Pimecrolimus (ASM 981), a derivative of ascomycin, is a topical macrolactam immunomodulator. Ascomycin was originally isolated in the early 1960s from Streptomyces hygroscopics var ascomyceticus. Pimecrolimus has similar clinical effects as tacrolimus; however, they differ in therapeutic effectiveness and formulation. Pimecrolimus has been shown to prevent atopic dermatitis flares more effectively than conventional therapy; after 6 months of treatment, 61% of patients completed treatment with pimecrolimus without a flare as compared to 35% of those treated with conventional therapy. As opposed to topical corticosteroids, no skin atrophy is noted following pimecrolimus treatment. The FDA approved pimecrolimus cream for use in children and adults with atopic dermatitis in January 2002. The safety and tolerability in infants and children less then 2 years of age is currently being investigated. Data from a study released in 2005 demonstrate that pimecrolimus can maintain control of atopic dermatitis for up to 18 months without any additional treatment. On February 15, 2005, the FDA announced the addition of a Black Box warning to the professional label for Elidel(R) (pimecrolimus cream), instructing prescribers to use only after failure of other eczema treatments due to a possible increased cancer risk; a Medication Guide will also accompany all prescriptions for Elidel(R).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-A proper skin care and sun avoidance program including avoidance of the sun and protective clothing should be part of the treatment regimen.
-Apply topically; may be used on all skin surfaces including the head, neck, and intertriginous areas.
-Wash hands with soap and water before and after application. If treating the hands, only wash hands before application.
-Do not use with occlusive dressings, as systemic exposure may be increased.
Application site reactions were reported with the use of pimecrolimus cream in clinical trials, in 14.6% of adults and 2.1-3.3% of children. Specifically, skin irritation (6.4% in adults; 0.4-3% in children), described as burning, stinging, or soreness (8-26%), is most common during the first few days of treatment and typically improves as lesions resolve. Erythema (2.1% in adults; 0.4-2.2% in children) and pruritus (5.5% in adults; 0.6-1.8% in children) at the application site were also reported. Urticaria (0.9% in adults; 0.3-1.1% in children) has been reported, though there is an increased incidence in patients who sequentially used pimecrolimus and a topical corticosteroid as compared to pimecrolimus alone. Acne vulgaris outbreaks were reported in 1.8% of adults and 0.3-1.5% of children. Skin flushing (associated with alcohol use), skin discoloration, and ocular irritation after application of the cream to the eye lids or near the eyes were reported post-marketing.
With pimecrolimus use, 0.4-3.3% of pediatric patients age 2-12 years developed skin papilloma or warts. If this occurs with use, and the warts either worsen or do not respond to conventional therapy, discontinue pimecrolimus until resolution of the warts is achieved. Patients who sequentially used both pimecrolimus cream and a topical corticosteroid, compared to those who used pimecrolimus alone, experienced an increased rate of certain infections including impetigo (reported in 2.4% of adults and 1.9-4% of children), unspecified skin infections (6.4% adults; 2.2-5.4% children), and superinfection (infected atopic dermatitis). Both bacterial or viral upper respiratory tract infections were reported in 0.3-4.3% of adults and 0.4-19.4% of pediatric patients, as well as pharyngitis (0.9% adults; 0.7-8.1% pediatrics, with 0.7-3% reporting streptococcal pharyngitis; nasopharyngitis was also reported in 7.6% adults and 10.1-26.5% pediatric), ear infection (0.6% adults; 2.2-5.7% pediatrics, with 0.7-2.9% reporting an earache and 2.2-3% reporting otitis media), sinusitis (0.6% adults; 1.1-3.3% pediatric), tonsillitis (0.6% adults; 0.4-6.3% pediatric, with 2.6% reporting acute tonsillitis), ocular infection (0.3% adults; 1.1% pediatric), and conjunctivitis (3% adults; 0.7-2.2% pediatrics). Other reported infections during clinical trials include influenza (9.8% adults; 3-13.2% pediatric), influenza-like illness (1.8%; 0.4-1.8%), pneumonia (0.3%; 1.1-1.5%), bronchitis (2.4%; 0.4-10.7%, with 1.5% of children reporting acute bronchitis), folliculitis (6.1%; 0.9-2.2%), herpes simplex dermatitis (0.6%; 0.3-1.5%), chickenpox (0.3%; 0.7-2.9%), molluscum contagiosum (0; 0.7-1.8%), herpes simplex (4%; 0.4-3.3%), gastroenteritis (1.8%; 0.6-7.4%), unspecified bacterial infection (1.8%; 1.1-1.5%), unspecified staphylococcal infection (0.9%; 0.4-2.1%), and unspecified viral infection (0; 0.3-6.6%).
