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boxed warning
WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN INHIBITORS HAS NOT BEEN ESTABLISHED Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including pimecrolimus cream, 1% [see Warnings and Precautions (5.1) ]. Therefore: Continuous long-term use of topical calcineurin inhibitors, including pimecrolimus cream, 1%, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis [see Dosage and Administration (2) , Warnings and Precautions (5.1) ]. Pimecrolimus cream, 1% is not indicated for use in children less than 2 years of age [see Warnings and Precautions (5.1) , Use in Specific Populations (8.4) ]. WARNING: LONG-TERM SAFETY OF TOPICAL CALCINEURIN INHIBITORS HAS NOT BEEN ESTABLISHED See full prescribing information for complete boxed warning. Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including pimecrolimus cream, 1%. ( 5.1 ) Therefore: Continuous long-term use of topical calcineurin inhibitors, including pimecrolimus cream, 1%, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis. ( 2 , 5.1 ) Pimecrolimus cream, 1% is not indicated for use in children less than 2 years of age. ( 1 , 5.1 , 8.4 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Should not be used in immunocompromised adults and children, including patients on systemic immunosuppressive medications. ( 5.1 ) Avoid treatment on malignant or pre-malignant skin conditions, as these can present as dermatitis. ( 5.2 ) Should not be used in patients with Netherton’s Syndrome or skin diseases with a potential for increased systemic absorption. ( 5.2 ) 5. 1 Risk of Immunosuppression Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression. Based on this information and the mechanism of action, there is a concern about a potential risk with the use of topical calcineurin inhibitors, including pimecrolimus cream, 1%. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including pimecrolimus cream, 1%. Therefore: Continuous long-term use of topical calcineurin inhibitors, including pimecrolimus cream, 1%, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis Pimecrolimus cream, 1% is not indicated for use in children less than 2 years of age Pimecrolimus cream, 1% should not be used in immunocompromised adults and children, including patients on systemic immunosuppressive medications. If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed. The safety of pimecrolimus cream, 1% has not been established beyond one year of non-continuous use. 5. 2 Application to Malignant or Pre-malignant Skin Conditions The use of pimecrolimus cream, 1% should be avoided on malignant or pre-malignant skin conditions. Malignant or pre-malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis. Pimecrolimus cream, 1% should not be used in patients with Netherton’s Syndrome or other skin diseases where there is the potential for increased systemic absorption of pimecrolimus. The safety of pimecrolimus cream, 1% has not been established in patients with ge...
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adverse reactions
6 ADVERSE REACTIONS The most commonly reported adverse reactions (greater than or equal to 1%) were application site burning, headache, nasopharyngitis, cough, influenza, pyrexia and viral infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6. 1 Clinical Trials Experience 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. No phototoxicity and no photoallergenicity were detected in clinical trials with 24 and 33 normal volunteers, respectively. In human dermal safety trials, pimecrolimus cream, 1% did not induce contact sensitization or cumulative irritation. In a one-year safety trial in pediatric subjects age 2 to 17 years old involving sequential use of pimecrolimus cream, 1% and a topical corticosteroid, 43% of pimecrolimus cream, 1% treated subjects and 68% of vehicle-treated subjects used corticosteroids during the trial. Corticosteroids were used for more than 7 days by 34% of pimecrolimus cream, 1% treated subjects and 54% of vehicle-treated subjects. An increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis, and urticaria were found in the subjects that had used pimecrolimus cream, 1% and topical corticosteroid sequentially as compared to pimecrolimus cream, 1% alone. In 3 randomized, double-blind vehicle-controlled pediatric trials and one active-controlled adult trial, 843 and 328 subjects respectively, were treated with pimecrolimus cream, 1%. In these clinical trials, 48 (4%) of the 1,171 pimecrolimus treated subjects and 13 (3%) of 408 vehicle-treated subjects discontinued therapy due to adverse events. Discontinuations for AEs were primarily due to application site reactions, and cutaneous infections. The most common application site reaction was application site burning, which occurred in 8% to 26% of subjects treated with pimecrolimus cream, 1%. Table 1 depicts the incidence of adverse events pooled across the 2 identically designed 6-week trials with their open label extensions and the 1-year safety trial for pediatric subjects ages 2 to 17. Data from the adult active-con...
