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Formulary Monograph
Pimecrolimus (Elidel, Novartis)
Therapeutic Use: Atopic Dermatitis
Similar Drugs: Tacrolimus (Protopic)
ISSUES FOR THE COMMITTEE
Issue 1: Should pimecrolimus be added to the formulary?
Issue 2: Is there a specific therapeutic niche and/or subpopulation of patients to which its use should be restricted? If so, how are they to be defined/identified?
Issue 3: Should pimecrolimus be declared to be therapeutically equivalent to tacrolimus?
INDICATIONS1,2
Pimecrolimus is FDA approved for short-term and intermittent long-term treatment of mild to moderate atopic dermatitis in immunocompetent patients two years of age and older.
Treatment of chronic irritant contact dermatitis and plaque psoriasis, as well as use in children under the age of two is currently off-label.
CLINICAL PHARMACOLOGY2
The anti-inflammatory properties of pimecrolimus are believed to result from its binding to the cytosolic immunophilin receptor, macrophilin-12. The resulting drug-receptor complex inhibits calcineurin and blocks T-cell activation. It is also believed to inhibit mast cell activation and the release of inflammatory cytokines – specifically IL-2, IL-4, IL-10, and interferon gamma.
PHARMACOKINETICS2
Rt of Admin: Topical. Absorption is believed to be minimal with blood levels of less than 2 ng/mL after twice daily dosing for six months. The drug is thought to be absorbed intact through the skin, but the extent of hepatic metabolism is unknown.
ADVERSE EFFECTS1
Summary: Local application site irritation was reported more often in vehicle/placebo group than in pimecrolimus treated subjects during the six week trial, but more often in the active group over a year long study. There was not an increase in cutaneous bacterial infection in the pimecrolimus group, however there were increased percentages of papilloma and nasopharyngitis cases found during both study periods.
Monitoring: Patients should be advised to watch for improvement of atopic dermatitis symptoms, particularly pruritis, erythema, exudation, excoriation, and lichenification to assess efficacy of therapy, as well as any signs of signs of hypersensitivity reactions such as swelling, increased pruritis, and urticaria.
Table I. Reported Adverse Effects1
Reported Incidence in Trials(%): 6 weeks / 1 yearAdverse Effect / Drug Therapy (n=267) / (n=272) / Placebo (n=136) / (n=75)
Nasopharyngitis / 10.1 / 26.5 / 7.4 / 21.3
Influenza / 3.0 / 13.2 / 0.7 / 4.0
Upper Respiratory Tract Infection NOS / 14.2 / 4.8 / 13.2 / 8.0
Otitis Media / 2.2 / 2.9 / 0.7 / 5.3
Skin Papilloma / 0.4 / 3.3 / 0 / <1.0
Herpes Simplex / 0.4 / 3.3 / 0 / 2.7
Application Site Burning / 10.4 / 8.5 / 12.5 / 6.7
Pyrexia / 7.5 / 12.5 / 8.8 / 5.3
Cough / 11.6 / 15.8 / 8.1 / 10.7
ALLERGIES AND INTERACTIONS
Potential drug interactions have not been systematically evaluated.
AVAILABILITY AND DOSING
Available Products: Pimecrolimus 1% cream is available in 15 gram, 30 gram, 60 gram, and 100 gram tubes.
Atopic Dermatitis: In all populations, a thin layer should be applied to affected areas and rubbed in gently and completely, twice a day, until the rash is resolved. Symptoms persisting beyond six weeks should be evaluated by the prescriber.
THERAPEUTIC EFFICACY
See Evidence table, next page.)
The results from four trials show pimecrolimus to be effective at reducing atopic dermatitis flare-ups, pruritic symptoms, and the need for topical corticosteroids. Several of the trials use the Investigator’s Global Assessment (IGA) score to assess atopic dermatitis based on lesion morphology. Scores range from zero equal to no symptoms up to five equal to cases with very severe disease characterized by severe erythema, and papulation/infiltration plus accompanying oozing and crusting. Another scale used to assess atopic dermatitis is the Eczema Area and Severity Index (EASI). The EASI assigns proportionate values to the head and neck, trunk, upper limbs, and lower limbs along with a severity score between 0 and 3 for none, mild, moderate, and severe expression of disease. Pimecrolimus was shown to reduce both IGA and EASI scores in the trials where they were used. Interesting is the trial that showed the best results in infants between the ages of 3 to 12 months, a population that is currently not approved for pimecrolimus use by the FDA. There are currently no head to head trials between pimecrolimus and tacrolimus.
Table II. Summary of Published Evidence
Ref. / Drug Regimens / n / Time / Demographics* / Design** / End Points* / Results/Comments / NNT3. / 1. Vehicle (Placebo) BID
2. Pimecrolimus 1% BID
/ 136
267 / 6 wks / Mild to moderate atopic dermatitis:
· Children age 1-17 yrs. old
· Atopic dermatitis covering at least 5% TBSA
· IGA Score 2-3
· Exclusion criteria included: pregnancy or nursing, phototherapy, systemic therapy within 1 month, or topical therapy within 7 days before baseline, systemic antibiotics and major concomitant disease. / DB, 1:2 RCT, Two independent studies with pooled analysis.
Multiple centers in USA / Primary
· IGA Score 0-1
Secondary
· EASI Score: mean change from baseline.
· Severity of pruritis.
· Overall AD control as judged by primary caregiver.
