Chloroquine

Chloroquine is a an Antimalarial Agent belonging to Tricyclic Class

Chloroquine can be used in the treatment of Amebiasis, extraintestinal, Malaria.

Chloroquine is Rapidly and almost completely absorbed from the gastrointestinal tract. Increased bioavailability with food. Time to peak plasma concentration: 1-2 hours and Widely get distributed in the body tissues including eyes, skin, heart, kidneys, liver, lungs, spleen and leucocytes. Crosses the placenta; enters breast milk (small amounts). Plasma protein binding: Approx 50-70% and Partially metabolized in the liver to the main metabolite, desethylchloroquine. Bisdesethylchloroquine and other metabolites are also formed in small amounts and excreted Via urine (approx 70%; approx 35% as unchanged drug). Elimination half-life: 74.7 ± 30.1 hours.

The common side effects associated with Chloroquine include Retinal toxicity which may cause irreversible retinopathy (high doses and prolonged use); hearing defects, proteinuria (with or without moderate decrease in GFR); skeletal muscle myopathy or neuropathy, resulting in progressive weakness and atrophy of proias, QT interval prolongation, AV conduction disturbance

Chloroquine is available in the form of oral solid.

The molecule is available in India, USA, Germany, Japan.

Chloroquine is a 4-aminoquinoline anti-protozoal agent. The exact mechanism by which it exerts its antimalarial effect is unknown; however, it may exert its effect against Plasmodium species by concentrating in the parasite's acid vesicles and by inhibiting the polymerisation of haeme. Additionally, it binds to and inhibits DNA and RNA polymerase. Its precise mechanisms of action on rheumatoid arthritis and lupus erythematosus are not completely elucidated, but it is reported to antagonise histamine in vitro and prevents prostaglandin effects in mammalian cells possibly by inhibiting arachidonic acid conversion to prostaglandin F₂. It may also have antiserotonin effects.

(Tmax of Chloroquine was Within 1 to 2 hours.

Chloroquine is available in Tablets

Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.

Chloroquine can be used in the treatment of Amebiasis, extraintestinal, Malaria. It is also used to treat Discooid Lupus erythematosus.

Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children.

Chloroquine is approved for use in the following clinical indications

Amebiasis, extraintestinal: Treatment of extraintestinal amebiasis.

Malaria: Treatment of uncomplicated malaria due to susceptible strains of Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium falciparum; prophylaxis of malaria (in geographic areas where chloroquine resistance is not present). Note: The CDC guidelines also recommend chloroquine for chloroquine-sensitive Plasmodium knowlesi malaria

Although not approved there have been certain off labelled uses documented for Chloroquine which include:

Discoid lupus erythematosus

Amebiasis, extraintestinal: Oral: 1 g (600 mg base) daily for 2 days followed by 500 mg daily (300 mg base) for at least 2 to 3 weeks; may be combined with an intestinal amebicide.

Discoid lupus erythematosus (off-label use): Oral: Not considered first-line agent . Due to the risk of retinal toxicity, do not exceed a daily dose of 2.3 mg/kg/day using actual body weight; intermediate doses may be obtained by splitting tablets or eliminating a tablet on certain days of the week.

Malaria, prophylaxis: Oral: 500 mg (300 mg base) weekly on the same day each week; begin 1 to 2 weeks prior to exposure; continue while in endemic area and for 4 weeks after leaving endemic area. Note: For use only in areas with chloroquine-sensitive malaria.

Malaria, uncomplicated, treatment: Oral: 1 g (600 mg base) on day 1, followed by 500 mg (300 mg base) 6-, 24-, and 48 hours after first dose or 16.7 mg/kg (10 mg/kg base) as a single dose on day 1 and day 2, followed by 8.3 mg/kg (5 mg/kg base) as a single dose on day 3 (for a total dose of 41.7 mg/kg [25 mg/kg base]). Note: For treatment of chloroquine-sensitive P. vivax and P. ovale, concomitant therapy with an 8-aminoquinoline (eg, primaquine, tafenoquine) is necessary

(Chloroquine can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician).

250 mg, 500 mg

Tablets

Dose Adjustment in Kidney Patient

GFR ≥10 mL/minute: No dosage adjustment necessary.

GFR <10 mL/minute: No dosage adjustment necessary with short-term use at recommended doses and durations (eg, malaria treatment) ; use with caution. With prolonged use (eg, lupus erythematosus), administer 50% of dose .

Hemodialysis: No dosage adjustment necessary with short-term use at recommended doses and durations (eg, malaria treatment); use with caution. With prolonged use (eg, lupus erythematosus), administer 50% of dose.