During clinical trials, lymphadenopathy was reported during topical pimecrolimus treatment. These cases of lymphadenopathy were usually related to infections and resolved upon appropriate antibiotic therapy. If lymphadenopathy develops, identify the etiology and treat appropriately; in the absence of a clear etiology, or in the presence of acute infectious mononucleosis, discontinue pimecrolimus use and continue to monitor for resolution. A new primary malignancy, especially lymphomas and skin cancers, may develop in patients receiving pimecrolimus. As of December 2004, the FDA has received 10 post-marketing reports of cancer-related adverse events (6 cutaneous tumors, 1 lymph node/cutaneous tumor related event, and 3 unreported locations) associated with topical pimecrolimus use; 3 cases occurred in patients less than 6 years of age, and 6 cases occurred in adults. Two of the 10 cases were associated with lymphadenopathy. Four cases described lymphomas; 5 cases described a variety of tumors, including basal cell carcinoma and squamous cell carcinoma; and 1 case described granulomatous lymphadenitis. The median time until diagnosis after initiation of treatment with Elidel was 90 days (range, 7 to 300 days). Due to the post-marketing nature of the reports, a causal relationship between cancer development and topical pimecrolimus has not been established; the role of topical pimecrolimus in the development of lymphomas and skin cancers including malignant melanoma is uncertain. For example, of the 10 cases, 1 was associated with the presence of nodules prior to the diagnosis of basal cell carcinoma and another with a pre-existing condition associated with an increased risk for malignant transformation. Furthermore, the extent of systemic absorption and subsequent immunosuppression, if any, in each case is unknown.
Gastrointestinal and reproductive-system adverse events were reported in both adult and pediatric patients with pimecrolimus use in clinical trials, including: abdominal pain (0.3% adults; 0.4-5.5% children, who reported more specifically upper abdominal pain), nausea (1.8% adults; 0.4-4% children), vomiting (0.6% adults; 3-6.6% children), diarrhea (2.1% adults; 0.6-7.7% children, with <= 1.2% also reporting loose stools), dental pain (specifically, toothache, 0.6% adults; 0.4-2.6% children), constipation (0.4-3.7% children), and dysmenorrhea (1.2% adults; 1.1-1.5% pediatric).
Respiratory adverse events reported in patients during the use of pimecrolimus include: cough (2.4% adults; 9.3-15.8% pediatrics), nasal congestion (0.6%; 1.5-2.6%), sinus congestion (0.9%; 0.6-1.1%), rhinorrhea (0; 0.4-1.9%), aggravation of pre-existing asthma (2.4%; 0.7-3.9%), rhinitis (2.1%; 0.4-4.4%), wheezing (0; 0.4-1.2%), epistaxis (0.3%; 3.3%), sore throat (3.7%; 3.4-8.1%), and dyspnea (0.6%; 1.8%). Of note, an increased incidence of rhinitis was found in the patients who used both pimecrolimus cream and topical corticosteroid sequentially as compared to pimecrolimus alone.
During clinical trials with pimecrolimus cream, hypersensitivity reactions (not described) were reported in 3.4% of adults and 4.1-5.1% of pediatric patients; anaphylactoid reactions, angioedema, and facial edema were reported post-marketing. Fever (1.2% adults; 7.5-12.5% pediatric) and headache (7% adults; 11.3-25.4% pediatric) were also reported.
During clinical trials with both adult and pediatric patients who used pimecrolimus cream, accidents (unspecified, <= 1.1% of all patients), lacerations (<= 1.5% of all patients), back pain (1.8% of adults, < 1% of children), and arthralgia (1.5% of adults, <= 1.1% of children) were reported.
The safety of pimecrolimus cream under occlusion, which may promote systemic absorption, has not been evaluated. Pimecrolimus cream should not be used with an occlusive dressing.
