Calcineurin Inhibitor Immunosuppressant

Elidel

Approved 13 Dec 2001TopicalCream

Indications

Pimecrolimus Cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. 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) ] .

Pimecrolimus Cream, 1% is a calcineurin inhibitor immunosuppressant indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. ( 1 )

Contraindications

Pimecrolimus Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream. Pimecrolimus Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream. ( 4 , 6.2 )

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 )

5.1Risk 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:

At a glance

Brand name: Elidel
Active substance: pimecrolimus
Pharmacologic class: Calcineurin Inhibitor Immunosuppressant
Route: Topical
Dosage form: Cream
Applicant: Bausch
Status: Prescription
FDA approval: 13 Dec 2001
Application: NDA021302-001

Indications

Contraindications

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 )

5.1Risk of Immunosuppression

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C

There are no adequate and well-controlled studies with Pimecrolimus Cream, 1% in pregnant women. Therefore, Pimecrolimus Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14X MRHD based on body surface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65X MRHD based on AUC comparisons).

The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits). A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately 22 hours.

No maternal, reproductive, or embryofetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66X MRHD based on AUC comparisons), the highest dose evaluated in this study. No teratogenicity was noted in this study at any dose. A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (2 weeks prior to mating until gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45 mg/kg/day in rats and 20 mg/kg/day in rabbits.

In the absence of maternal toxicity, indicators of embryofetal toxicity (post-implantation loss and reduction in litter size) were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9X MRHD based on AUC comparisons), which was the highest dose tested in this study.

A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days 6 – 17) at doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity were noted at 45 mg/kg/day (271X MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose.

No maternal toxicity, embryolethality or fetotoxicity were noted at 10 mg/kg/day (16X MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose. A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (gestational days 7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12X MRHD based on AUC comparisons).

A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5X MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose. An oral peri- and postnatal developmental study was conducted in rats. Pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg/kg/day.

Only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg/kg/day (12X MRHD based on AUC comparisons), the highest dose evaluated in this study. Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies.

Adverse reactions

The most commonly reported adverse reactions (≥1%) were application site burning, headache, nasopharyngitis, cough, influenza, pyrexia and viral infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 1-year safety trial in pediatric subjects age 2-17 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 three 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 1171 Pimecrolimus Cream, 1% 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%-26% of subjects treated with Pimecrolimus Cream, 1%. Table 1 depicts the incidence of adverse events pooled across the two identically designed 6-week trials with their open label extensions and the 1-year safety trial for pediatric subjects ages 2-17. Data from the adult active-controlled trial are also included in Table 1. Adverse events are listed regardless of relationship to trial drug.

