Amodiaquine

355.86

355.86

201-669-3

220236ED28

13453

DTXSID2022597

C65231

Crystals from absolute ethanol

P - Antiparasitic products, insecticides and repellents

2933499090

48.4

3.7

Solid

1.3±0.1 g/cm3

208 °C (decomp)

478.0±45.0 °C at 760 mmHg

242.9±28.7 °C

1.669

24.9 [ug/mL]

-20°C Freezer

7X10-11 mm Hg at 25 deg C (est)

LD50 oral in mouse: 550mg/kg

Henry's Law constant = 1X10-17 atm cu m/mol at 25 °C (est)

191.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Yellow bitter crystals. Decomposes at 150-160 °C. UV max (methanol) 342 nm; 341.5 nm (water). Soluble in water, sparingly soluble in alcohol. Very slightly soluble in benzene, chloroform, and ether. pH 1% aqueous soln = 4-4.8. /Amodiaquine dihydrochloride dihydrate/|Hydroxyl radical reaction rate constant = 3.6X10-10 cu cm/molec-sec at 25 °C (est)

3

S22-S24/25-S8

P264, P270, P301+P312, P330, P501

H302

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products, incl amodiaquine hydrochloride under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amodiaquine hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 18 companies from 1 notifications to the ECHA C&L Inventory.|Aggregated GHS information provided by 2 companies from 1 notifications to the ECHA C&L Inventory.

LD50 (mouse, intraperitoneal) 225 mg/kg, LD50 (mouse, oral) 550 mg/kg. Symptoms of overdose include headache, drowsiness, visual disturbances, vomiting, hypokalaemia, cardiovascular collapse and cardiac and respiratory arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, broadening of the QRS complex, and progressive bradycardia leading to ventricular fibrillation and/or arrest.

Amodiaquine has been linked to serum aminotransferase elevations in a small proportion of patients (1%). More importantly, there have been multiple reports of idiosyncratic acute liver injury due to amodiaquine. The onset of injury is usually within 1 to 4 months and is often associated with agranulocytosis. The pattern of serum enzyme elevations is most frequently hepatocellular, and symptoms resembling acute viral hepatitis are typical. Features of hypersensitivity are uncommon, as are autoantibodies. The hepatitis can be severe, and several fatal instances or cases requiring emergency liver transplantation have been reported. The frequency of serious hepatic injury is estimated to be ~1:15,000. Because of the risks of agranulocytosis and liver injury, amodiaquine is no longer recommended for use as prophylaxis against malaria and is used largely for therapy in endemic areas outside of the United States. General recommendations on the therapy of malaria including specific details on diagnosis, management, drug dosage and safety are available at the CDC website: http://www.cdc.gov/malaria/.

Since magnesium trisilicate and kaolin are known to decrease the gastrointestinal absorption of chloroquine when administered simultaneously, it is likely that this also follows for amodiaquine.|Concomitant administration of chloroquine at recommended doses for malaria suppression of chemoprophylaxis during pre-exposure prophylaxis of rabies with intra-dermally administered rabies vaccine may interfere with the antibody response to the vaccine. However, the clinical significance of this interaction remains to be clearly established but should be considered and may have relevance in the case of amodiaquine.|Concomitant use with other antimalarials should be avoided and regular laboratory investigations should be performed to assure that blood values and liver function tests remain within normal limits.

A mild degree of itching with or without a rash can follow the use of amodiaquine in all races. However, in Africans, a more severe itching has been reported. The itching has a curious biting or pricking character, and affects all parts of the body including the scalp, the palms of the hands, and the soles of the feet. It is often unassociated with urticaria or any other kind of rash. It begins within a few hours of taking the drug and often continues for between 48 and 72 hours. It is usually severe enough to make sleep impossible for as long as it lasts. The itching occurs in all age groups but it is unusual for it to be experienced on the first exposure to the drug.

While data specific to amodiaquine were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils(1).

For treatment of acute malarial attacks in non-immune subjects.

Amodiaquine is an aminoquinoline used for the therapy of malaria. Amodiaquine has been linked to severe cases of acute hepatitis which can be fatal, for which reason it is recommended for use only as treatment and not for prophylaxis against malaria.

