2-(4-(4-Chlorophenyl)cyclohexyl)-3-hydroxy-1,4-naphthoquinone

366.83746

366.102

Y883P1Z2LT|F1W7QUV0KI

759582

DTXSID7022629

C28838

Crystals from acetonitrile

P01AX06|P - Antiparasitic products, insecticides and repellents

54.4

5.8

216-219 deg C

Practically insoluble in water

P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501

H315

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl atovaqone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H315 (33.33%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P391, P403+P233, P405, and P501|Aggregated GHS information provided by 46 companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The median lethal dose is higher than the maximum oral dose tested in mice and rats (1825 mg/kg per day). Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose.

Atovaquone has been linked to serum aminotransferase elevations in a small proportion of patients (1% to 6%). There have also been rare reports of clinically apparent, acute liver injury due to atovaquone. In one published case report (Case 1), the onset of injury was 25 days after starting (and a few days after stopping) treatment. The pattern of serum enzyme elevations was cholestatic. Immunoallergic manifestations (fever, rash and eosinophilia) were not prominent and autoantibodies were not present. The liver injury resolved within 2 months of stopping the medication. Because a combination of proguanil and atovaquone was used, either agent could have been responsible for the injury. Atovaquone has also been linked to rare instances of Stevens Johnson syndrome, which is frequently accompanied by mild liver injury or liver enzyme elevations.

Because atovaquone is very highly plasma protein-bound, it could ptentially displace other medications that are also very highly plasma protein-bound; this could increase the risk of toxicity from medications that have narrow therapeutic indexes; however, atovaquone protein binding has not been affected in vitro by therapeutic concentrations of phenytoin, and the binding of phenytoin has not been affected by atovaquone.|Concurrent administration of oral rifampin with atovaquone suspension resulted in a 52% decrease in the average steady-state plasma concentration of atovaquone and a decrease in the elimination half-life of atovaquone from 82 hours to 50 hours; the average steady-state plasma concentration of rifampin increased by 37%; alternative agents to rifampin should be considered when treating patients with atovaquone. Although interaction trials have not been conducted with atovaquone and rifabutin, rifabutin is structurally similar to rifampin and it may have some of the same drug interactions as rifampin.|Concurrent administration of sulfamethoxazole and trimethoprim combination with atovaquone suspension resulted in an 8% and 17% decrease in the steady-state serum concentration of sulfamethoxazole and trimethoprim, respectively; this effect is thought to be minor and is not expected to produce clinically significant events.|Concurrent administration of zidovudine with atovaquone tablets resulted in a decrease in zidovudine clearance by 24% and a 35% increase in the area under the plasma concentration-time curve (AUC) of zidovudine; the glucuronide metabolite:parent ratio of zidovudine decreased from a mean of 4.5 when zidovudine was administered alone to 3.1 when zidovudine was adminstered with atovaquone; this effect is thought to be minor and is not expected to produce clinically significant events; zidovudine has no effect on atovaquone pharmacokinetics.

Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 µg/mL.

For the treatment or prevention of Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX). Also indicated for the acute oral treatment of mild to moderate PCP in patients who are intolerant to TMP-SMX.|FDA Label

Atovaquone is a naphthoquinone used for the prevention and treatment of Pneumocystis jevorici (formerly carinii) pneumonia and, in combination with proguanil, prevention and treatment of P. falciparum malaria. Atovaquone therapy is associated with low rates of serum enzyme elevations and has been linked to only rare cases of clinically apparent liver injury.

Antimalarial Agents

Antipneumocystic|A tablet containing a fixed dose of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, taken orally, has been highly effective and safe in a 3-day regimen for treating mild to moderate attacks of chloroquine- and multidrug-resistant falciparum malaria.|Atovaquone is indicated in the treatment of mild to moderate Pneumocystis carinii pneumonia (A-a gradient < or = 45 mmHg and pO2 > or = 60 mmHg on room air) in patients who are intolerant of sulfamethoxazole and trimethoprim combination. /Included in US product labeling/|Atovaquone is indicated in the prevention of Pneumocystis carinii pneumonia in patients who are intolerant of sulfamethoxazole and trimethoprim combination. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for ATOVAQUONE (18 total), please visit the HSDB record page.

Patients should be advised regarding pulmonary manifestations of possibly concurrent bacterial, viral, fungal, or mycobacterial infections associated with HIV infection and/or progression of the underlying Pneumocystis carinii pneumonia and to contact a clinician if pulmonary symptomatology develops or worsens during atovaquone therapy. Clinical deterioration during atovaquone therapy could represent secondary infection with a nonsusceptible pathogen and/or progression of the underlying P. carinii pneumonia. All patients for whom atovaquone therapy is being considered should be evaluated carefully for other possible causes of pulmonary disease and treated with additional agents as appropriate.|Fever was reported in up to 40% of patients receiving atovaquone in controlled clinical trials and occasionally has required discontinuance of the drug. Oral candidiasis was reported in 10%, cough in 25%, sweating in 10%, sinusitis in 7%, and rhinitis in 24% of patients receiving atovaquone in controlled clinical trials. Infection of dyspnea has occurred in 22 or 15% of patients receiving atovaquone. Hypotension, vortex keratopathy, transient sinus arrhythmia, increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, and transient conjunctivitis also have been reported rarely.|Hyperglycemia (exceeding 1.8 times the upper limit of normal) occurred in 9% of patients receiving atovaquone in controlled clinical trials. Hypoglycemia has occurred rarely.|Increased BUN and serum creatinine concentrations have been reported rarely in patients receiving atovaquone and occasionally have required discontinuance of the drug. Hyponatremia (less than 0.96 times the lower limit of normal range) was reported in up to 10% of patients receiving atovaquone in controlled clinical trials. Acute renal impairment has occurred in patients receiving atovaquone.|For more Drug Warnings (Complete) data for ATOVAQUONE (13 total), please visit the HSDB record page.

