Atovaquone Suspension
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Questions & Answers
Side Effects & Adverse Reactions
Clinical experience with atovaquone for the treatment of PCP has been limited to patients with mild-to-moderate PCP ([(A-a)DO2]1≤45 mm Hg). Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of atovaquone in patients who are failing therapy with TMP-SMX has not been systematically studied.
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Atovaquone Suspension is indicated for the prevention of Pneumocystis jiroveci pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX).
Atovaquone Suspension is also indicated for the acute oral treatment of mild-to-moderate PCP in patients who are intolerant to TMP-SMX.
Prevention of PCP: The indication for prevention of PCP is based on the results of 2 clinical trials comparing Atovaquone Suspension to dapsone or aerosolized pentamidine in HIV-infected adult and adolescent patients at risk of PCP (CD4 count <200 cells/mm3 or a prior episode of PCP) and intolerant to TMP-SMX.
Dapsone Comparative Study: This randomized, open-label trial enrolled a total of 1,057 patients at 48 study centers. Patients were randomized to receive 1,500 mg Atovaquone Suspension once daily (n = 536) or 100 mg dapsone once daily (n = 521). Median follow-up was 24 months. Patients randomized to the dapsone arm who were seropositive for Toxoplasma gondii and had a CD4 count <100 cells/mm3 also received pyrimethamine and folinic acid. PCP event rates are shown in Table 3. There was no significant difference in mortality rates between the groups.
Aerosolized Pentamidine Comparative Study: This randomized, open-label trial enrolled a total of 549 patients at 35 study centers. Patients were randomized to receive 1,500 mg Atovaquone Suspension once daily (n = 175), 750 mg Atovaquone Suspension once daily (n = 188), or 300 mg aerosolized pentamidine once monthly (n = 186). Median follow-up was 11.3 months. The results of the PCP event rates appear in Table 3. There were no significant differences in mortality rates among the groups.
| Table 3. Confirmed or Presumed/Probable PCP Events (As-Treated Analysis)a | |||||
| Assessment | Study 115-211 | Study 115-213 | |||
| Atovaquone1,500 mg/day(n = 527) | Dapsone100 mg/day(n = 510) | Atovaquone750 mg/day(n = 188) | Atovaquone1,500 mg/day(n = 172) | AerosolizedPentamidine300 mg/month(n = 169) | |
| % | 15 | 19 | 23 | 18 | 17 |
| Relative Riskb (CI)c | 0.77(0.57, 1.04) | 1.47(0.86, 2.50) | 1.14(0.63, 2.06) | ||
a Those events occurring during or within 30 days of stopping assigned treatment.
b Relative risk <1 favors atovaquone and values >1 favor comparator. These trials were designed to show superiority of atovaquone to the comparator. This was not shown.
c The confidence level of the interval for the dapsone comparative study was 95% and for the pentamidine comparative study was 97.5%.
An analysis of all PCP events (intent-to-treat analysis) showed results similar to those above.
Treatment of PCP: The indication for treatment of mild-to-moderate PCP is based on the results of comparative pharmacokinetic studies of the suspension and tablet formulations (see CLINICAL PHARMACOLOGY) and clinical efficacy studies of the tablet formulation which established a relationship between plasma atovaquone concentration and successful treatment. The results of a randomized, double-blind trial comparing atovaquone to TMP-SMX in AIDS patients with mild-to-moderate PCP (defined in the study protocol as an alveolar-arterial oxygen diffusion gradient [(A-a)DO2]1≤45 mm Hg and PaO2≥60 mm Hg on room air) and a randomized trial comparing atovaquone to IV pentamidine isethionate in patients with mild-to-moderate PCP intolerant to trimethoprim or sulfa-antimicrobials are summarized below:
TMP-SMX Comparative Study: This double-blind, randomized trial initiated in 1990 was designed to compare the safety and efficacy of atovaquone to that of TMP-SMX for the treatment of AIDS patients with histologically confirmed PCP. Only patients with mild-to-moderate PCP were eligible for enrollment.
A total of 408 patients were enrolled into the trial at 37 study centers. Eighty-six patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 patients with histologically confirmed PCP, 160 were randomized to receive
atovaquone and 162 to TMP-SMX.
Study participants randomized to treatment with atovaquone were to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to TMP-SMX were to receive 320 mg TMP plus 1,600 mg SMX 3 times daily for 21 days.
Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Therapy failures included lack of response, treatment discontinuation due to an adverse experience and unevaluable.
There was a significant difference (P = 0.03) in mortality rates between the treatment groups. Among the 322 patients with confirmed PCP, 13 of 160 (8%) patients treated with atovaquone and 4 of 162 (2.5%) patients receiving TMP-SMX died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all 408 randomized patients, there were 16 (8%) deaths in the arm treated with atovaquone and 7 (3.4%) deaths in the TMP-SMX arm (P = 0.051). Of the 13 patients treated with atovaquone who died, 4 died of PCP and 5 died with a combination of bacterial infections and PCP; bacterial infections did not appear to be a factor in any of the 4 deaths among TMP-SMX-treated patients.
A correlation between plasma atovaquone concentrations and death was demonstrated; in general, patients with lower plasma concentrations were more likely to die. For those patients for whom day 4 plasma atovaquone concentration data are available, 5 (63%) of the 8 patients with concentrations <5 mcg/mL died during participation in the study. However, only 1 (2%) of the 49 patients with day 4 plasma atovaquone concentrations ≥5 mcg/mL died.
