«Erica D. Radden, MD Pediatric and Maternal Health Staff Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration ...»
Pediatric Focused Safety Review:
Pediatric Advisory Committee Meeting
May 7, 2012
Erica D. Radden, MD
Pediatric and Maternal Health Staff
Office of New Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
• Background Information
• Pediatric Studies
• Pediatric Labeling Changes
• Additional Relevant Safety Labeling
• Drug Use Trends
• Adverse Events
• Summary Background Drug Information Differin® (adapalene) Drug: Differin® (adapalene) •
• Formulation: lotion, 0.1%
• Indication: Topical treatment of acne vulgaris in patients 12 years and older.
• Dosage and Administration: Apply a thin film to the entire face and other affected areas of the skin once daily
• Therapeutic Category: Topical retinoid
• Sponsor: Galderma Research and Development, Inc. 3 Background Drug Information (continued) Differin® (adapalene)
• Original Market approval: March 17, 2010
• PREA labeling changes: March 17, 2010 – PREA studies waived in patients less than 12 years old
• Additional pediatric study requested for pharmacokinetic data under maximal use conditions in adolescents age 12-17 years (due Feb 2012).
Background Drug Information (continued) Differin® (adapalene)
• Related product: Epiduo® (adapalene/benzoyl peroxide) originally approved December 8, 2008
• Other Approved Differin® formulations:
– Topical solution 0.1% (discontinued) (approved May 31, 1996) – Topical gel 0.1% (approved May 31, 1996) – Topical cream 0.1% (approved May 26, 2000) – Topical gel 0.3% (approved June 19, 2007) Pediatric Studies: Safety and Efficacy Differin® (adapalene)
• Two 12-week multicenter, randomized, double-blind, vehiclecontrolled, parallel group studies in patients 12 years of age and older with moderate to severe acne vulgaris.
• Patients randomized to Differin® lotion or vehicle – Study 1 (n=1075, age 12-50; n=670, age 12-18) – Study 2 (n=1066, age 12-64; n=674, age 12-18) – Median age (both studies): 16.7 years
• Differin® lotion demonstrated superiority over vehicle in decline of Investigator Global Assessment and lesion count from baseline.
Pediatric Labeling Changes Differin® (adapalene)
8.4 Use in Specific Populations, Pediatric Use – Safety and effectiveness in pediatric patients less than 12 years have not been established.
Pediatric information included throughout labeling for patients 12 years and older.
Relevant Safety Labeling Differin® (adapalene) 4 CONTRAINDICATIONS: none
5 WARNINGS AND PRECAUTIONS:
5.1 Ultraviolet Light and Environmental Ex
• Top diagnosis code in pediatric patients aged 0-16 years was “Acne Not Elsewhere Classified” (ICD-9 706.1).² ¹Source: IMS Vector One®: National, March 2010-December 2011 Data Extracted February 2012.
²Source: SDI Physician Drug and Diagnosis Audit, March 2010-December 2011 Data Extracted February 2012.
Previous Safety Reviews adapalene
• July 24, 2009. Phototoxicity with adapalene and tetracycline/doxycycline.
– One report of phototoxicity in a 16 year old patient on multiple medications was identified, but timing of administration of tetracycline and adapalene could not be determined.
– No action was recommended as a result of the review.
• August 30, 2010. Epiduo® post-marketing adverse event reports in patients 16 years of age and younger.
– Labeling change recommended: add hypersensitivity-related adverse event information to the Contraindications and Postmarketing Experience sections of the Epiduo® label.
Epiduo® Pediatric Focused Safety Review
• Summary – The Epiduo safety review at the Pediatric Advisory Committee (PAC) on Dec. 7, 2010 identified the concern of an association of Epiduo® with hypersensitivity reactions – The PAC advised the FDA to revise labeling to include the potential for patient hypersensitivity to the product (PAC vote: 12 yes; 0 No; 0 Abstain; 1 committee member recused) – Labeling changes describing cutaneous reactions
including irritant and allergic contact dermatitis added to:
• 5.2 Local Cutaneous Reactions • 6.2 Postmarketing Experience Epiduo® Labeling Changes* • 5.2 Local Cutaneous Reactions:
Erythema, scaling, dryness, and stinging/burning may be experienced with use of EPIDUO gel. These are most likely to occur during the first four weeks of treatment, are mostly mild to moderate in intensity, and usually lessen with continued use of the medication. Irritant and allergic contact dermatitis may occur.
Depending upon the severity of these adverse reactions, patients should be instructed to use a moisturizer, reduce the frequency of the application of EPIDUO gel, or discontinue use. The product should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of “waxing” as a depilatory method should be avoided on skin treated with EPIDUO gel. Avoid concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).
• 6.2 Postmarketing Experience:
The following adverse reactions have been identified during postapproval use of EPIDUO Gel: eyelid edema, sunburn, blister, pain of skin, pruritus, swelling face, conjunctivitis, skin discoloration, rash, eczema, throat tightness and allergic contact dermatitis.
*Labeling changes are underlined.
Total Number1 of Differin® Adverse Event Reports Since Pediatric Approval2 (May 31,1996 to January 3, 2012)
• Central Nervous System (n=5) – All unlabeled
• Hepatobiliary (n=3) – All unlabeled
• Congenital Anomalies (n=3) – Pregnancy Category C Serious Non-Fatal Labeled Adverse Events Differin® (adapalene) Dermatologic - labeled (n=3) • 16 year old female experienced a photoallergic reaction 6 days after re-initiating topical clindamycin and adapalene (formulation not specified), which improved following treatment with steroids. She had used both medications previously for one year.
• 15 year old male using adapalene gel 0.3%, clindamycin/benzoyl peroxide combination and an unspecified facial cleanser reported application of adapalene “felt funny” resulting in occasional non compliance.
• 13 year old female with a history of atopy experienced acute contact eczema after her second application of adapalene cream 0.1%. Skin biopsy was performed in the emergency room, but results were not reported.
Labeling - WARNINGS AND PRECAUTIONS: avoid sun exposure;
ADVERSE REACTIONS: dermatitis, contact dermatitis, eczema 22 Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Dermatologic (n=3) • 10 year old female developed ecchymotic spots on her face 2 months after initiation of adapalene cream 0.1%, that were believed to be erythema multiforme. She was instructed to discontinue the adapalene, but did not return for follow-up.
• 16 year old male using adapalene (formulation not specified) for approximately 1 year experienced thinning of the hair and receding of the hairline. Concomitant medications: fexofenadine and esomeprazole for an unknown period of time.
Esomeprazole (Nexium®) labeling - ADVERSE REACTIONS:
alopecia *Unlabeled events are underlined Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Dermatologic (n=3) (continued) • 16 year old female experienced angioedema 13 days after the initiation of minocycline and adapalene gel 0.1%. Laboratory studies revealed a WBC of 13,800 cells/microliter and a positive Mycoplasma titer. She was hospitalized and improved with discontinuation of the minocycline and adapalene and treatment with prednisolone and furosemide.
Minocycline (Minocin) labeling - ADVERSE REACTIONS:
Hypersensitivity reactions: angioneurotic edema.
Mycoplasma is associated with urticaria and angioedema.1,2 *Unlabeled events are underlined.
1Shah KN, Honig PJ, and Yan AC. “Urticaria Multiforme”: A Case Series and Review of Acute Annular Urticarial Hypersensitivity Syndromes in Children. Pediatrics. May 2007;119(5):e1177-83.
2Stockner I, Thaler J, Fichtel F, Egarter-Vifl E, Wallnofer W, Wiedermann CJ. Non-episodic angioedema associated with eosinophilia following Mycoplasma pneumoniae infection. Clin Rheumatol. Dec 2008;27(12):1573-6.
Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Central Nervous System (n=5) Neuropsychiatric Events (n=1) • 16 year old male developed “lack of concentration, trouble focusing, trouble sleeping, anxiety and was dispirited and depressed” 7 months after initiation of adapalene gel 0.3% and an unknown time after initiation of a clindamycin/benzoyl peroxide topical combination product. He recovered 1 month after discontinuation of adapalene. Clindamycin/benzoyl peroxide was continued.
*Unlabeled events are underlined.
Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Central Nervous System (n=5) (continued) Neuromuscular Events (n=1) • 16 year old female developed ptosis, muscular weakness, and difficulty swallowing 3 months after initiating treatment with oral lymecycline, and topical erythromycin and adapalene gel (unspecified strength).
