ATOVACUE^®

MIMS Revision Date: 01 January 2025

1 Name of Medicine

Atovaquone.

2 Qualitative and Quantitative Composition

Atovacue oral liquid suspension contains the active atovaquone 750 mg in 5 mL.
Excipient with known effect. Saccharin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Atovacue oral suspension is a bright yellow liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Atovacue oral suspension is indicated for:
Acute treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) (difference of alveolar and arterial oxygen tensions [(A-a) DO₂] ≤ 45 mmHg (6 kPa) and oxygen tension in arterial blood (PaO₂) ≥ 60 mmHg (8 kPa) breathing room air) in adult patients with AIDS who are intolerant of trimethoprim/sulfamethoxazole therapy.

4.2 Dose and Method of Administration

The importance of taking the full prescribed dose of Atovacue with food should be stressed to patients. The presence of food, particularly high-fat food, increases bioavailability two to three fold.
Shake well before use. Do not dilute.
Dosage in adults. Pneumocystis carinii pneumonia. The recommended oral dose of Atovacue suspension is 750 mg (5 mL) administered with food twice daily for 21 days (see Section 5.2, Pharmacokinetics in adults). For patients with difficulty in swallowing and unable to take two meals a day, the dose should be 1,500 mg (2 x 5 mL) with food once a day for 21 days.
Dosage in children. Experience with atovaquone oral suspension in the paediatric population shows it to be well tolerated, but data are limited to a pharmacokinetic and safety study and at present there is insufficient data to recommend the use of atovaquone in children (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Dosage in elderly. There have been no studies of Atovacue in the elderly (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

4.3 Contraindications

Atovacue oral suspension is contra-indicated in individuals with known hypersensitivity to atovaquone or to any components of the formulation.

4.4 Special Warnings and Precautions for Use

Atovaquone has not been systematically evaluated i) in patients failing other PCP therapy, ii) for the treatment of severe episodes of PCP [(A-a) DO₂ > 45 mmHg (6 kPa)], or iii) as a prophylactic agent for PCP.
Absorption of atovaquone is limited but can be significantly increased when the drug is taken with food. In clinical studies using atovaquone tablets, atovaquone plasma concentrations have been shown to correlate generally with the likelihood of successful treatment and survival. There is limited efficacy data on atovaquone suspension that examined the correlation between plasma concentration and treatment success rate. Gastro-intestinal disorders may further reduce absorption of orally administered drugs and patients may not achieve plasma levels of atovaquone associated with response to therapy. Therefore, alternative therapies should be considered for such patients and for patients who have difficulty taking atovaquone with food.
The prescriber must be aware that diarrhoea at the start of treatment has been shown to be correlated with higher incidences of therapy failures and a lower survival rate. Therefore, alternative therapies should be considered for such patients.
Patients with pulmonary disease should be carefully evaluated for causes of disease other than PCP and treated with additional agents as appropriate. Atovaquone is not expected to be effective therapy for concurrent bacterial, viral, fungal or mycobacterial diseases.
The concomitant administration of atovaquone and rifampicin is not recommended. A potential drug interaction has been reported for concomitant administration of zidovudine and rifabutin with atovaquone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
This medicine contains 50 mg benzyl alcohol in each 5 mL. Benzyl alcohol may cause allergic reaction.
Use in hepatic impairment. Atovaquone has not been specifically studied in patients with impaired hepatic function. Elimination of atovaquone is substantially liver dependent.
Use in renal impairment. Atovaquone has not been specifically studied in patients with significant renal impairment. There is no theoretical reason for patients with renal impairment to be at increased risk (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in adults).
Use in the elderly. No clinical experience of atovaquone treatment has been gained in patients over 65 years of age. Therefore, use in the elderly should be closely monitored reflecting the greater frequency of decreased hepatic, renal and cardiac function in this population.
Paediatric use. Experience with atovaquone tablets in the paediatric population shows it to be well tolerated, but data are limited to a pharmacokinetic and safety study (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in children). There is no data from clinical studies using atovaquone suspension in the paediatric population.
Effects on laboratory tests. See Section 4.8 Adverse Effects (Undesirable Effects), Table 3 Lab test abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As experience is limited, care should be taken when combining other drugs with atovaquone. The causal relationship between the change in plasma concentrations of atovaquone and the administration of the drugs mentioned below is unknown.
Concomitant treatment with metoclopramide and rifampicin has been associated with significant decreases in plasma concentrations of atovaquone (mean decreases of 4.0 and 7.6 microgram/mL, respectively). Concomitant administration of tetracycline with atovaquone is associated with approximately 40% lower plasma atovaquone concentration. Caution should be exercised in prescribing either of these drugs with atovaquone until the potential interaction has been further studied.
Concomitant administration of rifabutin and atovaquone has been associated with a moderate reduction in the steady state plasma concentrations of both atovaquone (on average by 34%) and rifabutin (on average by 19%).
In clinical trials of atovaquone, small decreases in plasma concentrations of atovaquone (mean < 3 microgram/mL) were associated with concomitant administration of paracetamol, benzodiazepines, aciclovir, opiates, cephalosporins, anti-diarrhoeals and laxatives. The causal relationship between the change in plasma concentrations of atovaquone and the administration of these drugs is unknown.
Zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy. There are no data available for other antiretrovirals.
In clinical trials of atovaquone the following medications were not associated with a change in steady state plasma concentrations of atovaquone: fluconazole, clotrimazole, ketoconazole, antacids, systemic corticosteroids, non-steroidal anti-inflammatory drugs, anti-emetics (excluding metoclopramide) and H₂-antagonists.
Atovaquone is highly bound to plasma proteins and caution should be used when administering concurrently with other highly plasma protein bound drugs with narrow therapeutic indices. e.g. warfarin. There is no plasma protein binding interaction between atovaquone and quinine, or phenytoin in vitro.
Concomitant administration of atovaquone and indinavir results in a significant decrease in the C_min of indinavir (23% decrease; 90% CI 8-35%). Caution should be exercised in prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. There are no data on the effect of atovaquone on human fertility. Data from animal studies show that atovaquone does not affect reproductive potential or performance at oral doses up to 1000 mg/kg.
In dosage range of 600 to 1200 mg/kg in rabbits gave indications of maternal and embryotoxic effects. At these doses maternal toxicity was observed, as demonstrated by weight loss, decrease in food consumption and foetal loss, was accompanied by both lower foetal body weight and foetal length. There were no teratogenic effects observed even at maternally toxic doses.
Use in pregnancy. (Category B2)
There is no information on effects of atovaquone administration during human pregnancy. Atovaquone should not be used during pregnancy unless the benefit of treatment to the mother outweighs any possible risk to the developing foetus.
Use in lactation. It is not known whether atovaquone is excreted in human milk and breast feeding is not recommended.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of atovaquone on driving performance or the ability to operate machinery but a detrimental effect on such activities is not predicted from the pharmacology of the drug.

