Adapalene and benzoyl peroxide (adapalene; benzoyl peroxide): safety-related changes to the instructions for medical use approved by the FDA Center for Drug Evaluation and Research (CDER)
The FDA Center for Drug Evaluation and Research (CDER) has published a warning on the use of medicinal products containing adapalene and benzoyl peroxide (adapalene; benzoyl peroxide), associated with the risk of hypersensitivity reactions and photosensitivity, together with data on use during pregnancy and lactation.
Section «Contraindications»
Underlined additions and/or changes:
Adapalene/benzoyl peroxide is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any of the components of the medicinal product.
Section “Warnings and precautions”
Hypersensitivity
A new subsection has been added
Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If a serious hypersensitivity reaction occurs, discontinue the medicinal product adapalene/benzoyl peroxide immediately and initiate appropriate therapy.
Photosensitivity
Underlined additions and/or changes:
Avoid exposure to sunlight and ultraviolet light, including lamps, while using adapalene/benzoyl peroxide. Particular caution should be exercised by patients with high sun exposure and those who are inherently sensitive to the sun. It is recommended to use broad-spectrum sunscreens and protective clothing (for example, a hat) when exposure cannot be avoided. Extreme weather conditions, such as wind or cold, may cause irritation in patients treated with adapalene/benzoyl peroxide.
“Adverse reactions” section
Clinical trial experience
Underlined additions and/or changes:
The following adverse reactions are discussed in more detail in other sections of the instructions for medical use:
Hypersensitivity [see Warnings and Precautions (5.1)]
Skin irritation/contact dermatitis [see Warnings and Precautions (5.3)]
Post-marketing experience
Underlined additions and/or changes:
During post-registration use of adapalene/benzoyl peroxide, the following adverse reactions were identified. 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.
Skin and subcutaneous tissue disorders: sunburn, blisters (including vesicles and bullae), pruritus, hyperpigmentation and hypopigmentation.
Section “Use in specific population groups”
Subsection «Pregnancy»
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Risk summary
The available pharmacovigilance data on the use of adapalene/benzoyl peroxide in pregnant women are insufficient to establish a medicinal product-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction studies with the combination gel have not been conducted.
Adapalene gel 0,3%
The available clinical study data on the use of adapalene gel 0,3% in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse outcomes for the mother or fetus. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits during organogenesis at doses 41 and 81 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 2 g resulted in skeletal and visceral fetal malformations (see Data).
Benzoyl peroxide gel 2,5%
The systemic effect of benzoyl peroxide is unknown. According to the published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is excreted in the urine. Therefore, use of the product by the mother is not expected to result in exposure of the fetus to the product. The background risk of major birth defects and miscarriage for the indicated population is unknown. Every pregnancy carries a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal data
In rats given oral adapalene at doses from 0,15 to 5,0 mg/kg/day, up to 8 times the MRHD of 2 grams of adapalene/benzoyl peroxide based on a mg/m2 comparison, no malformations were observed. However, malformations were observed in rats and rabbits treated with oral doses ? 25 mg/kg/day of adapalene (41 and 81 times the MRHD, respectively, based on a mg/m2 comparison). Findings included cleft palate, microphthalmia, encephalocele and skeletal abnormalities in rats, and umbilical hernia, exophthalmos, and kidney and skeletal abnormalities in rabbits.
Embryo-fetal development studies of dermal adapalene in rats and rabbits at doses up to 6,0 mg/kg/day (9,7 and 19,5 times the MRHD, respectively, based on a mg/m2 comparison) revealed no fetotoxicity and only a minimal increase in skeletal variations (supernumerary ribs) in both species and delayed ossification in rabbits).
Subsection «Lactation»
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Summary of risks
Adapalene gel 0,3%
There are no data on the presence of adapalene topical gel or its metabolite in breast milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, adapalene is present in the milk of rats after oral administration of the drug. If a medicinal product is present in animal milk, it is highly likely to be present in human milk. It is possible that topical application of large amounts of adapalene may result in sufficient systemic absorption to produce detectable amounts in breast milk (see "Clinical recommendations").
