MEPRON Oral suspension Ref.[10869] Active ingredients: Atovaquone

5.1 Risk of Limited Oral Absorption

Absorption of orally administered MEPRON oral suspension is limited but can be significantly increased when the drug is taken with food. Failure to administer MEPRON 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 MEPRON 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 MEPRON.

The following adverse reaction is discussed in another section of the labeling:

• Hepatotoxicity [see Warnings and Precautions (5.2)]

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 MEPRON had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by MEPRON from those caused by underlying medical conditions.

PCP Prevention Trials

In 2 clinical trials, MEPRON 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/mm³ 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 MEPRON 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 MEPRON 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 MEPRON oral suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with MEPRON 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:

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 MEPRON 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 MEPRON oral suspension or aerosolized pentamidine.

Rash occurred more often in subjects treated with MEPRON oral suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with MEPRON 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 MEPRON 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:

Other reactions occurring in ≥10% of subjects receiving the recommended dose of MEPRON 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 MEPRON tablet formulation: 1) a randomized, double-blind trial comparing MEPRON tablets with TMP-SMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to-moderate PCP [(A-a)DO₂] ≤45 mm Hg and PaO₂ ≥60 mm Hg on room air; 2) a randomized, open-label trial comparing MEPRON 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 MEPRON 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 MEPRON and 24% of subjects who received TMP‑SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving MEPRON and 8% of subjects in the TMP-SMX group discontinued therapy due to rash.

The incidence of adverse reactions with MEPRON 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:

Two percent of subjects treated with MEPRON 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 MEPRON 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 MEPRON reported adverse reactions than subjects who received pentamidine (63% vs. 72%). However, only 7% of subjects discontinued treatment with MEPRON due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the 5 subjects who discontinued therapy with MEPRON, 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):

Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 subjects (3%) who received MEPRON, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving MEPRON 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 MEPRON tablets or pentamidine, respectively.

The following adverse reactions have been identified during post-approval use of MEPRON oral suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Methemoglobinemia, thrombocytopenia.

Immune System Disorders: Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria.

Eye Disorders: Vortex keratopathy.

Gastrointestinal Disorders: Pancreatitis.

Hepatobiliary Disorders: Hepatitis, fatal liver failure.

Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation.

Renal and Urinary Disorders: Acute renal impairment.

7.1 Rifampin/Rifabutin

Concomitant administration of rifampin or rifabutin and MEPRON oral suspension is known to reduce atovaquone concentrations [see Clinical Pharmacology (12.3)]. Concomitant administration of MEPRON oral suspension and rifampin or rifabutin is not recommended.

7.2 Tetracycline

Concomitant administration of tetracycline and MEPRON oral suspension has been associated with a reduction in plasma concentrations of atovaquone [see Clinical Pharmacology (12.3)]. Caution should be used when prescribing tetracycline concomitantly with MEPRON oral suspension. Monitor patients for potential loss of efficacy of MEPRON if coadministration is necessary.

7.3 Metoclopramide

Metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available [see Clinical Pharmacology (12.3)].

7.4 Indinavir

Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and C_max of indinavir but resulted in a decrease in the C_trough of indinavir [see Clinical Pharmacology (12.3)]. Caution should be exercised when prescribing MEPRON oral suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if coadministration with MEPRON oral suspension is necessary.

Risk Summary

Available data from postmarketing experience with use of MEPRON in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with HIV who are infected with PCP are at increased risk of adverse pregnancy outcomes (see Clinical Considerations). Atovaquone given orally by gavage to pregnant rats and rabbits during organogenesis did not cause fetal malformations at plasma concentrations up to 3 times and 0.5 times, respectively, the estimated human exposure based on steady-state plasma concentrations (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with HIV who are infected with PCP are at increased risk of severe illness and maternal death associated with PCP compared with non-pregnant women.

Data

Animal Data

Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day to pregnant rats during organogenesis (Gestation Day [GD] 6 to GD15) did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations approximately 3 times the estimated human exposure during the treatment of PCP based on steady-state plasma concentrations. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day during organogenesis (GD6 to GD18) caused decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to a plasma concentration that is approximately 0.5 times the estimated human exposure based on steady-state plasma concentrations. In a pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first generation offspring at doses up to 1,000 mg/kg/day corresponding to approximately 3 times the estimated human exposure based on steady-state plasma concentrations during the treatment of PCP. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue.

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1–infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. There are no data on the presence of atovaquone in human milk, the effects on the breastfed child, or the effects on milk production. Atovaquone was detected in rat milk when lactating rats were administered oral atovaquone (see Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. Because of the potential for HIV-1 transmission to HIV-negative infants, instruct mothers with HIV-1 not to breastfeed if they are taking MEPRON for the prevention or treatment of PCP.

Data

In a rat study with doses of 10 and 250 mg/kg given orally by gavage on postpartum Day 11, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

Evidence of safety and effectiveness in pediatric patients (aged 12 years and younger) has not been established. In a trial of MEPRON oral suspension administered once daily with food for 12 days to 27 HIV-1–infected, asymptomatic infants and children aged between 1 month and 13 years, the pharmacokinetics of atovaquone were age-dependent. The average steady-state plasma atovaquone concentrations in the 24 subjects with available concentration data are shown in Table 5.

Table 5. Average Steady-state Plasma Atovaquone Concentrations in Pediatric Subjects:

C_ss = Concentration at steady state.

Clinical trials of MEPRON did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.