampicillin decreased bioavailability of ampicillin.100 Chloroquine should be administered at least 2 hours before or after ampicillin.100
Concomitant use of chloroquine and antacids can reduce absorption of chloroquine.100 Chloroquine should be administered at least 4 hours before or after antacids.100
Concomitant use of chloroquine and insulin or other antidiabetic agents may result in enhanced hypoglycemic effects; decreased dosage of insulin or other antidiabetic drugs may be required.100
Cimetidine can inhibit metabolism of chloroquine resulting in increased plasma concentrations of the antimalarial.100 Concomitant use of chloroquine and cimetidine should be avoided.100
Concomitant use of chloroquine may increase serum concentrations of cyclosporine.100 Therefore, serum cyclosporine concentrations should be monitored and, if necessary, chloroquine should be discontinued.100
Concomitant use of mefloquine and chloroquine may increase the risk of seizures.100
Concomitant use of praziquantel and chloroquine has been reported to reduce bioavailability of praziquantel.100
Concomitant use of chloroquine and drugs known to induce retinal toxicity (e.g., tamoxifen) may increase the risk of retinal damage and is not recommended.100
Because 4-aminoquinoline derivatives are rapidly and completely absorbed from the GI tract, symptoms of acute toxicity may occur within 30 minutes following ingestion of the drugs and death has occurred within 2 hours. Children are especially sensitive to 4-aminoquinoline derivatives;136 however, reports of suicides have indicated that the margin of safety also is small in adults. Without prompt effective therapy, acute ingestion of 5 g or more of chloroquine in adults has usually been fatal, although death has occurred with smaller doses. Fatalities have been reported following the accidental ingestion of relatively small doses of chloroquine (e.g., 750 mg or 1 g of chloroquine phosphate in a 3-year-old child).136
Symptoms of overdosage of 4-aminoquinoline derivatives include headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, and seizures followed by sudden and early respiratory and cardiac arrest.136 Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest.136 Hypokalemia has been reported with arrhythmias.136 Extrapyramidal disorders also have been reported in the context of chloroquine overdosage.136
Treatment of overdosage of 4-aminoquinoline derivatives must be prompt, since acute toxicity with the drugs can progress rapidly, possibly leading to cardiovascular collapse and respiratory and cardiac arrest.136 ECG should be monitored. Because of the importance of supporting respiration, early endotracheal intubation and mechanical ventilation may be necessary. Early gastric lavage may provide some benefit in reducing absorption of the drugs, but generally should be preceded by measures to correct severe cardiovascular disturbances, if present, and by respiratory support that includes endotracheal intubation with cuff inflated and in place to prevent aspiration (since seizures may occur). Intervention options may include diazepam for life-threatening symptoms, seizures, and sedation; epinephrine for treatment of vasodilation and myocardial depression; and potassium replacement with close monitoring of serum potassium concentrations.136
IV diazepam may control seizures and other manifestations of cerebral stimulation and, possibly, may prevent or minimize other toxic effects (e.g., cardiotoxicity, including ECG abnormalities and conduction disturbances) of 4-aminoquinoline derivatives. If seizures are caused by anoxia, anoxia should be corrected with oxygen and respiratory support. Equipment and facilities for cardioversion and for insertion of a transvenous pacemaker should be readily available. Administration of IV fluids and placement of the patient in Trendelenburg's position may be useful in managing hypotension, but more aggressive therapy, including administration of vasopressors (e.g., epinephrine, isoproterenol, dopamine), may be necessary, particularly if shock appears to be impending.
Administration of activated charcoal by stomach tube, after lavage and within 30 minutes after ingestion of 4-aminoquinoline derivatives, may inhibit further intestinal absorption of the drugs; the dose of activated charcoal should be at least 5 times the estimated dose of chloroquine or hydroxychloroquine ingested.136 Peritoneal dialysis, hemodialysis, and hemoperfusion do not appear to be useful in the management of overdosage with 4-aminoquinoline derivatives.
