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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression: Reversible HPA axis suppression and resulting glucocorticoid insufficiency can occur during or after withdrawal of treatment. Risk factors include the use of high-potency topical corticosteroids, use over large surface area, prolonged use, use under occlusion, concomitant use with other corticosteroid-containing products, altered skin barrier, liver failure, and use in pediatric patients. Minimize risk by mitigating the risk factors and use product as recommended. Modify use if HPA axis suppression is suspected. ( 5.1 , 8.4 ) • Skin Irritation and Sensitization: CUTIVATE® Lotion contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Discontinue use if irritation or sensitization develops. ( 5.2 ) 5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Adverse Endocrine Effects Topical corticosteroids, including CUTIVATE ® Lotion, can produce reversible HPA axis suppression with the potential for glucocorticoid insufficiency. Risk factors that predispose to HPA axis suppression include the use of high-potency topical corticosteroids, large treatment surface areas, prolonged use, use under occlusion, concomitant use of more than one corticosteroid-containing product, altered skin barrier, and liver failure. Pediatric patients may be at greater risk of HPA axis suppression due to their higher skin surface area to body mass ratios [ see Use in Specific Populations ( 8.4 ) ]. HPA axis suppression may occur during or after withdrawal of treatment. If HPA axis suppression is suspected, gradually withdraw the drug, reduce the frequency of application, or substitute a less potent topical corticosteroid. Evaluation of HPA axis suppression may be done by using the cosyntropin stimulation test. The effects of CUTIVATE ® Lotion on HPA axis function in pediatric patients were investigated in two trials. Among a total of 89 evaluable subjects from the two trials who were treated with CUTIVATE ® Lotion twice daily for 3 to 4 weeks, a single subject with >90% body surface area treated showed laboratory evidence of transient suppression immediately post-treatment. The post cosyntropin stimulation test serum cortisol returned to a normal level (22.1µg/dL) within one week of the final treatment visit [ see Use In Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.2 ) ]. Cushing’s syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic absorption of topical corticosteroids. Use of more than one corticosteroid-containing product at the same time may increase the total systemic absorption of topical corticosteroids. 5.2 Local Adverse Reactions CUTIVATE ® Lotion may cause local adverse reactions, including skin atrophy [ see Adverse Reactions ( 6.1 , 6.2 ) ]. The risk is greater with use under occlusion and with higher potency products. CUTIVATE ® Lotion contains the excipient imidurea which releases formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin. Avoid using CUTIVATE ® Lotion in individuals with hypersensitivity to formaldehyde as it may prevent healing or worsen dermatitis. If irritation develops, discontinue CUTIVATE ® Lotion and institute appropriate therapy. Allergic Contact Dermatitis Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noticing a clinical exacerbation. Such an observation can be corroborated with appropriate diagnostic patch testing. Discontinue CUTIVATE ® Lotion if appropriate. 5.3 Concomitant Skin Infections If skin infections are present or develop at the treatment site, an appropriate antimicrobial agent should be used. If a favorable response does not occur promptly, discontinue use of CUTIVATE ® Lotion until the infection has been adequately controlled.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • HPA Axis Suppression and Other Adverse Endocrine Effects [ see Warnings and Precautions ( 5.1 ) ] • Local Adverse Reactions [ see Warnings and Precautions ( 5.2 ) ] • Concomitant Skin Infections [ see Warnings and Precautions ( 5.3 ) ] The most common adverse reactions (2%) were burning/stinging at the application site. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PharmaDerm®, A division of Fougera Pharmaceuticals Inc. at 1-800-645-9833 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience: Controlled Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In 2 multicenter vehicle-controlled clinical trials of once-daily application of CUTIVATE ® Lotion by 196 adult and 242 pediatric patients, the total incidence of adverse reactions considered drug related by investigators was approximately 4%. These were local cutaneous reactions, usually mild and self-limiting, and consisted primarily of burning/stinging (2%). All other drug-related events occurred with an incidence of less than 1%, and included were contact dermatitis, exacerbation of atopic dermatitis, folliculitis of legs, pruritus, pustules on arm, rash, and skin infection. See Table 1 . The incidence of adverse reactions between the 242 pediatric subjects (age 3 months to < 17 years) and 196 adult subjects (17 years or older) was similar (4% and 5%, respectively). Table 1: Adverse Reactions from Controlled Clinical Trials (n=438) ADVERSE REACTIONS CUTIVATE ® Lotion VEHICLE n=221 n=217 Burning/Stinging skin 4 (2%) 3 (1%) Contact Dermatitis 0 1 (<1%) Exacerbation of Atopic dermatitis 0 1 (<1%) Folliculitis of legs 2 (<1%) 0 Irritant Contact Dermatitis 0 1 (<1%) Pruritus 1 (<1%) 1 (<1%) Pustules on Arms 1 (<1%) 0 Rash 1 (<1%) 2 (<1%) Skin Infection 0 3 (1%) During the clinical trials, eczema herpeticum occurred in a 33-year old male patient treated with CUTIVATE ® Lotion. Table 2 summarizes all adverse events by body system that occurred in at least 1% of patients in either the drug or vehicle group in the phase 3 controlled clinical trials. Table 2: Adverse Events Occurring in ≥ 1% of Patients from Either Arm from Controlled Clinical Trials (n=438) Body System CUTIVATE ® Lotion Vehicle Lotion n=221 n=217 Any Adverse Event 77 (35%) 82 (38%) Skin Burning and Stinging 4 (2%) 3 (1%) Pruritus 3 (1%) 5 (2%) Rash 2 (<1%) 3 (1%) Skin Infection 0 3 (1%) Ear, Nose, Throat Common Cold 9 (4%) 5 (2%) Ear Infection 3 (1%) 3 (1%) Nasal Sinus Infection 2 (<1%) 4 (2%) Rhinitis 1 (<1%) 3 (1%) Upper Respiratory Tract Infection 6 (3%) 7 (3%) Gastrointestinal Normal Tooth Eruption 2 (< 1%) 3 (1%) Diarrhea 3 (1%) 0 Vomiting 3 (1%) 2 (<1%) Lower Respiratory Cough 7 (3%) 6 (3%) Influenza 5 (2%) 0 Wheeze 0 3 (1%) Neurology Headache 4 (2%) 5 (2%) Non-Site Specific Fever 8 (4%) 8 (4%) Seasonal Allergy 2 (<1%) 3 (1%) 6.2 Clinical Trials Experience: Pediatric Open Label Trials In an open label HPA axis suppression trial of 44 pediatric subjects (ages ≥3 months to ≤6 years) CUTIVATE ® Lotion was applied twice daily (rather than the indicated dosing regimen of once daily) to at least 35% of body surface area for 3 or 4 weeks. Subjects whose lesions cleared after 2 or 3 weeks of treatment continued to apply CUTIVATE ® Lotion for an additional week. The overall incidence of adverse reactions was 14%. These were local, cutaneous reactions and included dry skin (7%), stinging at application site (5%), and excoriation (2%). Additionally, a 4-month-old patient treated with CUTIVATE ® Lotion had marked elevations of the hepatic enzymes AST and ALT. [ See Use in Specific Populations ( 8.4 ) ] In another open label HPA axis suppression trial in which CUTIVATE ® Lotion was also applied twice daily (rather than the indicated dosing regimen of once daily), 56 pediatric subjects (ages ≥3 months to 12 months), were enrolled [ see Use in Specific Populations ( 8.4 ) ]. The adverse reactions included 2 cases of Herpes simplex at the application site (3.6%) and 3 cases of bacterial skin infections (5.4%). 6.3 Postmarketing Experience The following local adverse reactions have been identified during post-approval use of CUTIVATE ® Lotion: erythema, edema/swelling, and bleeding. The following systemic adverse reactions have been identified during post-approval use of CUTIVATE ® Cream and CUTIVATE ® Ointment: immunosuppression/ Pneumocystis jirovecii pneumonia/leukopenia/thrombocytopenia; hyperglycemia/ glycosuria; Cushing syndrome; generalized body edema/blurred vision; and acute urticarial reaction (edema, urticaria, pruritus, and throat swelling). The following local adverse reactions have also been reported with the use of topical corticosteroids, and they may occur more frequently with the use of occlusive dressings or higher potency corticosteroids. These reactions include: acneiform eruptions, hypopigmentation, perioral dermatitis, skin atrophy, striae, hypertrichosis and miliaria. 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.