adverse reactions table
Table 1. Treatment Emergent Adverse Events (≥1%) in Pimecrolimus Cream Treatment Groups P e di a t r i c Subj e c t s* P e di a t r i c Subj e c t s* P e di a t r i c Subj e c t s* Adu l t A c t i v e V e h i c le -C o nt r o lle d O p e n- La b e l V e h i c le -C o nt r o lle d C o m p ara to r ( 6 wee k s) ( 2 0 w ee k s) ( 1 y e ar ) ( 1 y e ar) Pimecrolimus Cream Vehicle Pimecrolimus Cream Pimecrolimus Cream Vehicle Pimecrolimus Cream (N=267) (N=136) (N=335) (N=272) (N=75) (N=328) N (%) N (%) N (%) N (%) N (%) N (%) At least 1 AE 182 (68.2%) 97 (71.3%) 240 (72.0%) 230 (84.6%) 56 (74.7%) 256 (78.0%) I n f e c ti o n s a n d I nf e s t a t io n s Upper Respiratory Tract Infection NOS 38 (14.2%) 18 (13.2%) 65 (19.4%) 13 (4.8%) 6 (8.0%) 14 (4.3%) Nasopharyngitis 27 (10.1%) 10 (7.4%) 32 (19.6%) 72 (26.5%) 16 (21.3%) 25 (7.6%) Skin Infection NOS 8 (3.0%) 9 (5.1%) 18 (5.4%) 6 (2.2%) 3 (4.0%) 21 (6.4%) Influenza 8 (3.0%) 1 (0.7%) 22 (6.6%) 36 (13.2%) 3 (4.0%) 32 (9.8%) Ear Infection NOS 6 (2.2%) 2 (1.5%) 19 (5.7%) 9 (3.3%) 1 (1.3%) 2 (0.6%) Otitis Media 6 (2.2%) 1 (0.7%) 10 (3.0%) 8 (2.9%) 4 (5.3%) 2 (0.6%) Impetigo 5 (1.9%) 3 (2.2%) 12 (3.6%) 11 (4.0%) 4 (5.3%) 8 (2.4%) Bacterial Infection 4 (1.5%) 3 (2.2%) 4 (1.2%) 3 (1.1%) 0 6 (1.8%) Folliculitis 3 (1.1%) 1 (0.7%) 3 (0.9%) 6 (2.2%) 3 (4.0%) 20 (6.1%) Sinusitis 3 (1.1%) 1 (0.7%) 11 (3.3%) 6 (2.2%) 1 (1.3%) 2 (0.6%) Pneumonia NOS 3 (1.1%) 1 (0.7%) 5 (1.5%) 0 1 (1.3%) 1 (0.3%) Pharyngitis NOS 2 (0.7%) 2 (1.5%) 3 (0.9%) 22 (8.1%) 2 (2.7%) 3 (0.9%) Pharyngitis Streptococcal 2 (0.7%) 2 (1.5%) 10 (3.0%) 0 <1% 0 Molluscum Contagiosum 2 (0.7%) 0 4 (1.2%) 5 (1.8%) 0 0 Staphylococcal Infection 1 (0.4%) 5 (3.7%) 7 (2.1%) 0 <1% 3 (0.9%) Bronchitis NOS 1 (0.4%) 3 (2.2%) 4 (1.2%) 29 (10.7%) 6 (8.0%) 8 (2.4%) Herpes Simplex 1 (0.4%) 0 4 (1.2%) 9 (3.3%) 2 (2.7%) 13 (4.0%)