4.8 Adverse Effects (Undesirable Effects)

Patients participating in clinical trials with atovaquone have often had complications of advanced human immunodeficiency virus (HIV) disease and therefore the causal relationship between the adverse experiences and atovaquone is difficult to evaluate. No life-threatening or fatal adverse experiences have been specifically attributed to atovaquone. See Tables 1, 2 and 3.

Nine percent of patients discontinued atovaquone as the result of an adverse experience. Of the most common adverse experiences, only rash, which occurred at a rate of 23% was shown to be related to plasma atovaquone concentration. The most common reasons for discontinuation of atovaquone were rash and vomiting. The incidence of adverse experiences with atovaquone suspension at the recommended dose was similar to that seen with the tablet formulation. See Table 4 and 5.
Hypersensitivity reactions including angioedema, bronchospasm and throat tightness have also been commonly reported.
Although experience is limited, adverse experiences reported in children with AIDS (Acquired Immune Deficiency Syndrome) do not appear to differ significantly from those of adults with AIDS receiving atovaquone.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute toxicity of atovaquone was not obvious in rats and mice given the highest practicable dose level.
There is insufficient experience to predict the consequences, or suggest specific management, of atovaquone overdose. If overdose occurs the patient should be monitored and standard supportive treatment administered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Atovaquone is a hydroxy-1,4-naphthoquinone, an analogue of ubiquinone, with antipneumocystis activity.
Atovaquone belongs to a therapeutic class with a novel mechanism of action. It is a selective and potent inhibitor of the eukaryotic mitochondrial electron transport chain in a number of parasitic protozoa. The site of action appears to be the cytochrome bc1 complex (complex III). The ultimate metabolic effect of such blockade is likely to be inhibition of nucleic acid and ATP synthesis.
Microbiology. Atovaquone has potent antiprotozoal activity, both in vitro and in animal models, particularly against the parasitic protozoa Pneumocystis carinii (IC₅₀ 0.3 - 3.0 microM), Toxoplasma gondii (IC₅₀ 0.002 - 0.2 microM) and Plasmodium species (e.g. P. falciparum IC₅₀ 0.7 - 4.3 nanoM).
Clinical trials. A comparative study of atovaquone with trimethoprim-sulphamethoxazole for the oral treatment of mild to moderate PCP was conducted in AIDS patients receiving 750 mg atovaquone tablets three times daily for 21 days, the mean steady-state atovaquone concentration was 13.0 microgram/mL (n=133). Analysis of this data established a relationship between plasma atovaquone concentration and successful treatment. The dosing regimen for atovaquone suspension has been selected to achieve average plasma atovaquone concentrations of approximately 20 microgram/mL because this concentration was previously shown to be well tolerated and associated with the highest treatment success rates (see Table 6).

