Pimecrolimus


Article Author:
David Ahn


Article Editor:
Carolyn Hardin


Editors In Chief:
Alexandra Caley
Sameh Boktor


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
7/26/2019 7:35:10 PM

Indications

FDA-approved Use

Pimecrolimus cream is an FDA-approved topical calcineurin inhibitor (TCI) for the treatment of 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 potentially 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, in 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 as well as 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).

Contraindications

Absolute Contraindication:

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

Use of pimecrolimus cream should be avoided in:

  • 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.[17] In those study populations, there is an increased risk of infections, lymphoma, and skin malignancies 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.[18] 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.[19] 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 treated often 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. Physicians (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 interacions. 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, as well as 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 V]

In 2014, a workgroup consisting of experts in the field of 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 the treatment of 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.


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Pimecrolimus - Questions

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Which non-steroidal natural product made from fungi is approved for use in atopic dermatitis?



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A 55-year-old male comes into the clinic with an eczematous rash on his face. He describes a topical medication that his provider prescribed to him several years ago that was "a cream that decreased inflammation" in his skin but "definitely not a steroid." He found the medication helpful and wishes to restart it. Upon resuming treatment, which of the following side effects is the patient most likely to experience?



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A mother comes into the emergency department with a neonate who has been hyperventilating for the past hour. The mother had suspected perioral and flexural atopic dermatitis of the neonate three weeks ago and has been applying thick layers of pimecrolimus daily since then. She had been using pimecrolimus for herself and had not consulted a medical provider before applying the medication to the neonate. The neonate looks weak and in respiratory distress. Sternal retractions are present. T 37.1 C (98.8 F), BP 70/40 mmHg, HR 140/min, and RR 60/min. The arterial blood gas shows pH 7.2, bicarbonate 16 mEq/L, pC02 30 mmHg. WBC 5.0/hpf, Platelets 88,000/mm3, ALT: 1100 U/L, AST: 980 U/L. Which of the following is a nonactive component of pimecrolimus that may have induced this clinical presentation?



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A patient comes into the clinic with fatigue, chills and weight loss for the past month and has used a prescription topical cream for the past 30 years for intermittent atopic dermatitis flares mainly on the face but also on the torso. Which of the following tests would be most warranted at this time?



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A 27-year-old female presents with a history of chronic moderate atopic dermatitis of the face and eyelids. She has failed treatment with topical agents in the past such as an over-the-counter emollient and desonide cream that was previously prescribed. You counsel the patient about starting a topical calcineurin inhibitor. Which of the following most accurately describes the mechanism of action of this class of medications?



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A 23-year-old male patient comes into the clinic complaining of an intermittent flexural eczematous rash that has increased in frequency since starting medical school three months ago. Fluocinolone 0.025% has provided partial relief, but the rash seems to flare every 5 to 7 days. Which of the following drug would be the next best option for treatment?



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A 17-year-old Caucasian female presents to her healthcare provider with a history of mild flexural atopic dermatitis. This skin condition was previously well-controlled with the use of pimecrolimus cream two to three times weekly. Now she presents with multiple monomorphic punched out erosions bilaterally on her antecubital fossae. Which of the following are the most appropriates steps in the management of this patient?



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Pimecrolimus - References

References

Goldstein AT,Creasey A,Pfau R,Phillips D,Burrows LJ, A double-blind, randomized controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus. Journal of the American Academy of Dermatology. 2011 Jun;     [PubMed]
Eichenfield LF,Tom WL,Berger TG,Krol A,Paller AS,Schwarzenberger K,Bergman JN,Chamlin SL,Cohen DE,Cooper KD,Cordoro KM,Davis DM,Feldman SR,Hanifin JM,Margolis DJ,Silverman RA,Simpson EL,Williams HC,Elmets CA,Block J,Harrod CG,Smith Begolka W,Sidbury R, Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. Journal of the American Academy of Dermatology. 2014 Jul     [PubMed]
El-Batawy MM,Bosseila MA,Mashaly HM,Hafez VS, Topical calcineurin inhibitors in atopic dermatitis: a systematic review and meta-analysis. Journal of dermatological science. 2009 May     [PubMed]
Murrell DF,Calvieri S,Ortonne JP,Ho VC,Weise-Riccardi S,Barbier N,Paul CF, A randomized controlled trial of pimecrolimus cream 1% in adolescents and adults with head and neck atopic dermatitis and intolerant of, or dependent on, topical corticosteroids. The British journal of dermatology. 2007 Nov     [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
Tennis P,Gelfand JM,Rothman KJ, Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors. The British journal of dermatology. 2011 Sep     [PubMed]
Shehab N,Lewis CL,Streetman DD,Donn SM, Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2009 Mar     [PubMed]
Gershanik J,Boecler B,Ensley H,McCloskey S,George W, The gasping syndrome and benzyl alcohol poisoning. The New England journal of medicine. 1982 Nov 25     [PubMed]

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