Benzoyl peroxide gel 2,5%
The systemic effect of benzoyl peroxide is unknown. According to published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is excreted in the urine. Any amount of benzoyl peroxide excreted into the breast milk of a breastfeeding mother is expected to be rapidly metabolized by tissue and gastric esterases. There are no data on the presence of benzoyl peroxide in human milk, its effects on the breastfed infant, or its effects on milk production.
The developmental and health benefits of breastfeeding should be considered together with the mother’s clinical need for adapalene/benzoyl peroxide and any potential adverse effects of adapalene/benzoyl peroxide on the breastfed child or from the mother’s underlying condition.
Clinical recommendations
To minimize the potential exposure of a breastfed infant through breast milk, apply adapalene/benzoyl peroxide to the smallest area of skin and for the shortest period possible while breastfeeding. Advise breastfeeding women not to apply adapalene/benzoyl peroxide directly to the nipple and areola to avoid direct exposure of the infant.
INFORMATION FOR HEALTHCARE PROFESSIONALS
Underlined additions and/or changes:
Hypersensitivity
Inform patients that serious hypersensitivity reactions have occurred with the use of benzoyl peroxide products. If a patient develops a serious hypersensitivity reaction, ask the patient to immediately stop taking adapalene/benzoyl peroxide and seek medical attention (see Warnings and Precautions (5.1)).
Photosensitivity
Advise patients to minimize or avoid exposure to natural or artificial light, including tanning beds or UVA/B treatment. Recommend the use of broad-spectrum sunscreens and protective clothing (for example, a hat) if exposure cannot be avoided (see Warnings and Precautions (5.2)).
Skin irritation/contact dermatitis
Inform patients that adapalene/benzoyl peroxide may cause irritation such as erythema, scaling, dryness, stinging or burning
[see Warnings and precautions (5.3)].
Lactation
Use adapalene/benzoyl peroxide on the smallest area of skin for the shortest possible period of time during breastfeeding. Advise breastfeeding women not to apply adapalene/benzoyl peroxide directly to the nipple and areola to avoid direct exposure of the infant (see Use in specific populations (8.2)).
Administration instructions
Wash your hands after use, because adapalene/benzoyl peroxide may bleach hair and colored fabric.
INFORMATION FOR THE PATIENT
Underlined additions and/or changes:
Do not use adapalene/benzoyl peroxide if you have had an allergic reaction to benzoyl peroxide or any of the ingredients of adapalene/benzoyl peroxide.
Before using adapalene/benzoyl peroxide, tell your doctor about all your medical conditions, including if you:
- you are breastfeeding or plan to breastfeed. It is not known whether adapalene/benzoyl peroxide passes into your breast milk or whether it can harm your baby. Talk to your doctor about the best way to feed your baby if you use adapalene/benzoyl peroxide. If you use adapalene/benzoyl peroxide while breastfeeding, apply it to the smallest area of skin and for the shortest time possible. Do not apply adapalene/benzoyl peroxide directly to the nipple and areola to minimize contact with the baby.
What are the possible side effects of adapalene/benzoyl peroxide?
Adapalene/benzoyl peroxide may cause serious side effects, including:
- allergic reactions. Stop using adapalene/benzoyl peroxide and seek medical help immediately if you experience any of the following symptoms during treatment with adapalene/benzoyl peroxide:
- hives, rash or severe itching
- swelling of the face, eyes, lips, tongue, or throat
- breathing problems or tightness in the throat
- feeling of weakness, dizziness, or lightheadedness
- skin irritation. Skin irritation is common with the use of adapalene/benzoyl peroxide and is most likely to occur during the first 4 weeks of treatment and usually decreases with continued use of adapalene/benzoyl peroxide. Skin reactions at the application site include redness, peeling, dryness, burning, stinging, itching and swelling. Tell your doctor if you develop skin reactions.
- Sensitivity to sunlight. See “What should I avoid while using adapalene/benzoyl peroxide?”
The original text is available at the link https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=2611