Atovaquone suspension open label study. In an open-label PCP treatment study with atovaquone suspension, dosing regimens of 1000 mg once daily, 750 mg twice daily, 1500 mg once daily and 1000 mg twice daily were administered to AIDS patients with PCP. The average steady-state plasma atovaquone concentration (± SD), achieved at 750 mg twice daily dose, given with meals was 22.0 ± 10.1 microgram/mL (n=18). Sixty-seven percent (12/18) and sixty-one percent (11/18) achieved plasma atovaquone concentration of ≥ 15 microgram/mL and ≥ 20 microgram/mL, respectively. Sixty-two percent of patients treated with atovaquone suspension in this trial were successfully treated, regardless of the dosing regimen used. The small number of patients enrolled in each cohort precludes precise inferences about the relative efficacy of atovaquone suspension compared to the tablet formulation. The outcome of treatment is shown in Table 7.
Comparative study - atovaquone tablets versus trimethoprim-sulphamethoxazole (TMP-SMX). A double-blind, randomised, multicentre efficacy and safety study was conducted in 408 adult AIDS patients with mild to moderate PCP. Eighty-six patients without histological confirmation of PCP were excluded from the efficacy analyses but were included in the safety analyses (see Section 4.8 Adverse Effects (Undesirable Effects), Tables 1 and 2). Of the 322 patients with histologically confirmed PCP, 160 received atovaquone (three 750 mg tablets, tds) and 162 received TMP-SMX (320 mg TMP and 1600 mg SMX, tds). Treatment was administered for 21 days.
Sixty-two percent of patients on atovaquone and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes. The outcome of treatment is shown in Table 8. The failure rate due to lack of response was significantly larger for patients receiving atovaquone while the failure rate due to adverse experiences was significantly larger for patients receiving TMP-SMX.
Mortality rates assessed during the 21 treatment period or during the 8 week follow-up period were significantly different between groups (P=0.03). Of the 13 patients treated with atovaquone who died, four died of PCP and five died with a combination of bacterial infections and PCP. Bacterial infections did not appear to be a factor in any of the four deaths among TMP-SMX-treated patients. In the intent-to-treat analysis (n=408 patients), the mortality rate was 8% and 3.4%, respectively, in the atovaquone and TMP-SMX arms (P=0.051).
A correlation between plasma atovaquone concentrations and death was demonstrated. For those patients for whom plasma atovaquone levels were available at day 4, five (63%) of the eight patients with concentrations < 5 microgram/mL died during the study. However, only one (2.0%) of the 49 patients with day 4 plasma atovaquone levels ≥ 5 microgram/mL died.
Comparative study - atovaquone versus pentamidine. An open-label, randomised, multicentre efficacy and safety study was conducted in 174 adult AIDS patients. Thirty-nine patients without histological confirmation of mild or moderate PCP were excluded from the efficacy analyses (see Section 4.8 Adverse Effects (Undesirable Effects), Tables 3 and 4). Approximately 80% of patients had a history of intolerance to TMP or sulphur containing antibiotics (primary therapy group) or were experiencing intolerance to TMP-SMX (salvage treatment group).
Of the 134 patients with histologically confirmed PCP, 70 were randomised to receive atovaquone (three 750 mg tablets, tds for 21 days) and 64 to pentamidine (single daily iv infusion of 3 to 4 mg/kg for 21 days). The therapeutic outcome is shown in Table 9.
During the 21 day treatment period and follow-up period (8 weeks), mortality rates were similar between the treatment groups; 14% for either atovaquone and pentamidine groups. The mortality rate was similar for the intent-to-treat analysis. In patients for whom day 4 plasma atovaquone levels were available, 3 (60%) of 5 that had concentrations < 5 microgram/mL, died during the study period. However, only 2 (9%) of 21 of patients with day 4 plasma atovaquone ≥ 5 microgram/mL died.