Antimalarial Agents

THERAP CAT: Antimalarial|There are very few recent data on the in vivo susceptibility of P. ovale and P. malariae to antimalarials. Both species are regarded as very sensitive to chloroquine, although there is a single recent report of chloroquine resistance in P. malariae. Experience indicates that P. ovale and P. malariae are also susceptible to amodiaquine, mefloquine and the artemisinin derivatives.|Summary of recommendations on the treatment of uncomplicated vivax malaria: Amodiaquine (30 mg base/kg bw divided over 3 days as 10 mg/kg bw single daily doses) combined with primaquine should be given for chloroquine-resistant vivax malaria.|/Indicated/ for /the/ treatment of acute malarial attacks in non-immune subjects. It is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported.

Agranulocytosis Associated with the Use of Amodiaquine for Malaria Prophylaxis Seven cases of agranulocytosis associated with the use of amodiaquine (Camoquine) among British travelers have recently been reported (1). Sixteen additional cases of agranulocytosis from Western Europe associated with the use of amodiaquine have recently been reported to the drug manufacturer, and two U.S. cases have been reported to CDC. Twenty-three of these 25 cases occurred in 1985 or 1986, and seven are reported to have been fatal. Among 20 cases for which the duration of amodiaquine prophylaxis is known, usage ranged from 3 weeks to 24 weeks. In all but four of the 25 cases, amodiaquine was used at the appropriate dosage (adults 400 mg base per week) for prophylaxis. Fourteen of the patients are known to have used another antimalarial drug concurrently for prophylaxis ... It is now apparent that any possible prophylactic advantage that amodiaquine may afford is not justified by the possible risk of agranulocytosis associated with the use of the drug. CDC, therefore, no longer recommends that amodiaquine be used for prophylaxis.|Because amodiaquine may concentrate in the liver, the drug should be used with caution in patients with hepatic disease or alcoholism, and in patients receiving hepatotoxic drugs.|Children are especially sensitive to 4-aminoquinoline derivatives. Because of the narrow margin between the therapeutic and toxic concentrations in children, amodiaquine should not be administered parenterally in this age group.|Amodiaquine is contraindicated in patients who are hypersensitive /to 4-aminoquinoline derivatives/.|For more Drug Warnings (Complete) data for AMODIAQUINE (14 total), please visit the HSDB record page.

It is likely that the fatal dose for amodiaquine would be similar to that of chloroquine phosphate (2 to 3 g, adult) since amodiaquine appears to completely parallel the adverse effects of those seen with chloroquine when equivalent doses are used.

Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, dizziness and nausea.

Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)

Rapidly absorbed following oral administration.|Amodiaquine hydrochloride is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active metabolite desethylamodiaquine, which contributes nearly all of the antimalarial effect (10). There are insufficient data on the terminal plasma elimination half-life of desethylamodiaquine. Both amodiaquine and desethylamodiaquine have been detected in the urine several months after administration.|After oral administration amodiaquine hydrochloride is rapidly absorbed...|After oral administration of amodiaquine (600 mg) to 7 healthy adult males ... The peak concentration of amodiaquine was 32 +/- 3 ng/mL at 0.5 +/- 0.03 hr. The peak concentrations of amodiaquine in whole blood and packed cells were 60 +/- 10 and 42 +/- 6 ng/mL respectively, reached at 0.5+/- 0.1hr in both. Thereafter the concentration of amodiaquine declined rapidly, and was detectable for no more than 8 hr.|Mean peak plasma concentration of the metabolite (desethylamodiaquine) was 181 +/- 26 ng/mL. Times to peak for whole blood and packed cells were 2.2 +/- 0.5 and 3.6 +/- 1.1 hr respectively|For more Absorption, Distribution and Excretion (Complete) data for AMODIAQUINE (10 total), please visit the HSDB record page.

Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.|... Amodiaquine hydrochloride ... undergoes rapid and extensive metabolism to desethylamodiaquine which concentrates in blood cells. It is likely that desethylamodiaquine, not amodiaquine, is responsible for most of the observed antimalarial activity, and that the toxic effects of amodiaquine after oral administration may in part be due to desethylamodiaquine.|When amodiaquine is given orally relatively little of the parent compound is present in the blood. Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.|The hepatic metabolism of the antimalarial drug amodiaquine was investigated in order to gain further insight into the postulated metabolic causation of the hepatotoxicity, which restricts the use of the drug. After intraportal administration (54 mumol/kg) to the anaesthetized rat, the drug was excreted in bile (23 +/- 3% dose over 5 h; mean +/- SD, n = 6) primarily as thioether conjugates. After intraportal administration, 20% of the dose was excreted into urine over 24 h as parent compound and products of N-dealkylation and oxidative deamination. Desethylamodiaquine accumulated in liver, but was not a substrate for bioactivation as measured by biliary elimination of a glutathione adduct. Prior administration of ketoconazole, an inhibitor of P450, reduced biliary excretion by 50% and effected a corresponding decrease in the amount of drug irreversibly bound to liver proteins. This indicated a role for P450 in the bioactivation of amodiaquine to a reactive metabolite that conjugates with glutathione and protein. De-ethylation and irreversible binding were observed in vitro using male rat liver microsomes, and were again inhibited by ketoconazole. However, no such binding was observed with human (six individuals) hepatic microsomes despite extensive turnover of amodiaquine to desethylamodiaquine. Amodiaquine quinoneimine underwent rapid reduction in the presence of either human or rat liver microsomes. Therefore in vitro studies may underestimate the bioactivation of amodiaquine in vivo. These data indicate that the extent of protein adduct formation in the liver will depend on the relative rates of oxidation of amodiaquine and reduction of its quinoneimine. This in turn may be a predisposing factor in the idiosyncratic hepatotoxicity associated with amodiaquine. Substitution of a fluorine for the phenolic hydroxyl group in amodiaquine blocked bioactivation of the drug in vivo. Insertion of an N-hydroxyethyl function enabled partial clearance of amodiaquine and its deshydroxyfluoro analogue via O-glucuronidation and altered the balance between phase I oxidation and direct phase II conjugation of amodiaquine.|Amodiaquine (AQ) metabolism to N-desethylamodiaquine (DEAQ) is the principal route of disposition in humans. Using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) /the authors/ performed studies to identify the CYP isoform(s) involved in the metabolism of AQ. CYP2C8 was the main hepatic isoform that cleared AQ and catalyzed the formation of DEAQ. The extrahepatic P450s, 1A1 and 1B1, also cleared AQ and catalyzed the formation of an unknown metabolite M2. The K(m) and V(max) values for AQ N-desethylation were 1.2 microM and 2.6 pmol/min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 microM and 1462 pmol/min/mg of protein for human liver microsomes (HLMs), respectively. Relative contribution of CYP2C8 in the formation of DEAQ was estimated at 100% using the relative activity factor method. Correlation analyses between AQ metabolism and the activities of eight hepatic P450s were made on 10 different HLM samples. Both the formation of DEAQ and the clearance of AQ showed excellent correlations (r(2) = 0.98 and 0.95) with 6alpha-hydroxylation of paclitaxel, a marker substrate for CYP2C8. The inhibition of DEAQ formation by quercetin was competitive with K(i) values of 1.96 for CYP2C8 and 1.56 microM for HLMs. Docking of AQ into the active site homology models of the CYP2C isoforms showed favorable interactions with CYP2C8, which supported the likelihood of an N-desethylation reaction. These data show that CYP2C8 is the main hepatic isoform responsible for the metabolism of AQ. The specificity, high affinity, and high turnover make AQ desethylation an excellent marker reaction for CYP2C8 activity.

5.2 ± 1.7 (range 0.4 to 5.5) minutes|Amodiaquine 600 mg was given by mouth, the apparent terminal half-life of amodiaquine was 5.2 + 1.7 (range 0.4 to 5.5) minutes and the geometric mean of the estimated elimination phase half-lives was 2.1 (range 0.5 to 5.7) hours.

The mechanism of plasmodicidal action of amodiaquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function.|Amodiaquine is a Mannich base 4-aminoquinoline with a mode of action similar to that of chloroquine. It is effective against some chloroquine-resistant strains of P. falciparum, although there is cross-resistance.|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, the drugs apparently concentrate in parasite digestive vacuoles, increase the pH of the vacuoles, and interfere 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 /these medications/.|The 4-aminoquinoline derivatives ... 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. /4-aminoquinoline derivatives/ 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.|The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension; they depress respiration and cause diplopia, dizziness and nausea.