Pimecrolimus cream should not be applied to areas of active cutaneous viral infection. Before initiating pimecrolimus therapy clinical infections should be cleared. Although patients with atopic dermatitis are predisposed superficial herpes infection (e.g., eczema herpeticum, Kaposi's varicelliform eruption), treatment with pimecrolimus cream may be associated with an increased risk of varicella zoster virus infection (chickenpox or shingles), herpes simplex infection, or eczema herpeticum. In the presence of these infections, the risks and benefits associated with pimecrolimus treatment must be considered.
Despite the absence of observed phototoxicity in humans, pimecrolimus cream shortened the time to skin tumor formation in an animal photo-carcinogenicity study. The enhancement of ultraviolet (UV) carcinogenicity is not necessarily dependent on phototoxic mechanisms. However, it is prudent for patients to minimize or avoid artificial or natural sunlight (UV) exposure during treatment with pimecrolimus cream.
Pimecrolimus cream is not for use in neonates, infants, or children < 2 years of age. However, two phase III studies have examined the use of pimecrolimus cream in pediatric patients 3 months to 2 years of age. Adverse reactions occurred more frequently in infants treated with pimecrolimus cream versus placebo. Also, although not causally established, a higher incidence of upper respiratory symptoms/infections occurred in children 3-23 months of age as compared with patients 2-14 years of age. The effect of pimecrolimus cream on the developing immune system of infants is unknown.
Pimecrolimus cream should only be prescribed as directed and only after other eczema treatments have failed due to a possible risk of new primary malignancy, especially skin cancer or lymphoma. To date, there have been reports of cancers in three different animal species. The risk increased as the drug dosage increased. There have also been a small number of cancers reported in children and adults using pimecrolimus cream. The manufacturer will begin conducting research to determine the risk of cancers to humans during pimecrolimus treatment. There are no data to support the use of pimecrolimus cream in patients with immunosuppression. Increased susceptibility to infection and possible development of neoplastic disease, especially skin cancer or lymphoma, may result from immunosuppression. Patients who receive pimecrolimus cream and develop a new or changed skin lesion or lymphadenopathy should have the lesion or the etiology of their lymphadenopathy investigated due to the risk of cancer. In the absence of a clear etiology for the lymphadenopathy or in the presence of cancer or acute infectious mononucleosis, discontinuation of pimecrolimus treatment should be considered. Monitor patients to assure that the lymphadenopathy resolves.
The use of pimecrolimus cream in patients with ichthyosis, specifically Netherton's syndrome (congenital ichthyosiform erythroderma), is not recommended due to the potential for increased absorption of pimecrolimus.
Pimecrolimus cream is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies of topically administered pimecrolimus in pregnant women. The experience with pimecrolimus cream when used by pregnant women is too limited to permit assessment of its safety during pregnancy.
It is not known whether pimecrolimus is excreted into breast milk. The manufacturer recommends caution when used in nursing women. However, systemic absorption after topical use is minimal. In adult patients (n=52) treated (13-62% BSA involvement) for periods up to a year, a maximum concentration of 1.4 ng/mL was observed among those subjects with detectable serum concentrations. In the majority of patients, blood concentrations were below 0.5 ng/mL. Avoid using on the breast when breast-feeding. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For short-term and intermittent long-term treatment of mild to moderate atopic dermatitis in non-immunocompromised patients who are unresponsive or intolerant of other therapies or as an alternative to conventional therapies in at-risk patients:
NOTE: Topical pimecrolimus is a second line agent to treat atopic dermatitis in patients unresponsive to or intolerant of other first line agents; long-term safety has not been established.
Adults: Apply a thin layer to the affected skin area(s) twice daily. Rub in gently and completely. Use for as long as symptoms persist; discontinue if resolution of disease occurs. If symptoms persist beyond 6 weeks, the patient should be re-evaluated.
Children and Adolescents 2 to 17 years: Apply a thin layer to the affected skin area(s) twice daily. Rub in gently and completely. Use for as long as symptoms persist; discontinue if resolution of disease occurs. If symptoms persist beyond 6 weeks, the patient should be re-evaluated.
For the treatment of vulvar lichen sclerosus*:
Adults, Adolescents, and Children: In several case reports of female patients (ages 4 to 62 years), twice daily application of 1% pimecrolimus cream resulted in symptom resolution (i.e., pruritus, pain, and inflammation); some patients exhibited reversal of the histological changes of lichen sclerosus following 3 months of therapy. Further investigation is needed.
