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.

MALARONE (NDA-021078)

(ATOVAQUONE; PROGUANIL HYDROCHLORIDE)

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

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06/10/2026 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following reactions have been identified during postapproval use of MALARONE. 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. These adverse reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal relationship to MALARONE.

Blood and Lymphatic System Disorders

Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil [see Contraindications (4)].

Immune System Disorders

Allergic reactions including anaphylaxis, angioedema, urticaria, and vasculitis.

Nervous System Disorders

Seizures and psychiatric adverse reactions, such as hallucinations, depression, anxiety, panic attacks, crying, nightmares, and psychotic disorders.

. . .

03/23/2026 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 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 MALARONE [see Adverse Reactions (6.2)].

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

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are discussed in another section of the labeling:

Vomiting and Diarrhea [see Warnings and Precautions (5.1)].
Hepatotoxicity [see Warnings and Precautions (5.3)].
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.4)].

6.2 Postmarketing Experience

Additions and/or revisions underlined:

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of MALARONE. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to MALARONE.

…

Skin and Subcutaneous Tissue Disorders

Photosensitivity, rash, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS).

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 take MALARONE at the same time each day with food or a milky drink [see Dosage and Administration (2)].
Advise patients to take a repeat dose of MALARONE if vomiting occurs within 1 hour after dosing [see Dosage and Administration (2)].
Advise patients to take a dose as soon as possible if a dose is missed, then return to their normal dosing schedule. However, if a dose is skipped, the patient should not double the next dose.

Severe Cutaneous Adverse Reactions (SCARs)

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking MALARONE immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions (5.4)].

Hepatotoxicity

Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of MALARONE. [see Warnings and Precautions (5.3)].

Advise patients to immediately report symptoms such as yellowing of the skin or eyes, dark urine, pale stools, abdominal pain, nausea, vomiting, fatigue, or itching.

02/22/2019 (SUPPL-23)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Available data from published literature and postmarketing experience with use of MALARONE in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. The proguanil component of MALARONE acts to inhibit parasitic dihydrofolate reductase; however, pregnant women and females of reproductive potential should continue folate supplementation to prevent neural tube defects. Pregnant women with malaria are at increased risk for adverse pregnancy outcomes.

Atovaquone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis was not associated with fetal malformations at plasma exposures approximately 7 times and equal to, respectively, the estimated human exposure for the treatment of malaria based on AUC. Proguanil administered to pregnant rats and rabbits during the period of organogenesis was not associated with embryo-fetal toxicity at maternally toxic plasma exposures approximately 0.07 and 0.8 times, respectively, the estimated human exposure for treatment of malaria based on AUC.

The combination of atovaquone and proguanil hydrochloride given orally by gavage during the period of organogenesis was not associated with embryo-fetal developmental effects in pregnant rats or rabbits at atovaquone:proguanil hydrochloride doses of 50:20 mg/kg/day and 100:40 mg/kg/day, respectively (1.7 and 0.1 times and 0.3 and 0.5 times, respectively, the estimated human exposure for treatment of malaria). In a pre- and post-natal study with atovaquone and another pre-and post-natal study with proguanil, neither compound impaired the growth, development, or reproductive ability of first generation offspring at maternal AUC exposures of approximately 7.3 and 0.04 times, respectively, the estimated human AUC exposure for treatment of malaria.

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: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.

8.1 Pregnancy continued

PLLR conversion; additions and/or revisions underlined:

Data

Animal Data:

Atovaquone: Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 6 to GD15) in pregnant rats did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma exposures up to 7.3 times the estimated human exposure for the treatment of malaria based on AUC. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day by gavage during organogenesis (GD6 to GD18) was associated with decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to plasma exposures that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. 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 AUC exposures of approximately 7.3 times the estimated human exposure during treatment of malaria. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue.

Proguanil: Proguanil administered orally to pregnant rats during organogenesis (GD6 to GD17) was not associated with fetal malformations, but increased ureter variations at a maternally toxic dose of 20 mg/kg/day corresponding to a plasma concentration approximately equal to 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Proguanil given orally by gavage at a maternally toxic dose of 40 mg/kg/day to pregnant rabbits during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal effects at a plasma concentration up to 0.8 times the estimated human exposure for the treatment of malaria based on AUC. In a pre- and post-natal study in female rats, proguanil hydrochloride administered in oral doses of 4, 8, or 16 mg/kg/day from GD6 until LD20 did not impair the growth, development, or reproductive ability of first generation offspring or the survivability of second generation offspring at doses up to 16 mg/kg/day (0.04 times the average human exposure based on AUC). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

Atovaquone and Proguanil: The combination of atovaquone and proguanil hydrochloride administered orally to pregnant rats in atovaquone:proguanil hydrochloride doses of 12.5:5, 25:10, and 50:20 mg/kg/day during organogenesis (GD6 to GD17) did not produce maternal toxicity or adverse embryo-fetal developmental effects with doses up to 50:20 mg/kg/day corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride administered orally in atovaquone:proguanil hydrochloride doses of 25:10, 50:20, or 100:40 mg/kg/day during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal developmental effects at a maternally toxic dose of 100:40 mg/kg/day corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of atovaquone in human milk; however, proguanil is present in human milk. Atovaquone is present in rat milk. When a drug is present in animal milk, it is likely the drug will be present in human milk. There are no data on the effects of atovaquone and proguanil on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MALARONE and any potential adverse effect on the breastfed child from MALARONE or from the underlying maternal condition.

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.

Other

Update reflects labeling change from February 2019.