Peritoneal dialysis: No dosage adjustment necessary with short-term use at recommended doses and durations (eg, malaria treatment); use with caution. With prolonged use (eg, lupus erythematosus), administer 50% of dose.

CRRT: No dosage adjustment necessary

• Dose Adjustment in Hepatic Impairment Patient:

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.

• Dose Adjustment in Pediatric Patient:

Malaria, prophylaxis: Note: For use only in areas with chloroquine-susceptible malaria .

Infants, Children, and Adolescents: Oral: 8.3 mg/kg chloroquine phosphate once weekly on the same day each week; maximum dose: 500 mg chloroquine phosphate/dose. Begin 1 to 2 weeks before travel to malarious area; continue while in malarious area and for 4 weeks after leaving the area.

Malaria, uncomplicated, treatment: Infants, Children, and Adolescents: Oral: Initial: 16.7 mg/kg/dose chloroquine phosphate once (maximum initial dose: 1,000 mg chloroquine phosphate); followed by 8.3 mg/kg/dose chloroquine phosphate (maximum dose: 500 mg chloroquine phosphate/dose) administered at 6, 24, and 48 hours after initial dose for a total of 4 doses (. For infection caused by Plasmodium vivax or Plasmodium ovale, use in combination with appropriate antirelapse treatment (eg, primaquine).

Bioavailability may be increased with food.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity to chloroquine, 4-aminoquinoline compounds, or any component of the formulation; the presence of retinal or visual field changes of any etiology (when used for indications other than acute malaria).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Chloroquine and its desethylchloroquine metabolite are present in breast milk.

Per product labeling, 11 lactating women with malaria were given a single oral dose of chloroquine 600 mg. The maximum daily dose to the breastfeeding infant was calculated to be 0.7% of the maternal dose. Additional information has been published and results are variable, likely due to various maternal doses and dosing regimens, routes of administration, and assay methods. Using data from available studies, the relative infant dose (RID) of chloroquine and its metabolite was calculated to be 0.9% to 9.5% (chloroquine) and 0.19% to 2.5%. These RID calculations used a modified formula, based on average milk concentrations (not C_max) and total days of maternal therapy (not a single daily dose) to take into consideration the intermittent dosing and long half-life of chloroquine (Law 2008). In general, breastfeeding is considered acceptable when the RID of a medication is <10%.

Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother.

Available guidelines consider the amount of chloroquine exposure to the breastfeeding infant to be acceptable when used in normal maternal doses for malaria prophylaxis or treatment . The amount of chloroquine obtained by a breastfeeding infant from breast milk would not provide adequate protection if therapy for malaria in the infant is needed. Breastfed infants should be treated with chloroquine when otherwise indicated.

May enhance the sedative effect of alcohol.

Chloroquine and its desethylchloroquine metabolite are present in breast milk.

Per product labeling, 11 lactating women with malaria were given a single oral dose of chloroquine 600 mg. The maximum daily dose to the breastfeeding infant was calculated to be 0.7% of the maternal dose. Additional information has been published and results are variable, likely due to various maternal doses and dosing regimens, routes of administration, and assay methods (Akintonwa 1988; Boelaert 2001; Deturmeny 1984; Edstein 1986; Ette 1987; Law 2008; Ogunbona 1987). Using data from available studies, the relative infant dose (RID) of chloroquine and its metabolite was calculated to be 0.9% to 9.5% (chloroquine) and 0.19% to 2.5% . These RID calculations used a modified formula, based on average milk concentrations (not C_max) and total days of maternal therapy (not a single daily dose) to take into consideration the intermittent dosing and long half-life of chloroquine (Law 2008). In general, breastfeeding is considered acceptable when the RID of a medication is <10%.

Pregnancy Category (FDA): C

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 body. 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 judgment of the physician the benefit outweighs the potential risk to the fetus.

Bioavailability may be increased with food.

The adverse reactions related to Chloroquine can be categorized as

• Common

Retinal toxicity which may cause irreversible retinopathy (high doses and prolonged use); hearing defects, proteinuria (with or without moderate decrease in GFR); skeletal muscle myopathy or neuropathy, resulting in progressive weakness and atrophy of proias, QT interval prolongation, AV conduction disturbance

• Less Common

exacerbation of porphyria and psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS); suicidal behaviur, psychiatric disorders; increased risk of hemolytic anemia (particularly in patients with G6PD deficiency).

• Rare

Hematologic reactions (e.g. reversible agranulocytosis, neutropenia, aplastic anemia, pancytopenia, thrombocytopenia); convulsions, diffuse parenchymal lung disease. Ear and labyrinth disorders: Tinnitus, nerve type deafness, hypoacusis.

