Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

MEPRON (NDA-020500)

(ATOVAQUONE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/20/2026 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Severe Cutaneous Adverse Reactions

Newly added subsection:

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme (EM) have been reported in patients treated with MEPRON [see Adverse Reactions (6.2)].

SCARs can be life-threatening or fatal. If symptoms or signs of SCARs develop, discontinue MEPRON immediately and institute appropriate therapy. Patients who have developed SCARs with the use of MEPRON must not receive MEPRON [see Contraindications (4)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)].

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin and Subcutaneous Tissue Disorders

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), skin desquamation, and drug reaction with eosinophilia and systemic symptoms (DRESS).

…

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

…

For women with HIV-1, potential risks of breastfeeding include HIV-1 transmission (in infants without HIV-1). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MEPRON and any potential adverse effects on the breastfed child from MEPRON or from the underlying maternal condition.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Important Administration Instructions

Advise patients to…

Advise patients to shake MEPRON oral suspension gently before use each time [see Dosage and Administration (2.3)].

Severe Cutaneous Adverse Reactions (SCARs)

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking MEPRON immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions (5.3)].

Lactation

Inform women with HIV-1 that the potential risks of breastfeeding include HIV-1 transmission (in infants without HIV-1) [see Use in Specific Populations (8.2)].

…

02/22/2019 (SUPPL-17)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

8.1 Pregnancy

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. 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.

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.

8.2 Lactation

(Additions and/or revisions are underlined)

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. 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.

10/15/2017 (SUPPL-16)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

MEPRON 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 MEPRON.

5 Warnings and Precautions

5.1 Risk of Limited Oral Absorption

(Additions and/or revisions are underlined)

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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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…

Dapsone Comparative Trial :… Subjects received MEPRON oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521); … 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).

Aerosolized Pentamidine Comparative Trial: … 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%)…

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

…

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.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post-approval use of MEPRON oral suspension.

7 Drug Interactions

7.1 Rifampin/Rifabutin

(Additions and/or revisions are underlined)

Concomitant administration of rifampin or rifabutin and MEPRON oral suspension is known to reduce atovaquone concentrations. Concomitant administration of MEPRON oral suspension and rifampin or rifabutin is not recommended.

7.2 Tetracycline

(Additions and/or revisions are underlined)

Concomitant administration of tetracycline and MEPRON oral suspension has been associated with a reduction in plasma concentrations of atovaquone. Caution should be used when prescribing tetracycline concomitantly with MEPRON oral suspension…

7.4 Indinavir

(Additions and/or revisions are underlined)

…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.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

…In a trial of MEPRON oral suspension administered once daily with food for 12 days to 27 HIV-1-infected,…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Administration Instructions

Instruct patients to:

Ensure the prescribed dose of MEPRON oral suspension is taken as directed.
Take their daily doses of MEPRON oral suspension with food, as food will significantly improve the absorption of the drug.
Shake MEPRON oral suspension gently before use each time.