· Patient safety. / Vehicle Pimecrolimus
18.4% 34.8% p ≤ 0.05 . . . -1% -45% p ≤ 0.001
64 patients dropped-out of study, 34 in vehicle arm and 30 in treatment group.
Severity of pruritis / subject assessment also a secondary endpoint, but data is only presented in graph without statistical analysis.
Most common adverse events included upper respiratory symptoms and headache. / 6
to achieve IGA score of 0-1
4. / 1. Standard of Care + Vehicle BID
2. Standard of Care + Pimecrolimus 1% BID
/ 237
476 / 12 mos / Atopic Dermatitis
· Children age 2-17 yrs. old
· Majority of pts. With moderate disease at baseline / DB, 1:2 RCT. Both groups using emollient, and moderate potency steroid for flares. Vehicle or pimecrolimus used for early s/s of flares.
Multicenter trial. / Primary
· No Flares @ 6 monthes
· Secondary
· No Flares @ 12 monthes
· Corticosteroid use @ 6 monthes
· Corticosteroid use @ 12 monthes
/ Vehicle Pimecrolimus
34.2% 61% p < 0.001 . . .
28.3% 50.8% .p < 0.001 . . 62.9% 35% . . 68.4% 42.6%
51.5% of control group and 31.6% in treatment group dropped-out of study.
Most common adverse events included upper respiratory symptoms and headache. / 4 to achieve no flares @ 6 monthes.
5. / 1. Vehicle
2. Pimecrolimus 1%
/ 83
158 / 6 wks + 20 wks open-label phase / Mild to moderate atopic dermatitis:
· Children 2-8 yrs. old
· Atopic dermatitis covering at least 5% TBSA
· IGA Score 2-3 / DB, 1:2 RCT. Secondary analysis of Parent’s Index of Quality of Life from larger study.
11 centers across the USA / · Change in mean QOL Score from baseline at 6 weeks. / Vehicle Pimecrolimus
-1.3% -3.3%
Identical QOL scores @ 6 months of open-label use. / N/A
6. / 1. Vehicle
2. Pimecrolimus 1%
/ 63
123 / 6 wks + 20 wks open-label phase / Mild to moderate atopic dermatitis:
· Infants 3-23 mos old
· Atopic dermatitis covering at least 5% TBSA
· IGA Score 2-3
· Immunocompromised patients excluded as well as those with active viral or bacterial skin infections. / DB, 1:2 RCT
25 centers in Australia, Brazil, Canada, Germany, S.Africa, & Spain / Primary
· IGA Score 0-1 @ 6wks. Secondary
· EASI Score: mean change from baseline.
· Absent or mild pruritis.
· Other secondary end points included: assessment of disease control and patient safety. / Vehicle Pimecrolimus
23.8% 54.5% p ≤ 0.001 . . . . 25% 81.6% p ≤ 0.001 . . . .
33.3% 72.4% p ≤ 0.001
Best Improvement in 3-12 mos old group: 65.5% achieved IGA score of 0-1
109 finished 6 wks pimecrolimus treatment, 33 finished 6 wks of vehicle treatment.
173 stared open-label phase, 142 completed.
IGA, EASI, and pruritis metrics near-identical at end of open-label phase
Most adverse events mild to moderate in severity. Most common events were typical childhood infections and ailments, not believed to be related to medication.
/ 4 to achieve IGA score of 0-1
* Demographic and endpoint abbreviations: TBSA = Total Body Surface Area, IGA = Investigator’s Global Assessment, EASI = Eczema Area and Severity Index
**Study design abbreviations: DB = double-blind, RCT = randomized trial, PC = placebo-controlled, PG = parallel -group, XO = crossover.
SUMMARY AND RECOMMENDATION:
Pimecrolimus appears to be effective in a sizeable portion of the patients that it was tested on, and its ability to reduce lower IGA and EASI scores as well as pruritis severity tends to occurs within the first six weeks of therapy. Tacrolimus has been approved by the FDA for moderate to more severe atopic dermatitis symptoms, whereas pimecrolimus is approved for mild to moderate cases. With the similar pricing of the two products, it makes sense to have pimecrolimus available to plan holders in need of a product for less severe symptoms, as long as they have tried and failed other options such as emollients, and antihistamines. Efficacy should be evaluated by the prescriber no later than three months after initiation of therapy.
MONOGRAPH PREPARED BY:
John Pedey-Braswell, Pharm.D., candidate 2005.
REFERENCES:
1. Elidel Prescribing Information, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936. 2003.
2. DrugDex Editorial Staff: Pimecrolimus – DrugDex Drug Evaluation. In: Klasco R (Ed): DrugDex® System. MICROMEDEX, Greenwood Village, Colorado (Edition expires December 2003).
3. Eichenfield LF, Lucky AW, Boguniewicz M, Langly RGB, Cherill R, Marshall K, Bush C, and Graeber M. 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;46:495-504.
4. Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, Dobozy A, Paul C, Molloy S, Hultsch T, Graeber M, Cherill R, and de Prost Y. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002;110,1:1.e2.
5. Whalley D, Huels J, McKenna SP, and van Assche, D. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents’ quality of life in the treatment of pediatric atopic dermatitis. Pediatrics 2002; 110:1133-1136.
6. Ho VC, Gupta A, Kaufmann R, Todd G, Vanaclocha F, Takoka R, Folster-Holst R, Potter P, Marshall K, Thurston M, Bush C, and Cherill R. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr 2003;142:155-162.