Patients who survive the acute phase of overdosage and are asymptomatic should be closely observed for at least 48-96 hours after ingestion; however, the optimum duration for management of chloroquine overdosage has not been fully elucidated.
The exact mechanism of antimalarial activity of chloroquine has not been determined.136 The 4-aminoquinoline derivatives appear to bind to nucleoproteins and interfere with protein synthesis in susceptible organisms; the drugs intercalate readily into double-stranded DNA and inhibit both DNA and RNA polymerase. In addition, studies using chloroquine indicate that the drug apparently concentrates in parasite digestive vacuoles, increases the pH of the vacuoles, and interferes with the parasite's ability to metabolize and utilize erythrocyte hemoglobin. Plasmodial forms that do not have digestive vacuoles and do not utilize hemoglobin, such as exoerythrocytic forms, are not affected by chloroquine.
Chloroquine acts as a tissue amebicide; however, the precise mechanism of amebicidal activity of the drug is unknown.
The 4-aminoquinoline derivatives, including chloroquine, also have anti-inflammatory activity; however, the mechanism(s) of action of the drugs in the treatment of rheumatoid arthritis and lupus erythematosus has not been determined. Chloroquine reportedly antagonizes histamine in vitro, has antiserotonin effects, and inhibits prostaglandin effects in mammalian cells presumably by inhibiting conversion of arachidonic acid to prostaglandin F2. In vitro studies indicate that chloroquine also inhibits chemotaxis of polymorphonuclear leukocytes, macrophages, and eosinophils.
Chloroquine has activity against Plasmodium , Entamoeba histolytica , some other protozoa, and various bacteria, fungi, and viruses.213
Chloroquine, like hydroxychloroquine, is a blood schizonticidal agent and is active against the asexual erythrocytic forms of susceptible of P. malariae , P. ovale , P. vivax , and P. falciparum .100 The drug is not active against gametocytes and exoerythrocytic forms, including the hypnozoite liver stage forms of P. ovale and P. vivax .100
Chloroquine is active in vitro against the trophozoite form of Entamoeba histolytica .100
Resistance to 4-aminoquinoline derivatives (chloroquine and hydroxychloroquine) has been reported with increasing frequency in Plasmodium falciparum , and chloroquine-resistant P. falciparum is now found in all parts of the world where P. falciparum malaria occurs, except the Caribbean and Central America west of the Panama Canal.115
P. vivax with resistance or decreased susceptibility to chloroquine has been confirmed in Papua New Guinea and Indonesia.115, 121, 143 Chloroquine-resistant P. vivax also has been reported rarely in Burma (Myanmar), India, and Central and South America.143
Plasmodium with reduced susceptibility to chloroquine also have reduced susceptibility to hydroxychloroquine.100
To date, there has been no widespread evidence of chloroquine resistance in P. malariae , P. ovale , or P. knowlesi .143
The mechanism of plasmodial resistance to 4-aminoquinoline derivatives has not been fully elucidated. In chloroquine-resistant P. falciparum malaria, erythrocytes infected with the organism apparently do not concentrate chloroquine and less drug is attained in the digestive vacuoles of the parasites; resistant organisms apparently also develop alternate pathways to utilize erythrocyte hemoglobin.
Chloroquine is rapidly and almost completely absorbed from the GI tract following oral administration,136 and peak plasma concentrations of the drug are generally attained within 1-2 hours. Considerable interindividual variations in serum concentrations of chloroquine have been reported.
Oral administration of 310 mg of chloroquine daily reportedly results in peak plasma concentrations of about 0.125 mcg/mL. If 500 mg of chloroquine is administered once weekly, peak plasma concentrations of the drug reportedly range from 0.15-0.25 mcg/mL and trough plasma concentrations reportedly range from 0.02-0.04 mcg/mL. Results of one study indicate that chloroquine may exhibit nonlinear dose-dependent pharmacokinetics. In this study, administration of a single 500-mg oral dose of chloroquine resulted in a peak serum concentration of 0.12 mcg/mL, and administration of a single 1-g oral dose of the drug resulted in a peak serum concentration of 0.34 mcg/mL.