For the treatment of intertriginous psoriasis*:
NOTE: According to the American Academy of Dermatology (AAD), topical pimecrolimus is not generally effective for the treatment of chronic plaque psoriasis.
Adults: Apply 0.1% pimecrolimus cream twice daily to affected intertriginous areas. In a clinical trial of 57 patients with intertriginous psoriasis, a statistically significantly greater number of patients were clear or almost clear after 8 weeks of twice daily application of pimecrolimus 0.1% cream compared with vehicle (71% vs. 21%; p < 0.0001). Adverse events were similar between the groups.
Maximum Dosage Limits:
2 applications/day topically.
2 applications/day topically.
2 applications/day topically.
>= 2 years: 2 applications/day topically.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Ethanol: (Moderate) A flushing syndrome has been reported in patients treated with topical pimecrolimus upon ingestion of ethanol. The flushing occurred in the face or at the sites of medication application, usually within 5-15 minutes of ethanol ingestion, and lasted for an average duration of 1 hour. Roughly 3-7 percent of patients report redness and warm sensations, which sometimes result in discomfort.
Pimecrolimus inhibits calcineurin, a calcium-dependent phosphatase, by binding with high affinity to immunophilin-12 (FKBP-12), similar to tacrolimus. Immunophilins (cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein activation. Calcineurin inhibition results in blockade of signal transduction by the cytosol component of the nuclear factor of activated T-cells (NF-AT), which results in a failure to activate NF-AT regulated genes. As a result, pimecrolimus inhibits T-cell activation by blocking transcription of early cytokines. At nanomolar concentrations, pimecrolimus inhibits interleukin (IL)-2, IL-4, IL-10, and interferon gamma synthesis. Pimecrolimus prevents the release of inflammatory cytokines and mediators (e.g., hexosaminidase, tryptase, and histamine) from mast cells in vitro after stimulation with antigen/IgE and inhibits the transcription of tumor necrosis factor (TNF) alpha. In atopic dermatitis, topical pimecrolimus acts to inhibit inflammation primarily by inhibiting T-cells.
Pimecrolimus is administered topically. In vitro, 99.5% of pimecrolimus in plasma is bound to proteins over the pimecrolimus concentration range of 2-100 ng/ml; most pimecrolimus in plasma appears to be bound to various lipoproteins. Pimecrolimus appears to be metabolized in vitro by the cytochrome P450 3A family of enzymes. No evidence of skin mediated metabolism was identified in vivo or in vitro. Following a single oral dose, about 78% of the dose was recovered in the feces as metabolites; less than 1% is excreted as unchanged drug.
Following oral administration, O-demethylation metabolites of pimecrolimus are seen. Following a single oral dose, about 78% of the dose was recovered in the feces as metabolites; less than 1% is excreted as unchanged drug.
Typically, in adults being treated for atopic dermatitis (13-62% body surface area (BSA) involvement), blood concentrations of pimecrolimus are at or below the limit of detection of the assay. If pimecrolimus is detected, the concentration is routinely < 2 ng/ml and does not accumulate with time. Absorption into cutaneous lymphatic vessels or into regional lymph nodes is unknown. No evidence of skin mediated metabolism was identified in vivo or in vitro.
The effect of hepatic insufficiency on the pharmacokinetics of topically administered pimecrolimus has not been evaluated, but dose-adjustment is not expected to be needed.
The effect of renal insufficiency on the pharmacokinetics of topically administered pimecrolimus has not been evaluated, but dose-adjustment is not expected to be needed.
Pharmacokinetic studies in infants and children 3-23 months of age with mild to severe atopic dermatitis using twice daily applications yielded consistently low pimecrolimus blood concentrations (<= 1 ng/ml in > 80% of samples with a maximum of 2.6 ng/ml), regardless of disease severity and extent. The concentrations remained low during intermittent therapy for up to 1 year. These findings are consistent with those in older pediatric patients, suggesting that young pediatric patients are not at increased risk of systemic absorption of pimecrolimus following topical application. In another group of children 8 months to 14 years of age who had atopic dermatitis with 20-80% BSA involvement, pimecrolimus blood concentrations were less than 2 ng/ml, but 23 of the 28 patients had at least 1 detectable concentration; the quantification limit was 0.5 ng/ml.