Brand name: Elidel®
Generic name: Pimecrolimus
Manufacturer: Novartis Pharma GmbH ¹
Drug class: Topical Immunomodulator²

Uses: Elidel is FDA approved for short-term and intermittent long-term treatment of mild to moderate atopic dermatitis in non-immunocompromised patients at least 2 years old, when other therapies cannot be utilized.¹

Mechanism of Action: Pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin, thereby inhibiting T-cell activation by interfering with the transcription of cytokines, including interleukin-2, interferon gamma (Th1-type), interleukin-4 and interleukin-10 (Th2-type). It also prevents the release of cytokines and inflammatory mediators from mast cells in vitro.¹

Pharmacokinetics: ¹
T_max Vd t ½ Clearance Protein Binding Bioavailability

*In vitro studies indicated that 74-87% was bound to plasma proteins.

#Because of the low systemic absorption of pimecrolimus following topical application, calculation of these measures cannot be reliably done.

Metabolism: A single radiolabeled dose of pimecrolimus was administered orally and many O-demethylation metabolites were observed. In vitro, the CYP3A4 isoenzyme metabolized pimecrolimus.¹

Excretion: Following a single oral dose of radiolabeled pimecrolimus, a total of 81% of the radioactivity was recovered. Approximately 78% of the radiolabeled radioactivity was recovered as metabolites in the feces. Of the radioactivity recovered in the feces, less than 1% was unchanged pimecrolimus.¹

The objective of this randomized, multicenter, double-blind, vehicle-controlled study was to determine the safety and efficacy of pimecrolimus 1% cream compared to vehicle in children with moderate atopic dermatitis (AD). The study was limited to patients between the ages of 1-17 years old with AD affecting > 5% of total body surface area (TBSA), AD fulfilling the diagnostic criteria of Williams and colleagues (1994), patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 (mild to moderate disease) and receiving stable doses of an additive-free, basic bland emollient for at least seven days before day one of study. In addition, patients were required to give a complete medical history and a full physical examination was administered; samples for hematology, urinalysis, and serum chemistry were collected. Before administration of the first study treatment, baseline scores for IGA, Eczema Area and Severity Index (EASI), pruritus severity, and subject’s assessment of disease control was measured. The investigators evaluated 403 patients [pimecrolimus 1% (267) vs. vehicle (136)] mean age of 6-7 years for a 6 week period. Pimecrolimus 1% or the vehicle was applied to the affected area in a thin film every 12 hours. The primary efficacy measure was the IGA score. IGA scores range from 0 (clear) to 5 (very severe disease). The IGA score provides an overall evaluation of dermatitis and was performed at each visit. A secondary efficacy parameter was the EASI score. This is used to assess dermatitis severity including surface area affected. Another secondary efficacy measure was pruritus severity. This measure graded the intensity of overall itching/scratching in the 24 hours before the visit. Another secondary outcome measure was overall AD disease control in the week prior to the visit on a scale of 0 (complete control) to 3 (uncontrolled). Safety assessments consisted of monitoring and recording all adverse events; monitoring of hematology, blood chemistry, and urinalysis; and vital sign measurements. The overall completion rate was 84.1% across both treatment groups; 25% of the patients in the vehicle group dropped out compared to 11.2% in the pimecrolimus group. As classified by IGA, 34.8% of pimecrolimus treated patients were rated as clear or almost clear of disease, compared with only 18.4% of patients in the vehicle group (P< 0.05, Cochran-Mantel-Haenszel test). By completion of study, 59.9% of pimecrolimus treated patients improved by 1 or more IGA scores, 36% maintained baseline IGA, and only 4.1% worsened. For vehicle treated patients, 33.1% improved, 47.1% maintained baseline IGA, and 19.9% worsened. ANCOVA was used to determine the mean changes of EASI, adjusting for treatment and center. Maximal improvement in EASI relative to vehicle was observed on day 29 and was maintained throughout the remainder of the study (P< 0.001). Significantly, more pimecrolimus treated patients reported mild or no pruritus than patients receiving the vehicle. Adverse events were reported in more patients in the vehicle group (35%) than the pimecrolimus group (28%). The investigators concluded that pimecrolimus cream 1% is safe and effective for treatment of AD. A limitation of this study was that investigators only studied pimecrolimus treatment for 6 weeks, but AD is a chronic condition. Also, the study was supported by a grant from Novartis. Novartis is the manufacturer of pimecrolimus, so bias is a concern. ³

This study was a randomized, double-blind, placebo-controlled, right-and-left comparison designed to compare the safety and efficacy of pimecrolimus 1% to its cream base in adults with moderate AD. Eighteen patients were randomized to once daily application and 16 were randomized to twice daily application. The patients included in this study had AD per the criteria of Hanifin and Rajka, with at least 1% of the body surface area affected on both arms. Cream base was applied to a target area on one arm and pimecrolimus 1% was applied to the other arm. The target areas to which the creams were applied comprised 1-2% of the surface area of the right and left arms. Patients recorded the time of application on a diary card. In patients receiving twice daily treatment, a 71.9% reduction in the ADSI score was observed with pimecrolimus, compared to a 10.3% reduction at the placebo sites (P<0.001). In patients treated once daily, a reduction of 37.7% was observed with pimecrolimus versus a 6.2% reduction in the placebo-treated areas. Pimecrolimus is a very promising treatment option for patients with AD. Since this study was a phase 1 trial, other studies are necessary to determine the true effectiveness of pimecrolimus. A limitation in this study was that it was funded by Novartis, the manufacturer of pimecrolimus.