Atovaquone is a highly lipophilic drug that closely resembles the structure [ubiquinone]. Its inhibitory effect being comparable to ubiquinone, atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis in atovaquone-responsive parasites. Cytochrome bc1 complex (complex III) seems to serve as a highly discriminating molecular target for atovaquone in Plasmodia. There is no significant risk for myelosuppression associated with atovaquone, making this drug a beneficial therapeutic agent for recipients of bone marrow transplantation.

Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection. (See all compounds classified as Anti-Infective Agents.)|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.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

The bioavailability of atovaquone is low and variable and is highly dependent on formulation and diet. Bioavailability of the suspension increases two-fold when administered with meals. When administered with food, bioavailability is approximately 47%. Without food, the bioavailability is 23%.|The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. There was little or no excretion of atovaquone in the urine (less than 0.6%).|0.60 ± 0.17 L/kg|10.4 +/- 5.5 ml/min [HIV-infected patients receiving IV administration]|Drug absorption after a single oral dose is slow, erratic and variable; increased by 2- to 3-fold by fatty food; and dose-limited above 750 mg. More than 99% of the drug is bound to plasma protein, so its concentration in cerebrospinal fluid is less than 1% of that in plasma.|The bioavailability of atovaquone is low and variable, and decreases significantly with single doses greater than 750 mg. A standard breakfast containing 23 g of fat has been shown to enhance absorption significantly. Oral suspension: The oral suspension provides a two-fold increase in bioavailability in fasting or fed conditions compared to the tablets. Bioavailability of the suspension increases two-fold when administered with meals; when administered with food, bioavailability is approximately 47%. Tablets: Bioavailability increases three-fold when administered with meals; bioavailability of the tablets when administered with food is approximately 23%.|Fecal; > 94% of atovaquone was recovered in the feces over 21 days; < 0.6% was excreted in the urine.|Bioavailability is increased with meals. Time to peak blood level is 1 to 8 hours, with a second peak in 24 to 96 hours.|For more Absorption, Distribution and Excretion (Complete) data for ATOVAQUONE (8 total), please visit the HSDB record page.

Some evidence suggests limited metabolism (although no metabolites have been identified).|Atovaquone is not significantly metabolized by human beings. It is excreted in bile and more than 94% of the drug is recovered unchanged in feces; only traces appear in the urine.|Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.

2.2 to 3.2 days|Atovaquone has a half-life averaging 1.5 to 3 days|2.2 to 3.2 days in adult patients with acquired immunodeficiency syndrome (AIDS), adult healthy volunteers, and immunocompromised children (ages 5 months to 13 years).

The mechanism of action against Pneumocystis carinii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis. Atovaquone also has been shown to have good in vitro activity against Toxoplasma gondii.|Hydroxynaphthoquinone derivative that inhibits /parasitic/ mitochondrial electron transport.|Atovaquone has possible cidal activity against susceptible organisms. The action against Pneumocystis carinii is not fully understood. Atovaquone is structurally similar to ubiquinone, which inhibits the mitochondrial electron-transport chain at the site of the cytochrome bc1 complex (complex III) in Plasmodium species. This may ultimately inhibit the synthesis of nucleic acid and ATP. Atovaquone also has been shown to have good in vitro activity against Toxoplasma gondii.|At present, approaches to studying mitochondrial functions in malarial parasites are quite limited because of the technical difficulties in isolating functional mitochondria in sufficient quantity and purity. We have developed a flow cytometric assay as an alternate means to study mitochondrial functions in intact erythrocytes infected with Plasmodium yoelii, a rodent malaria parasite. By using a very low concentration (2 nM) of a lipophilic cationic fluorescent probe, 3,3'dihexyloxacarbocyanine iodide, we were able to measure mitochondrial membrane potential(DeltaPsim) in live intact parasitized erythrocytes through flow cytometry. The accumulation of the probe into parasite mitochondria was dependent on the presence of a membrane potential since inclusion of carbonyl cyanide m-chlorophenylhydrazone, a protonophore, dissipated the membrane potential and abolished the probe accumulation. We tested the effect of standard mitochondrial inhibitors such as myxothiazole, antimycin, cyanide and rotenone. All of them except rotenone collapsed the DeltaPsim and inhibited respiration. The assay was validated by comparing the EC50 of these compounds for inhibiting DeltaPsim and respiration. This assay was used to investigate the effect of various antimalarial drugs such as chloroquine, tetracycline and a broad spectrum antiparasitic drug atovaquone. We observed that only atovaquone collapsed DeltaPsim and inhibited parasite respiration within minutes after drug treatment. Furthermore, atovaquone had no effect on mammalian DeltaPsim. This suggests that atovaquone, shown to inhibit mitochondrial electron transport, also depolarizes malarial mitochondria with consequent cellular damage and death.

/SRP:/ Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

2-(4-(4'-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-naphthoquinone

Atovaquone is availible in tablets of 150 mg (United States) and 250 mg (Canada).|Mepron

Analyte: atovaquone; matrix: pharmaceutical preparation (oral suspension); procedure: liquid chromatography with detection at 220 nm and comparison to standards (assay purity)|Analyte: atovaquone; matrix: pharmaceutical preparation (oral suspension); procedure: ultraviolet absorption spectrophotometry with comparison to standards (chemical identification)|Analyte: atovaquone; matrix: chemical purity; procedure: liquid chromatography with detection at 220 nm and comparison to standards|Analyte: atovaquone; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients