Atovaquone

ATOVAQUONE- atovaquone suspension
Pharmaceutical Associates, Inc.

1 INDICATIONS AND USAGE

1.1 Prevention of Pneumocystis jirovecii Pneumonia

Atovaquone oral suspension USP is indicated for the prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX).

1.2 Treatment of Mild-to-Moderate Pneumocystis jirovecii Pneumonia

Atovaquone oral suspension USP is indicated for the acute oral treatment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX.

1.3 Limitations of Use

Clinical experience with atovaquone oral suspension USP for the treatment of PCP has been limited to subjects with mild-to-moderate PCP (alveolar-arterial oxygen diffusion gradient [(A-a)DO 2 ] ≤45 mm Hg). Treatment of more severe episodes of PCP with atovaquone oral suspension USP has not been studied. The efficacy of atovaquone oral suspension USP in subjects who are failing therapy with TMP-SMX has also not been studied.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage for the Prevention of P. jirovecii Pneumonia

The recommended oral dosage is 1,500 mg (10 mL) once daily administered with food.

2.2 Dosage for the Treatment of Mild-to-Moderate P. jirovecii Pneumonia

The recommended oral dosage is 750 mg (5 mL) twice daily (total daily dose = 1,500 mg) administered with food for 21 days.

2.3 Important Administration Instructions

Administer atovaquone oral suspension USP with food to avoid low plasma atovaquone concentrations that may limit response to therapy [see WARNINGS AND PRECAUTIONS (5.1), CLINICAL PHARMACOLOGY (12.3)] .

Atovaquone Oral Suspension

Shake unit dose cup gently before administering the recommended dosage.

3 DOSAGE FORMS AND STRENGTHS

Atovaquone oral suspension USP is a yellow colored, oral suspension containing 750 mg of atovaquone in 5 mL. Atovaquone oral suspension USP is supplied in a 5 mL unit dose cup.

4 CONTRAINDICATIONS

Atovaquone oral suspension is contraindicated in patients who develop or have a history of hypersensitivity reactions (e.g., angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of atovaquone oral suspension.

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Limited Oral Absorption

Absorption of orally administered atovaquone oral suspension is limited but can be significantly increased when the drug is taken with food. Failure to administer atovaquone oral suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Consider therapy with other agents in patients who have difficulty taking atovaquone oral suspension with food or in patients who have gastrointestinal disorders that may limit absorption of oral medications [see CLINICAL PHARMACOLOGY (12.3)].

5.2 Hepatotoxicity

Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone [see ADVERSE REACTIONS (6.2)].

If treating patients with severe hepatic impairment, closely monitor patients following administration of atovaquone.

6 ADVERSE REACTIONS

The following adverse reaction is discussed in another section of:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Additionally, because many subjects who participated in clinical trials with atovaquone had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by atovaquone from those caused by underlying medical conditions.

PCP Prevention Trials

In 2 clinical trials, atovaquone oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count <200 cells/mm 3 or a prior episode of PCP) and unable to tolerate TMP-SMX.

Dapsone Comparative Trial:

In the dapsone comparative trial (n = 1,057), the majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Subjects received atovaquone oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521); median durations of exposure were 6.7 and 6.5 months, respectively. Adverse reaction data were collected only for adverse reactions requiring discontinuation of treatment, which occurred at similar frequencies in subjects treated with atovaquone oral suspension or dapsone (Table 1). Among subjects taking neither dapsone nor atovaquone at enrollment (n = 487), adverse reactions requiring discontinuation of treatment occurred in 43% of subjects treated with dapsone and 20% of subjects treated with atovaquone oral suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with atovaquone oral suspension (Table 1).

Table 1. Percentage (>2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention Trial
Adverse Reaction All Subjects
Atovaquone Oral Suspension 1,500 mg/day (n = 536) % Dapsone 100 mg/day (n = 521) %
Rash 6.3 8.8
Nausea 4.1 0.6
Diarrhea 3.2 0.2
Vomiting 2.2 0.6

Aerosolized Pentamidine Comparative Trial:

In the aerosolized pentamidine comparative trial (n = 549), the majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received atovaquone oral suspension once daily at a dose of 750 mg (n = 188) or 1,500 mg (n = 175) or received aerosolized pentamidine 300 mg every 4 weeks (n = 186); the median durations of exposure were 6.2, 6.0, and 7.8 months, respectively. Table 2 summarizes the clinical adverse reactions reported by ≥20% of the subjects receiving either the 1,500-mg dose of atovaquone oral suspension or aerosolized pentamidine.