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. 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). IV diazepam may control seizures and other manifestations of cerebral stimulation and, possibly, may prevent or minimize other toxic effects (eg, cardiotoxicity, including ECG abnormalities and conduction disturbances) of 4-aminoquinoline derivatives. However, additional study and experience are necessary to further establish the effects of diazepam on noncerebral manifestations of toxicity with these drugs. 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 (eg, 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 /4-aminoquinoline derivative/ ingested. 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...|Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The cytotoxicity of amodiaquine (AQ), amodiaquine quinoneimine (AQQI) and desethylamodiaquine (AQm) has been assessed in comparison with that of chloroquine (CQ) using mononuclear leucocytes (MNL) and granulocyte/monocyte colony forming units (GM-CFU) from hematologically normal subjects. Toxicity toward MNL was assessed after 2 hr and 16 hr incubations with each compound. After 2 hr, AQ, AQm and AQQI but not CQ (within the concentration range 1 to 100 umol/L) produced a significant decrease in cell viability. After 16 hr, all four compounds significantly increased cell death. After both 2 hr and 16 hr incubations CQ was the least toxic and AQQI the most toxic of the four compounds towards MNL. Toxicity to GM-CFU was assessed by the inhibition of colony formation in vitro. After 10 to 14 days incubation, there was significant concentration-dependent inhibition of colony formation by AQ, AQm, AQQI and CQ (within the range 0.1 to 10.0 umol/L). There were no significant differences between the ability of the four compounds to inhibit colony formation but toxicity towards GM-CFU was observed at drug concentrations at least 10-fold lower than those that were toxic to MNL. These data show that the four compounds are equally toxic in vitro toward GM-CFU, although some differences in their toxicity toward MNL were seen.|/SIGNS AND SYMPTOMS/ The adverse effects of amodiaquine are similar to those of chloroquine. Amodiaquine is associated with less pruritus and is more palatable than chloroquine, but is associated with a much higher risk of agranulocytosis and, to a lesser degree, of hepatitis when used for prophylaxis. The risk of a serious adverse reaction with prophylactic use (which is no longer recommended) appears to be between 1 in 1,000 and 1 in 5,000. It is not clear whether the risks are lower when amodiaquine is used to treat malaria. Following overdose cardiotoxicity appears to be less frequent than with chloroquine. Large doses of amodiaquine have been reported to cause syncope, spasticity, convulsions and involuntary movements.|/SIGNS AND SYMPTOMS/ Oral administration of a single dose of amodiaquine may be followed by abdominal discomfort, nausea, vomiting, headache, dizziness, blurring of vision, mental and physical weakness, and fatigue. These symptoms are usually mild and transient.|/SIGNS AND SYMPTOMS/ Because the 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. ... Symptoms of overdosage of 4-aminoquinoline derivatives include headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, and seizures followed by sudden and early respiratory and cardiac arrest. 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.|For more Human Toxicity Excerpts (Complete) data for AMODIAQUINE (11 total), please visit the HSDB record page.

Amodiachin

Trade name: Camoquin hydrochloride (Parke-Davis).|Trade names: Basoquin, CAM-AQ,1 Camoquin, Camoquinal, Flavoquin, Fluroquine, Miaquin, and SN-10,75.

Analyte: amodiaquine; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: amodiaquine; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: amodiaquine; matrix: chemical purity; procedure: absorption spectrophotometry with detection at 342 nm and comparison to standards /chloroquine phosphate/|Analyte: amodiaquine; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /amodiaquine hydrochloride/|For more Analytic Laboratory Methods (Complete) data for AMODIAQUINE (9 total), please visit the HSDB record page.

Analyte: amodiaquine; matrix: blood (whole, plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 222 nm; limit of detection <120 ng/mL|Analyte: amodiaquine; matrix: blood (whole, plasma, serum, blood cell, dried blood); procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm|Analyte: amodiaquine; matrix: blood (whole, plasma, blood cell, dried blood); procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm

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