Continuing Education Activity

Pimecrolimus cream is a prescription non-steroidal medication in the class of topical calcineurin inhibitors (TCIs). It is FDA-approved for the treatment of mild to moderate atopic dermatitis. This article will discuss the mechanism of action, administration, adverse effects, contraindications, monitoring, and theoretical toxicity associated with topical pimecrolimus that is pertinent to members of the healthcare team in the care of patients with atopic dermatitis and other inflammatory skin conditions.

Objectives:

• Describe the use of topical steroids and the ancillary role of topical calcineurin inhibitors.

• Summarize the use of pimecrolimus in the treatment of atopic dermatitis and other selected inflammatory dermatoses.

• Review the mechanism of action of pimecrolimus.

• Explain the theoretical risk for toxicity and how appropriate counseling provided by members of the healthcare team can provide reassurance and improve outcomes for patients using topical pimecrolimus.

Indications

FDA-approved Use

Pimecrolimus cream is an FDA-approved topical calcineurin inhibitor (TCI) to treat mild-moderate atopic dermatitis in patients at least 2 years of age. It is considered a second-line treatment for immunocompetent patients who have failed first-line options such as topical corticosteroids and emollients.

Off-label Use

Off-label use of pimecrolimus cream applies to several inflammatory or otherwise “steroid-responsive” dermatoses, especially for sensitive or thin skin where there may be a higher risk of local side effects related to topical steroids. Such conditions include but are not limited to:

• Mild to severe atopic dermatitis in patients under 2 years of age[1][2]
• Eczematous dermatitis of the eyelids,[3] intertriginous (skin fold) areas, or hands[4]
• Facial and inverse psoriasis[5]
• Oral and genital lichen planus[6][7]
• Lichen sclerosis[8]
• Seborrheic dermatitis[9]
• Perioral dermatitis[10]
• Vitiligo[11]
• Pyoderma gangrenosum[12]
• Rosacea[13]
• Cutaneous dermatomyositis[14]
• Cutaneous lupus erythematosus[15]
• Cutaneous chronic graft-versus-host disease (GVHD)[16]

Mechanism of Action

Activation of T-lymphocytes starts with the interaction of costimulatory ligands on antigen-presenting cells and T-cell receptors. Intracellular free calcium increases and binds to calmodulin, which activates calcineurin (a protein phosphatase). Calcineurin dephosphorylates the cytoplasmic portion of the transcription factor called nuclear factor of activated T cells (NFAT), which is then transported to the nucleus and contributes to the transcription of several inflammatory cytokines.

TCIs, by definition, inhibit calcineurin. Pimecrolimus achieves this as it binds to the FK506-binding protein (FKBP) and blocks calcineurin’s ability to dephosphorylate NFAT, effectively halting calcineurin-dependent transcription of genes for T-cell activation and production of cytokines such as interleukins 2, 4, and 10 as well as interferon-gamma.

Administration

Pimecrolimus is obtained by prescription in a 1% concentration within a cream vehicle; each gram cream contains 10mg of pimecrolimus. Other ingredients that can be included in the cream base are benzyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, citric acid, propylene glycol, sodium cetostearyl sulfate, sodium hydroxide, water as well as mono-, di-, and triglycerides. The drug comes in tubes containing 30, 60, or 100 grams.

Pimecrolimus may be used in combination with steroids, as part of an alternating dosing regimen as a steroid-sparing agent, or as monotherapy. The use of topical calcineurin inhibitors 2 to 3 times per week has been shown to proactively reduce flares of atopic dermatitis, and the frequency of use of topical steroids and is more effective than using a bland emollient by itself.[1] A thin layer of pimecrolimus cream is to be applied only to the affected skin twice daily for no longer than 6 weeks continuously. If dermatitis does not respond within that time frame, the patient should seek re-evaluation. Pimecrolimus should not be used under occlusive dressings as its safety has received adequate study under such conditions.

Adverse Effects

The most common side effects of pimecrolimus cream are local sensations of burning, stinging, or pruritus; this may happen, especially when the site of the application is acutely inflamed. Generally, these side effects will improve with repetitive use or mitigated by using topical steroids before the initiation of pimecrolimus.

Several other side effects have been reported with the use of topical pimecrolimus, although they are relatively uncommon or have not been proven to be a direct result of treatment. Atopic patients, in particular, are at a higher risk than the general population of certain bacterial and viral skin infections such as Staphylococcus aureus colonization leading to impetigo or more widespread distribution of herpetic lesions called eczema herpeticum. The current prescribing instructions state to avoid use on active infections, and patients should have counseling on the possibility of skin infections due to limited long-term safety data.

Other possible adverse effects include application site reaction (i.e., erythema or skin discoloration), headache, fever, flu-like symptoms, nasopharyngitis or nasal congestion, sinusitis, epistaxis, upper respiratory tract infection, sore throat, tonsillitis, cough, bronchitis, dyspnea, pneumonia, asthma or asthma exacerbation, folliculitis, acne, urticaria, constipation, diarrhea, gastroenteritis, nausea, vomiting, abdominal pain, toothache, dysmenorrhea, hypersensitivity, arthralgia, conjunctivitis, eye infection, ear infection, anaphylaxis, angioedema, lymphadenopathy, and malignancy (basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and lymphoma).[17]

Contraindications

Absolute Contraindication[18]

• History of hypersensitivity to pimecrolimus or any other ingredients included in the cream formulation

When Pimecrolimus Cream Should be Avoided

• Patients who are immunocompromised or are taking systemic immunosuppressive medications

• Areas of skin with active pre-malignant or malignant lesions (such as cutaneous T-cell lymphoma (CTCL)) or skin infections (bacterial or viral)

• Patients who have severely impaired skin barrier function that may be at higher risk for increased systemic absorption (i.e., Netherton syndrome)

Monitoring

Calcineurin inhibitors applied topically have been shown to have negligible rates of systemic absorption. There is no recommendation for routine blood monitoring of patients using topical pimecrolimus.

Toxicity

Topical pimecrolimus is rated category C as there have been no adequate studies in pregnant women.

TCIs such as pimecrolimus have a black-box warning from theoretical risks based on high dose systemic calcineurin inhibitor use in post-transplant patients and animal studies.[19] There is an increased risk of infections, lymphoma, and skin malignancies in those study populations that correlates positively with the dosage and duration of systemic immunosuppression. Although there has been no definite establishment of a causal relationship, skin malignancies and lymphomas have rarely been reported in patients using topical pimecrolimus. Patients or parents should be made aware of the black-box warning but reassured that the risk of malignancy is low when adhering to the proper use of topical calcineurin inhibitors.

Some formulations of topical pimecrolimus contain benzyl alcohol and propylene glycol as inactive ingredients, which have been reported to cause serious adverse effects in neonates.[20] Benzyl alcohol toxicity has been known to cause “gasping syndrome” in neonates when administered intravenously, and large amounts of propylene glycol administered orally, intravenously, or topically may also result in neonate fatality.[21] No such reports stem directly from the use of benzyl alcohol or propylene glycol in topical pimecrolimus; in fact, data from clinical trials support the safe and effective use of pimecrolimus off-label in children less than 2 years of age and infants.[2]

Enhancing Healthcare Team Outcomes

Inflammatory dermatoses are often treated by primary care providers, nurse practitioners, dermatologists, and rheumatologists. Topical steroids have long been considered first-line treatment for inflammatory dermatoses but may cause local side effects including skin atrophy, telangiectasias, striae, acneiform eruptions, and rarely cataracts or glaucoma. Pimecrolimus is a non-steroidal agent belonging to the class of topical calcineurin inhibitors (TCIs) initially approved in the United States in 2001. Out of numerous ascomycin derivatives screened, researchers selected pimecrolimus for further development based on favorable anti-inflammatory properties, skin-selective properties, and overall safety profile. Although topical steroids are still regarded as first-line treatment for dermatitis, in some clinical scenarios, TCIs may even be preferred to topical steroids, such as when the skin condition is recalcitrant to steroids or located on sensitive skin or if the patient has experienced local side effects from topical steroids.

Therapy with pimecrolimus requires an interprofessional team approach. Clinicians (MDs, DOs, NPs, PAs), including specialists, will initiate treatment but should use pharmacist resources to verify dosing and indications, as well as potential drug-drug interactions. The pharmacist can also consult with nursing, so they can be alert for possible adverse effects, which with pimecrolimus can be severe. The nurse is also well-positioned to evaluate compliance and report any adverse events or the success or failure of therapy to the rest of the team. This type of interprofessional collaboration will optimize patient outcomes and minimize adverse reactions. [Level 5]

In 2014, a workgroup consisting of experts in atopic dermatitis put forth an update on evidence-based treatment guidelines. The results explicitly addressing the use of topical calcineurin inhibitors are summarized below[1]:

Level of Evidence: I Strength of Recommendation: A

• In treating atopic dermatitis, TCIs such as pimecrolimus are more efficacious than monotherapy with an emollient. When used as regularly (2 to 3 times weekly), atopic flares decrease, and patients require topical steroids less frequently.
• TCIs, such as pimecrolimus, can be recommended for use as steroid-sparing options on actively inflamed areas of atopic dermatitis.
• Off-label use of pimecrolimus cream can be recommended in atopic dermatitis patients less than 2 years of age.
• There currently is no recommendation for routine blood monitoring in patients using TCIs.

Level of Evidence: II Strength of Recommendation: B

• Localized skin burning, stinging, or pruritus is the most common adverse effects associated with the use of TCIs, particularly when applied to areas of acute dermatitis. Patients should receive counsel on these possible side effects and how to limit them. These symptoms may decrease over time with repetitive use or with pretreatment with topical steroids.
• TCIs may be used simultaneously with topical steroids.

Level of Evidence: III Strength of Recommendation: C

• As TCIs are a relatively new class of medication, there is no long-term safety data. Data regarding viral skin infections with the use of topical calcineurin inhibitors continuously or intermittently up to 5 years demonstrates no increased prevalence; however, patients should still understand the theoretical risk.
• Prescribers should be aware of and counsel patients regarding the black-box warning for topical calcineurin inhibitors.

With increased familiarity with current recommendations, members of the healthcare team can ensure more favorable outcomes in patients with atopic dermatitis and other inflammatory dermatoses receiving treatment with topical pimecrolimus.