While being evaluated, topical tretinoin was substituted for adapalene secondary to lack of efficacy, and 2 months later all acne medications were discontinued and replaced with an erythromycin/benzoyl peroxide combination.
She was diagnosed with myasthenia gravis, and responded to treatment with thymectomy and pyridostigmine.
*Unlabeled events are underlined. 26 Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Central Nervous System (n=5) (continued) General CNS Events (n=3) • 14 year old female (60 kg) hospitalized with intracranial hypertension after using adapalene gel 0.1% (unspecified duration). Lumbar puncture detected no infection. Resolution without sequelae; it is unclear if adapalene was discontinued.
• 13 year old female (weight not specified) developed blurred vision and headaches approximately 1-2 months after starting adapalene gel (unspecified strength). Increased pressure on the optic nerve was noted by Ophthalmology and her lumbar puncture revealed elevated intracranial pressure. Adapalene was discontinued and her headaches improved.
*Unlabeled events are underlined.
Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Central Nervous System (n=5) General CNS Events (n=3) (continued) • 14 year old female (48 kg) developed headache, nausea, vomiting, blurred vision, numbness and tingling in extremities and CN VI palsy 5 days after starting minocycline and adapalene gel (unspecified strength). Papilledema was noted and she was diagnosed with drug-induced pseudotumor cerebri.
After initial improvement on acetazolamide, symptoms worsened, and she was hospitalized. Lumbar puncture revealed an elevated opening pressure with normal CSF cell count and culture. MRI was normal. Furosemide was added to acetazolamide with improvement following discontinuation of minocycline and adapalene.
Minocycline (Minocin) labeling - PRECAUTIONS: pseudotumor cerebri (benign intracranial hypertension).
Idiopathic Intracranial Hypertension is associated with hypervitaminosis A and is labeled for the systemic, but not the topical retinoids.
* Unlabeled events are underlined.
Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Hepatobiliary (n=3) • A 16 year old male taking adapalene (formulation not specified) for an unknown duration and isotretinoin for 1 day was noted to have elevated transaminase levels on screening labs for initiation of isotretinoin. Liver biopsy showed globular hepatic lesions.
Adapalene was discontinued. Follow-up information was not provided.
Isotretinoin labeling - ADVERSE REACTIONS: mild/moderate elevations of liver enzymes *Unlabeled events are underlined. 29 Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Hepatobiliary (n=3) • 15 year old male with prior history of unspecified drug allergy and Haemophilus meningitis was hospitalized with cholestatic jaundice and hepatitis 2 months after the initiation of topical adapalene gel 0.1% and oral minocycline. Anti-HCV antibodies were positive.
Biopsy indicated cholestasis with cytolysis. Treatment status for the HCV was not reported. Improvement was noted 5 months following discontinuation of both drugs.
Minocycline labeling - WARNINGS AND PRECAUTIONS:
hepatotoxicity; ADVERSE REACTIONS: hepatic cholestasis, hepatitis *Unlabeled events are underlined.
Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Hepatobiliary (n=3) (continued) • 15 year old male with history of pneumonia and no significant family medical history developed acute liver failure while using adapalene gel 0.1% for 6 months and taking erythromycin 250 mg daily for an unknown period of time. Abdominal ultrasound, renal function, and viral hepatic serologies were normal.
Wilson’s disease, autoimmune disease, metabolic disease and alpha-1-antitrypsin deficiency were ruled out. Symptoms persisted despite discontinuation of adapalene and liver transplantation was considered.
Erythromycin labeling - WARNINGS and ADVERSE REACTIONS:
hepatic dysfunction *Unlabeled events are underlined.
Serious Non-Fatal Unlabeled Adverse Events Differin® (adapalene) Congenital Anomalies (n=3) • A male neonate whose mother had applied adapalene gel 0.1% twice during her pregnancy was born with one kidney.
• 4 year old male, whose mother used adapalene throughout pregnancy, was diagnosed with neurofibromatosis type 1 (NF1).
• A male neonate whose mother used adapalene gel (unspecified strength), clindamycin, and a topical antifungal liquid for the first 2 4 weeks of pregnancy was born with multiple birth deformities, including Scimitar syndrome, Dandy-Walker malformation, atrial septal defect and merged kidneys. No chromosomal abnormalities were detected.