Table 1. Treatment Emergent Adverse Events (≥1%) in Pimecrolimus Cream, 1% Treatment Groups Pediatric Subjects Ages 2-17 years Vehicle-Controlled (6 weeks) Pediatric Subjects Open-Label Pediatric Subjects Vehicle-Controlled (1 year) Adult Active Comparator (1 year) (20 weeks) Pimecrolimus Cream, 1% Vehicle Pimecrolimus Cream, 1% Pimecrolimus Cream, 1% Vehicle Pimecrolimus Cream, 1% (N=267) N (%) (N=136) N (%) (N=335) N (%) (N=272) N (%) (N=75) N (%) (N=328) N (%) At least 1 AE 182 (68.2%) 97 (71.3%) 240 (72.0%) 230 (84.6%) 56 (74.7%) 256 (78.0%) Infections and Infestations 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%) Tonsillitis NOS 1 (0.4%) 0 3 (0.9%) 17 (6.3%) 0 2 (0.6%) Viral Infection NOS 2 (0.7%) 1 (0.7%) 1 (0.3%) 18 (6.6%) 1 (1.3%) 0 Gastroenteritis NOS 0 3 (2.2%) 2 (0.6%) 20 (7.4%) 2 (2.7%) 6 (1.8%) Chickenpox 2 (0.7%) 0 3 (0.9%) 8 (2.9%) 3 (4.0%) 1 (0.3%) Skin Papilloma 1 (0.4%) 0 2 (0.6%) 9 (3.3%) <1% 0 Tonsillitis Acute NOS 0 0 0 7 (2.6%) 0 0 Upper Respiratory Tract Infection Viral NOS 1 (0.4%) 0 3 (0.9%) 4 (1.5%) 0 1 (0.3%) Herpes Simplex Dermatitis 0 0 1 (0.3%) 4 (1.5%) 0 2 (0.6%) Bronchitis Acute NOS 0 0 0 4 (1.5%) 0 0 Eye Infection NOS 0 0 0 3 (1.1%) <1% 1 (0.3%) General Disorders and Administration Site Conditions Application Site Burning 28 (10.4%) 17 (12.5%) 5 (1.5%) 23 (8.5%) 5 (6.7%) 85 (25.9%) Pyrexia 20 (7.5%) 12 (8.8%) 41 (12.2%) 34 (12.5%) 4 (5.3%) 4 (1.2%) Application Site Reaction NOS 8 (3.0%) 7 (5.1%) 7 (2.1%) 9 (3.3%) 2 (2.7%) 48 (14.6%) Application Site Irritation 8 (3.0%) 8 (5.9%) 3 (0.9%) 1 (0.4%) 3 (4.0%) 21 (6.4%) Influenza-Like Illness 1 (0.4%) 0 2 (0.6%) 5 (1.8%) 2 (2.7%) 6 (1.8%) Application Site Erythema 1 (0.4%) 0 0 6 (2.2%) 0 7 (2.1%) Application Site Pruritus 3 (1.1%) 2 (1.5%) 2 (0.6%) 5 (1.8%) 0 18 (5.5%) Respiratory, Thoracic and Mediastinal Disorders Cough 31 (11.6%) 11 (8.1%) 31 (9.3%) 43 (15.8%) 8 (10.7%) 8 (2.4%) Nasal Congestion 7 (2.6%) 2 (1.5%) 6 (1.8%) 4 (1.5%) 1 (1.3%) 2 (0.6%) Rhinorrhea 5 (1.9%) 1 (0.7%) 3 (0.9%) 1 (0.4%) 1 (1.3%) 0 Asthma Aggravated 4 (1.5%) 3 (2.2%) 13 (3.9%) 3 (1.1%) 1 (1.3%) 0 Sinus Congestion 3 (1.1%) 1 (0.7%) 2 (0.6%) <1% <1% 3 (0.9%) Rhinitis 1 (0.4%) 0 5 (1.5%) 12 (4.4%) 5 (6.7%) 7 (2.1%) Wheezing 1 (0.4%) 1 (0.7%) 4 (1.2%) 2 (0.7%) <1% 0 Asthma NOS 2 (0.7%) 1 (0.7%) 11 (3.3%) 10 (3.7%) 2 (2.7%) 8 (2.4%) Epistaxis 0 1 (0.7%) 0 9 (3.3%) 1 (1.3%) 1 (0.3%) Dyspnea NOS 0 0 0 5 (1.8%) 1 (1.3%) 2 (0.6%) Gastrointestinal Disorders Abdominal Pain Upper 11 (4.1%) 6 (4.4%) 10 (3.0%) 15 (5.5%) 5 (6.7%) 1 (0.3%) Sore Throat 9 (3.4%) 5 (3.7%) 15 (5.4%) 22 (8.1%) 4 (5.3%) 12 (3.7%) Vomiting NOS 8 (3.0%) 6 (4.4%) 14 (4.2%) 18 (6.6%) 6 (8.0%) 2 (0.6%) Diarrhea NOS 3 (1.1%) 1 (0.7%) 2 (0.6%) 21 (7.7%) 4 (5.3%) 7 (2.1%) Nausea 1 (0.4%) 3 (2.2%) 4 (1.2%) 11 (4.0%) 5 (6.7%) 6 (1.8%) Abdominal Pain NOS 1 (0.4%) 1 (0.7%) 5 (1.5%) 12 (4.4%) 3 (4.0%) 1 (0.3%) Toothache 1 (0.4%) 1 (0.7%) 2 (0.6%) 7 (2.6%) 1 (1.3%) 2 (0.6%) Constipation 1 (0.4%) 0 2 (0.6%) 10 (3.7%) <1% 0 Loose Stools 0 1 (0.7%) 4 (1.2%) <1% <1% 0 Reproductive System and Breast Disorders Dysmenorrhea 3 (1.1%) 0 5 (1.5%) 3 (1.1%) 1 (1.3%) 4 (1.2%) Eye Disorders Conjunctivitis NEC 2 (0.7%) 1 (0.7%) 7 (2.1%) 6 (2.2%) 3 (4.0%) 10 (3.0%) Skin and Subcutaneous Tissue Disorders Urticaria 3 (1.1%) 0 1 (0.3%) 1 (0.4%) <1% 3 (0.9%) Acne NOS 0 1 (0.7%) 1 (0.3%) 4 (1.5%) <1% 6 (1.8%) Immune System Disorders Hypersensitivity NOS 11 (4.1%) 6 (4.4%) 16 (4.8%) 14 (5.1%) 1 (1.3%) 11 (3.4%) Injury and Poisoning Accident NOS 3 (1.1%) 1 (0.7%) 1 (0.3%) <1% 1 (1.3%) 0 Laceration 2 (0.7%) 1 (0.7%) 5 (1.5%) <1% <1% 0 Musculoskeletal, Connective Tissue and Bone Disorders Back Pain 1 (0.4%) 2 (1.5%) 1 (0.3%) <1% 0 6 (1.8%) Arthralgias 0 0 1 (0.3%) 3 (1.1%) 1 (1.3%) 5 (1.5%) Ear and Labyrinth Disorders Earache 2 (0.7%) 1 (0.7%) 0 8 (2.9%) 2 (2.7%) 0 Nervous System Disorders Headache 37 (13.9%) 12 (8.8%) 38 (11.3%) 69 (25.4%) 12 (16.0%) 23 (7.0%) Two cases of septic arthritis have been reported in infants less than one year of age in clinical trials conducted with Pimecrolimus Cream, 1% (n = 2443).

Causality has not been established.

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pimecrolimus Cream, 1%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Elidel

Indications

Contraindications

Warnings and precautions

5.1Risk of Immunosuppression

At a glance

Two medicines in one question?

Elidel

Indications

Contraindications

Warnings and precautions

5.1Risk of Immunosuppression

At a glance

Two medicines in one question?

5.2Application to Malignant or Pre-malignant Skin Conditions

5.3Bacterial and Viral Skin Infections

5.4Patients with Lymphadenopathy

5.6Immunocompromised Patients

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Official product information