The clinically relevant drug interactions of Chloroquine is briefly summarized here

May increase the serum levels of ciclosporin and digoxin. Increased risk of convulsions with mefloquine. May inhibit the actions of antiepileptic drugs. Absorption may be reduced with antacids (e.g. Al, Ca, and Mg salts) and adsorbents (e.g. kaolin). May suppress the antibody response to pre-exposure primary immunisation with intradermal human diploid-cell rabies vaccine. May reduce the serum levels of praziquantel. May diminish the therapeutic effects of neostigmine and pyridostigmine. Cimetidine may inhibit the metabolism of chloroquine leading to increased plasma concentration. May enhance the hypoglycemic effects of insulin and other antidiabetic drugs. Increased risk of retinal toxicity with tamoxifen. May inhibit the intracellular α-galactosidase activity of agalsidase alfa and agalsidase beta.

Potentially Fatal: Increased risk of ventricular arrhythmia with agents known to prolong QT interval such as halofantrine, class IA and III (e.g. amiodarone) antiarrhythmics, TCAs, antipsychotics and certain anti-infectives (e.g. moxifloxacin). Increased risk of CV events and CV mortality with macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin).

The common side of Chloroquine include the following

Retinal toxicity which may cause irreversible retinopathy (high doses and prolonged use); hearing defects, proteinuria (with or without moderate decrease in GFR); skeletal muscle myopathy or neuropathy, resulting in progressive weakness and atrophy of proias, QT interval prolongation, AV conduction disturbance.

Pregnancy Category (FDA): C

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 body. 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 judgment of the physician the benefit outweighs the potential risk to the fetus.

• Labor and Delivery

There is no FDA guidance on use of Chloroquine phosphate during labor and delivery.

• 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 oral dose of chloroquine (400 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.

• Pediatric Use

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.

• Geriatic Use

Clinical studies of chloroquine phosphate 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.

• Gender

There is no FDA guidance on the use of Chloroquine phosphate with respect to specific gender populations.

• Race

There is no FDA guidance on the use of Chloroquine phosphate with respect to specific racial populations.

• Renal Impairment

There is no FDA guidance on the use of Chloroquine phosphate in patients with renal impairment.

• Hepatic Impairment

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.

• Females of Reproductive Potential and Males

There is no FDA guidance on the use of Chloroquine phosphate in women of reproductive potentials and males.

• Immunocompromised Patients

There is no FDA guidance one the use of Chloroquine phosphate in patients who are immunocompromised.

Symptoms: Nausea, vomiting, hypokalaemia, metabolic acidosis, headache, dizziness, blurred vision, diplopia, hypotension (may progress to cardiogenic shock and pulmonary oedema), width-increased QRS complex, bradyarrhythmias, nodal rhythm, QT prolongation, AV block, ventricular tachycardia, torsades de pointes, ventricular fibrillation, and cardiac arrest. Circulatory collapse due to potent cardiotoxic effects, respiratory arrest, and coma may also occur. Rarely, hepatotoxicity, gastric haemorrhage, nephritis, haematological abnormalities, psychiatric features, blindness, restlessness, excitability, and convulsions may be present.

Management: Symptomatic and supportive treatment. Maintain a clear airway and ensure adequate ventilation. Immediately perform gastric lavage or induce emesis. May consider the administration of activated charcoal within 1 hour of ingestion. To correct metabolic acidosis, consider giving IV Na bicarbonate. Administration of epinephrine and diazepam infusions may reduce the cardiotoxic effects of chloroquine.

Pharmacodynamics

Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children.

Pharmacokinetics

Absorption: Rapidly and almost completely absorbed from the gastrointestinal tract. Increased bioavailability with food. Time to peak plasma concentration: 1-2 hours.

Distribution: Widely distributed in the body tissues including eyes, skin, heart, kidneys, liver, lungs, spleen and leucocytes. Crosses the placenta; enters breast milk (small amounts). Plasma protein binding: Approx 50-70%.

Metabolism: Partially metabolised in the liver to the main metabolite, desethylchloroquine. Bisdesethylchloroquine and other metabolites are also formed in small amounts.

Excretion: Via urine (approx 70%; approx 35% as unchanged drug). Elimination half-life: 74.7 ± 30.1 hours.

1. https://www.uptodate.com/contents/Chloroquine-drug-information?search=Chloroquine&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F23890541
2. https://www.mims.com/india/drug/info/Chloroquine?type=full
3. https://www.ncbi.nlm.nih.gov/books/NBK537225/
4. https://go.drugbank.com/drugs/DB00321
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf