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  • CLASSES

    Topical Calcineurin Inhibitors

    BOXED WARNING

    Children, infants, neonates

    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.

    Immunosuppression, lymphoma, mononucleosis, neoplastic disease, skin cancer

    Pimecrolimus cream should only be prescribed as directed and only after other eczema treatments have failed due to a possible risk of neoplastic disease (cancer), especially skin cancer or lymphoma. The FDA has added a black box warning regarding this risk to the professional labeling. 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 (see Adverse Reactions). 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.

    DEA CLASS

    Rx

    DESCRIPTION

    Pimecrolimus (ASM 981), a derivative of ascomycin, is a topical macrolactam immunomodulator. Pimecrolimus has similar clinical effects as tacrolimus; however, they differ in therapeutic effectiveness and formulation. As opposed to topical corticosteroids, no skin atrophy is noted following pimecrolimus treatment.

    COMMON BRAND NAMES

    Elidel

    HOW SUPPLIED

    Elidel Topical Cream: 1%

    DOSAGE & INDICATIONS

    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.
    Topical dosage
    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.
    Topical dosage
    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.
    Topical dosage
    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2 applications/day topically.

    Elderly

    2 applications/day topically.

    Adolescents

    2 applications/day topically.

    Children

    >= 2 years: 2 applications/day topically.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Topical Administration

    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.

    STORAGE

    Elidel:
    - Do not freeze
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Occlusive dressing

    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.

    Herpes infection, varicella, viral infection

    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.

    Sunlight (UV) exposure

    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.

    Children, infants, neonates

    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.

    Immunosuppression, lymphoma, mononucleosis, neoplastic disease, skin cancer

    Pimecrolimus cream should only be prescribed as directed and only after other eczema treatments have failed due to a possible risk of neoplastic disease (cancer), especially skin cancer or lymphoma. The FDA has added a black box warning regarding this risk to the professional labeling. 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 (see Adverse Reactions). 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.

    Ichthyosis

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 0.4-3.7
    conjunctivitis / Delayed / 0.7-3.0
    erythema / Early / 0.4-2.2
    dyspnea / Early / 0.6-1.8
    wheezing / Rapid / 0.4-1.2
    ocular infection / Delayed / 0.3-1.1
    superinfection / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known

    Mild

    pharyngitis / Delayed / 0.7-26.5
    headache / Early / 7.0-25.4
    cough / Delayed / 2.4-15.8
    influenza / Delayed / 3.0-13.2
    fever / Early / 1.2-12.5
    diarrhea / Early / 0.6-7.7
    vomiting / Early / 0.6-6.6
    skin irritation / Early / 0.4-6.4
    folliculitis / Delayed / 0.9-6.1
    pruritus / Rapid / 0.6-5.5
    abdominal pain / Early / 0.3-5.5
    rhinitis / Early / 0.4-4.4
    nausea / Early / 0.4-4.0
    sinusitis / Delayed / 0.6-3.3
    epistaxis / Delayed / 0.3-3.3
    dental pain / Delayed / 0.4-2.6
    nasal congestion / Early / 0.6-2.6
    rhinorrhea / Early / 0.4-1.9
    back pain / Delayed / 0.3-1.8
    acne vulgaris / Delayed / 0.3-1.5
    dysmenorrhea / Delayed / 1.1-1.5
    arthralgia / Delayed / 0.3-1.5
    urticaria / Rapid / 0.3-1.1
    skin discoloration / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Pimecrolimus products.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    Mechanism of Action: 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.

    PHARMACOKINETICS

    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.

    Oral Route

    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.

    Topical Route

    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.