Results of one cross-over study in healthy adults indicate that the bioavailability of chloroquine is greater when the drug is administered with food than when the drug is administered in the fasting state. In this study, the rate of absorption of chloroquine was unaffected by the presence of food in the GI tract; however, peak plasma concentrations of chloroquine and areas under the plasma concentration-time curves (AUCs) were higher when 600 mg of the drug was administered with food than when the same dose was administered without food.
Chloroquine is widely distributed into body tissues.136 The drug has an apparent volume of distribution of 116-285 L/kg in healthy adults.106 Animal studies indicate that concentrations of chloroquine in liver, spleen, kidney, and lung are at least 200-700 times higher than those in plasma, and concentrations of the drug in brain and spinal cord are at least 10-30 times higher than those in plasma.136 Chloroquine binds to melanin-containing cells in the eyes and skin; skin concentrations of the drug are considerably higher than plasma concentrations. Animal studies indicate that the drug is concentrated in the iris and choroid and, to a lesser extent, in the cornea, retina, and sclera and is found in these tissues in higher concentrations than in other tissues.
Chloroquine is also concentrated in erythrocytes and binds to platelets and granulocytes. Serum concentrations of chloroquine are higher than those in plasma, presumably because the drug is released from platelets during coagulation, and plasma concentrations are 10-15% lower than whole blood concentrations of the drug.
Chloroquine readily crosses the placenta in mice.136 Small amounts of chloroquine and its major metabolite, desethylchloroquine, are distributed into milk.122, 123, 124, 136
Following oral administration of a single 300- or 600-mg dose of chloroquine, peak concentrations of the drug in milk range from 1.7-7.5 mcg/mL123 and generally are greater than concurrent plasma concentrations.122, 123
Chloroquine is 50-65% bound to plasma proteins.106, 136
The plasma half-life of chloroquine in healthy individuals is generally reported to be 72-120 hours. In one study, serum concentrations of chloroquine appeared to decline in a biphasic manner and the serum half-life of the terminal phase increased with higher dosage of the drug. In this study, the terminal half-life of chloroquine was 3.1 hours after a single 250-mg oral dose, 42.9 hours after a single 500-mg oral dose, and 312 hours after a single 1-g oral dose of the drug.
Chloroquine is partially metabolized; the major metabolite is desethylchloroquine.122, 123, 124, 136, 147 Desethylchloroquine also has antiplasmodial activity, but is slightly less active than chloroquine.114 Bisdesethylchloroquine, which is a carboxylic acid derivative, and several other unidentified metabolites are also formed in small amounts.136
Chloroquine and its metabolites are slowly excreted by the kidneys; unabsorbed drug is excreted in feces.136 Urinary excretion of the drug is increased by acidification of urine and decreased by alkalinization of urine.136 Up to 70% of a dose of chloroquine is reportedly excreted unchanged in urine and up to 25% of the dose may be excreted in urine as desethylchloroquine. Small amounts of chloroquine may be present in urine for weeks, months, and occasionally years after the drug is discontinued.
Chloroquine appears to be minimally removed by hemodialysis.110
Chloroquine is a synthetic antimalarial agent that is a 4-aminoquinoline derivative.100 Chloroquine is commercially available for oral administration as the phosphate salt.100
Chloroquine occurs as a white or slightly yellow, odorless, crystalline powder with a bitter taste and is very slightly soluble in water. Chloroquine phosphate occurs as a white, odorless, crystalline powder with a bitter taste136 and exists in 2 polymorphic forms. Chloroquine phosphate is freely soluble in water136 and practically insoluble in alcohol.
Chloroquine phosphate tablets should be stored in well-closed containers at 25°C, but may be exposed to temperatures ranging from 15-30°C.100 Chloroquine phosphate may slowly discolor on exposure to light.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg (150 mg of chloroquine base)* | Chloroquine Phosphate Tablets | |
500 mg (300 mg of chloroquine base)* | Chloroquine Phosphate Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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