5.2 Pharmacokinetic Properties

Pharmacokinetics in adults. Absorption and distribution. Atovaquone is a highly lipophilic compound with a low aqueous solubility. It is 99% bound to plasma proteins. The bioavailability of the drug demonstrates a relative decrease with single doses above 750 mg and multiple doses over 750 mg, and shows considerable inter-individual variability. Average absolute bioavailability of a 750 mg single dose of atovaquone suspension administered with food to adult HIV positive males is 47%.
The bioavailability of atovaquone is increased greatly when administered with food than in the fasting state. In healthy volunteers, a standardised breakfast (23 g fat; 610 kCal) increased bioavailability two to three-fold following a single 750 mg dose. The mean area under the atovaquone plasma concentration-time curve (AUC) was increased 2.5 fold and the mean C_max was increased 3.4 fold. The mean (± SD) AUC values for suspension were 324.3 (± 115.0) microgram/mL.hr fasted and 800.6 (± 319.8) microgram/mL.hr with food.
Significant differences in the bioavailability of atovaquone have been observed between healthy volunteers, asymptomatic HIV-infected volunteers and people with AIDS. In separate studies using the tablet formulation, steady state atovaquone plasma concentrations in people with AIDS ranged from one third to one half of the levels achieved in asymptomatic HIV-infected volunteers. For example, in volunteers with AIDS a dose of 3000 mg once daily produced a mean (± SD) maximum steady-state plasma concentration of 16.2 ± 6.6 microgram/mL, compared with asymptomatic HIV-infected volunteers who achieved 48.8 ± 21.6 microgram/mL.
In a safety and pharmacokinetics study in which patients with PCP received treatment with 750 mg atovaquone suspension twice daily the mean (± SD) steady state plasma concentration (C_avg,ss) was 22.0 (± 10.1) microgram/mL. Twelve of eighteen patients (67%) achieved a C_avg,ss level of ≥ 15 microgram/mL after 21 days of treatment. The mean C_avg,ss for the 1500 mg once daily treatment regimen was slightly lower at 17.6 microgram/mL (± 8.1; n = 9).
On pharmacokinetic grounds, the daily dose of 1500 mg might be taken as a single daily dose or divided between two daily doses. Previous study with the tablet formulation showed average steady state plasma concentrations of ≥ 15 microgram/mL are predictive of high (> 90%) successful treatment rate (see Section 5.1 Pharmacodynamic Properties, Clinical trials), therefore it is important to use twice daily dosing for atovaquone suspension to provide a higher plasma atovaquone concentration. The dependence of the absorption of atovaquone on a concomitant meal should be noted.
Metabolism and excretion. In healthy volunteers and people with AIDS atovaquone has a half-life of 2 to 3 days.
In healthy volunteers there is no evidence that the drug is metabolised and there is negligible excretion of atovaquone in the urine, with parent drug being predominantly (> 90%) excreted unchanged in faeces.
Pharmacokinetics in children. There are no studies on the use of atovaquone suspension in children. Studies using atovaquone tablets showed in children with AIDS, the pharmacokinetics of atovaquone appear to be similar to adults with AIDS. In 3 HIV positive children receiving atovaquone at a dose of 40 mg/kg/day, which approximates to the adult dose, maximum steady state concentrations ranged between 13 and 22 microgram/mL. The average half-life is 2.6 days.

5.3 Preclinical Safety Data

Genotoxicity and carcinogenicity. Oncogenicity studies in mice showed an increased incidence of hepatocellular adenomas and carcinomas at all dose levels tested. Studies in rats at dose of up to 500 mg/kg/day were negative. There was no evidence that atovaquone was mutagenic in bacterial and mammalian cell gene mutation assays in vitro, and in mouse bone marrow micronucleus assays for chromosome damage in vivo.

6 Pharmaceutical Particulars

6.1 List of Excipients

Benzyl alcohol, xanthan gum, poloxamer 188, hypromellose, saccharin sodium, citric acid monohydrate, sodium citrate dihydrate, purified water, tutti frutti flavour (051880 AP0551).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Unused product should be discarded 21 days after opening.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate. Do not freeze.

6.5 Nature and Contents of Container

210 mL in a plastic bottle (HDPE) with child resistant closure (polypropylene).
A measuring double sided spoon (2.5 mL and 5 mL) (polypropylene) is included.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Atovaquone is an extremely insoluble yellow crystalline powder. Solubility at 25°C in water and 0.1 M hydrochloric acid is < 2 x 10^-4 mg/mL; in 0.1 M sodium hydroxide it is 1.7 mg/mL.
The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4- naphthoquinone, with a molecular formula C₂₂H₁₉ClO₃ and a relative molecular mass of 366.84.
Chemical structure.

CAS number. 95233-18-4.

7 Medicine Schedule (Poisons Standard)

S4.

Date of First Approval

09 April 2024

Date of Revision

21 October 2024

Summary Table of Changes