Sixteen subjects (12 males, 4 females) were randomized, into a double-blind, vehicle and active controlled, within-subject study. All subjects gave written informed consent before participation. A Latin square design was utilized to rule out treatment site bias in the four groups. Four different preparations (pimecrolimus 1% cream, corresponding vehicle, betamethasone-17-valerate 0.1% cream, and triamcinolone acetonide 0.1% cream) were applied to the proximal and distal volar aspect (palm side) of the subjects’ arms twice daily for 6 days a week for 4 weeks by a nurse assigned to this task only. The nurse applied 10m L of each preparation to a 2 cm² area by gentle massage to the treatment areas without occlusion. The treated area was not to come into contact with any perfumes, other topical drugs, or cosmetics. Ultrasound, a safe, sensitive, and valid way of measuring skin thickness, was used to measure epidurmal plus dermal thickness at baseline and on days 8, 15, 22, and 29. Also, in 12 out of 16 patients, a 3-mm punch biopsy was taken from each of the four sites where the drug was applied to measure epidermal thickness. The change in total skin thickness was the primary outcome measure (reported as a percentage). All subjects received all 48 applications, of the four medications, which lead to successful completion of the study by all 16 patients. Total skin thickness with pimecrolimus 1% cream was not significantly different from the vehicle at day 29 (P<0.001, ANCOVA). The least squares (LS) estimate of the difference between pimecrolimus and vehicle was 0.62% with a 95% confidence interval (CI) ranging from –2.84 to 4.1%. The difference was significant (P<0.001) within the predefined 6% maximal limit of non-inferiority [ANCOVA, one sided test of equivalence (non-inferiority)]. The skin thickness was decreased at each of the sites that received topical corticosteroid therapy. Betamethasone cream and triamcinolone cream showed a greater reduction in skin thickness when compared with pimecrolimus 1% cream. The least square estimate of the difference for betamethasone was 7.9% with a 95% CI ranging from 4.4 to 11.3% (P<0.001) and was 12.2% with a 95% CI ranging from 8.7% to 15.8%; (P<0.001) for triamcinolone. Epidermal thickness was significantly less on sites treated with betamethasone (P<0.001) and triamcinolone (P=0.001) compared to the sites treated with pimecrolimus 1% cream. Topical adverse effects did not occur and only a total of 9 adverse effects were reported. The most common adverse even was headache. A major limitation in this study was that it was funded by Novartis Pharma AG, the manufacturer of pimecrolimus, which may have introduced bias. Another limitation of this study was that only 16 subjects were studied for 4 weeks. A study evaluating more patients for a longer period of time is necessary to show the effect of tacrolimus on skin thickness with long term use. This data suggests that pimecrolimus 1% cream has a lower potential for skin atrophy compared to topical corticosteroid treatments.

Drug Interaction: Elidel is applied topically, and is not well absorbed. The detected blood levels of pimecrolimus in patients are very low following topical administration. Since blood levels are so low, systemic drug interactions are not expected. However, drug interactions cannot be ruled out. Concomitant administration of drugs that inhibit the CYP3A family should be done cautiously. These drugs include cimetidine, calcium channel blockers, fluconazole, ketoconazole, itraconazole, and erythromycin.¹

Usual dose: (Children and Adults): Apply a thin layer of Elidel (pimecrolimus) cream to the affected area of skin twice daily. Rub cream in gently and completely. Cream may be used on all skin surfaces, including head, neck, and intertriginous areas.¹

Elidel may be used twice daily for as long as symptoms persist. Treatment should be discontinued when signs and symptoms resolve.¹

Greater than six weeks of use: If treatment continues beyond six weeks the patient should be re-evaluated.¹

Renal/ Hepatic Impairment: Since pimecrolimus is administered topically, systemic exposure of pimecrolimus is very low, and no change in dosing is required. Studies measuring the effects of renal and hepatic insufficiency on the pharmacokinetics of pimecrolimus have not been performed.¹

Geriatric Patients: Clinical studies did not include data of efficacy and safety on patients over 65.¹

Pediatric Patients: Elidel cream is not recommended in patients less than 2 years of age. For children 2 or older, dosing of Elidel is the same as adults.¹

Conclusions: Topically administered Elidel (pimecrolimus) 1% cream provides effective short term therapy of mild to moderate AD in patients > 2 years old. Unlike corticosteroids, pimecrolimus does not cause skin atrophy, striae, telangiectasia, or hypopigmentation and can be used in sensitive areas, such as the face and neck.⁶ Also, systemic absorption is very low with pimecrolimus. Therefore, less adverse effects would be experienced if pimecrolimus was utilized over a topical corticosteroid. Pimecrolimus has no documented drug interactions. However, it might be premature to use pimecrolimus as a first line agent or substitute it for another less expensive, topical treatment unless the patient is unresponsive to or intolerant of other therapies.

1. Anonymous. Elidel (pimecrolimus) cream 1% prescribing information. East Hanover, NJ: Novartis, December 2001. Available from: URL: http://www.elidel.com. [Accessed on 09/02/02]

2. Anonymous. Pimecrolimus (Elidel). In: Drug Facts and Comparisons. Updated Monthly. St. Louis: Walters Kluver; 2002. p. 1661c-1662.

3. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;Apr;46(4):495-504.

4. Van Leent, EJ, Graber M, Thurston M, Wagenaar A, Spuls P, Bos J. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 1998;134:805-9.

5. Queille-Roussel C, Duteil L, Lefevvre MC, Rapatz G, Zagula M. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: A randomized, double-blind controlled Study. Br J of Dermatol 2001;144:507-13.

6. Anonymous. Pimecrolimus (Elidel). Med Lett Drugs Ther 2002;44:48-50.

Zebulon Stickley, Pharm. D. Candidate