Sixty-two percent of patients on atovaquone and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes (Table 4).
| Table 4. Outcome of Treatment for PCP-Positive Patients Enrolled in the TMP-SMX Comparative Study | |||||
| Number of Patients(% of Total) | |||||
| Outcome of Therapya | Atovaquone (n = 160) | TMP-SMX(n = 162) | PValue | ||
| Therapy success | 99 | (62) | 103 | (64) | 0.75 |
| Therapy failure | |||||
| -Lack of response | 28 | (17) | 10 | (6) | <0.01 |
| -Adverse experience | 11 | (7) | 33 | (20) | <0.01 |
| -Unevaluable | 22 | (14) | 16 | (10) | 0.28 |
| Required alternate PCP therapy during study | 55 | (34) | 55 | (34) | 0.95 |
a As defined by the protocol and described in study description above.
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.
There were no significant differences in the effect of either treatment on additional indicators of response (i.e., arterial blood gas measurements, vital signs, serum LDH levels, clinical symptoms and chest radiographs).
Pentamidine Comparative Study: This unblinded, randomized trial initiated in 1991 was designed to compare the safety and efficacy of atovaquone to that of pentamidine for the treatment of histologically confirmed mild or moderate PCP in AIDS patients. Approximately 80% of the patients either had a history of intolerance to trimethoprim or sulfa-antimicrobials (the primary therapy group) or were experiencing intolerance to TMP-SMX with treatment of an episode of PCP at the time of enrollment in the study (the salvage treatment group).
Patients randomized to atovaquone were to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to pentamidine isethionate were to receive a 3- to 4-mg/kg single IV infusion daily for 21 days.
A total of 174 patients were enrolled into the trial at 22 study centers. Thirty-nine patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135 patients with histologically confirmed PCP, 70 were randomized to receive atovaquone and 65 to pentamidine. One hundred and ten (110) of these were in the primary therapy group and 25 were in the salvage therapy group. One patient in the primary therapy group randomized to receive pentamidine did not receive study medication.
There was no difference in mortality rates between the treatment groups. Among the 135 patients with confirmed PCP, 10 of 70 (14%) patients randomized to atovaquone and 9 of 65 (14%) patients randomized to pentamidine died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all randomized patients, there were 11 (12.5%) deaths in the arm treated with atovaquone and 12 (14%) deaths in the pentamidine arm. For those patients for whom day 4 plasma atovaquone concentrations are available, 3 of 5 (60%) patients with concentrations <5 mcg/mL died during participation in the study. However, only 2 of 21 (9%) patients with day 4 plasma concentrations ≥5 mcg/mL died.
The therapeutic outcomes for the 134 patients who received study medication in this trial are presented in Table 5.
| Table 5. Outcome of Treatment for PCP-Positive Patients Enrolled in the Pentamidine Comparative Study | ||||||||||
| Primary Treatment | Salvage Treatment | |||||||||
| Outcome of Therapy | Atovaquone (n = 56) | Pentamidine(n = 53) | P Value | Atovaquone (n = 14) | Pentamidine(n = 11) | P Value | ||||
| Therapy success | 32 | (57%) | 21 | (40%) | 0.09 | 13 | (93%) | 7 | (64%) | 0.14 |
| Therapy failure | ||||||||||
| -Lack of response | 16 | (29%) | 9 | (17%) | 0.18 | 0 | 0 | — | ||
| -Adverse experience | 2 | (3.6%) | 19 | (36%) | <0.01 | 0 | 3 | (27%) | 0.07 | |
| -Unevaluable | 6 | (11%) | 4 | (8%) | 0.75 | 1 | (7%) | 1 | (9%) | 1 |
| Required alternate PCP therapy during study | 19 | (34%) | 29 | (55%) | 0.04 | 0 | 4 | (36%) | 0.03 | |
History
There is currently no drug history available for this drug.
Other Information
Atovaquone is an antiprotozoal agent. The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula:
Atovaquone Suspension is a formulation of micro-fine particles of atovaquone.
The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. Atovaquone Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor (ethanol, propylene glycol, triacetin), poloxamer 188, purified water, saccharin sodium and xanthan gum.
MICROBIOLOGY
Mechanism of Action: Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jiroveci 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.
Activity In Vitro: Several laboratories, using different in vitro methodologies, have shown the IC50 (50% inhibitory concentration) of atovaquone against rat P. jiroveci to be in the range of 0.1 to 3 mcg/mL.
Drug Resistance: Phenotypic resistance to atovaquone in vitro has not been demonstrated for P. jiroveci. However, in 2 patients who developed Pneumocystis carinii pneumonia (PCP) after prophylaxis with atovaquone, DNA sequence analysis identified mutations in the predicted amino acid sequence of P. jiroveci cytochrome b (a likely target site for atovaquone). The clinical significance of this is unknown.
Sources
Atovaquone Suspension Manufacturers
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Amneal Pharmaceuticals, Llc
![Atovaquone Suspension [Amneal Pharmaceuticals, Llc]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Atovaquone Suspension | Bausch & Lomb Incorporated
2.1 Recommended DosingApply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. During the initial 24 to 48 hours, the dosing may be increased, to every one to two hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.
2.2 Prescription GuidelineNot more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation [see Warnings and Precautions (5.3)].
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Prasco Laboratories
Atovaquone Suspension | Supervalu Inc
• shake well before use • use dose cup • adults and children 12 years and over: 1 dose (30 mL or 2 TBSP) every 1/2 to 1 hour as needed • do not exceed 8 doses (240 mL or 16 TBSP) in 24 hours • use until diarrhea stops but not more than 2 days • children under 12 years: ask a doctor • drink plenty of clear fluids to help prevent dehydration caused by diarrhea
![Atovaquone Suspension [Prasco Laboratories]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=60383fa2-c550-43f8-93d6-27a41bd2e16b&name=45ab48b0-6710-49d8-9531-44b8d7e093ae-01.jpg)
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