Rash occurred more often in subjects treated with atovaquone oral suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with atovaquone oral suspension 1,500 mg once daily and in 7% of subjects treated with aerosolized pentamidine. The most frequent adverse reactions requiring discontinuation of dosing in the group receiving atovaquone oral suspension 1,500 mg once daily were rash (6%), diarrhea (4%), and nausea (3%). The most frequent adverse reaction requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%)

Table 2. Percentage (≥20%) of Subjects with Selected Adverse Reactions in the Aerosolized Pentamidine Comparative PCP Prevention Trial
Adverse Reaction Atovaquone Oral Suspension 1,500 mg/day (n = 175) % Aerosolized Pentamidine (n = 186) %
Diarrhea 42 35
Rash 39 28
Headache 28 22
Nausea 26 23
Fever 25 18
Rhinitis 24 17

Other reactions occurring in ≥10% of subjects receiving the recommended dose of atovaquone oral suspension (1,500 mg once daily) included vomiting, sweating, flu syndrome, sinusitis, pruritus, insomnia, depression, and myalgia.

PCP Treatment Trials

Safety information is presented from 2 clinical efficacy trials of the atovaquone tablet formulation: 1) a randomized, double-blind trial comparing atovaquone tablets with TMP-SMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to-moderate PCP [(A-a)DO 2 ] ≤45 mm Hg and PaO 2 ≥60 mm Hg on room air; 2) a randomized, open-label trial comparing atovaquone tablets with intravenous (IV) pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials.

TMP-SMX Comparative Trial :

In the TMP-SMX comparative trial (n = 408), the majority of subjects were white (66%) and male (95%); the mean age was 36 years. Subjects received atovaquone 750 mg (three 250-mg tablets) 3 times daily for 21 days or TMP 320 mg plus SMX 1,600 mg 3 times daily for 21 days; median durations of exposure were 21 and 15 days, respectively.

Table 3 summarizes all clinical adverse reactions reported by ≥10% of the trial population regardless of attribution. Nine percent of subjects who received atovaquone and 24% of subjects who received TMP-SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving atovaquone and 8% of subjects in the TMP-SMX group discontinued therapy due to rash.

The incidence of adverse reactions with atovaquone oral suspension at the recommended dose (750 mg twice daily) was similar to that seen with the tablet formulation.

Table 3. Percentage (≥10%) of Subjects with Selected Adverse Reactions in the TMP-SMX Comparative PCP Treatment Trial
Adverse Reaction Atovaquone Tablets (n = 203) % TMP-SMX (n = 205) %
Rash (including maculopapular) 23 34
Nausea 21 44
Diarrhea 19 7
Headache 16 22
Vomiting 14 35
Fever 14 25
Insomnia 10 9

Two percent of subjects treated with atovaquone and 7% of subjects treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST.

Pentamidine Comparative Trial:

In the pentamidine comparative trial (n = 174), the majority of subjects in the primary therapy trial population (n = 145) were white (72%) and male (97%); the mean age was 37 years. Subjects received atovaquone 750 mg (three 250-mg tablets) 3 times daily for 21 days or a 3- to 4-mg/kg single pentamidine isethionate IV infusion daily for 21 days; the median durations of exposure were 21 and 14 days, respectively.

Table 4 summarizes the clinical adverse reactions reported by ≥10% of the primary therapy trial population regardless of attribution. Fewer subjects who received atovaquone reported adverse reactions than subjects who received pentamidine (63% vs. 72%). However, only 7% of subjects discontinued treatment with atovaquone due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the 5 subjects who discontinued therapy with atovaquone, 3 reported rash (4%). Rash was not severe in any subject. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).

Table 4. Percentage (≥10%) of Subjects with Selected Adverse Reactions in the Pentamidine Comparative PCP Treatment Trial (Primary Therapy Group)
Adverse Reaction Atovaquone Tablets (n = 73) % Pentamidine (n = 71) %
Fever 40 25
Nausea 22 37
Rash 22 13
Diarrhea 21 31
Insomnia 19 14
Headache 18 28
Vomiting 14 17
Cough 14 1
Sweat 10 3
Monilia, oral 10 3

Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 subjects (3%) who received atovaquone, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving atovaquone had elevated creatinine and BUN levels and 1 subject (1%) had elevated amylase levels. In this trial, elevated levels of amylase occurred in subjects (8% versus 4%) receiving atovaquone tablets or pentamidine, respectively.

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