Pimecrolimus

Pharmacologic Category

Calcineurin Inhibitor; Immunosuppressant Agent; Topical Skin Product

Dosing: Adult

Atopic dermatitis (mild to moderate): Topical: Apply thin layer to affected area twice daily. Note: Limit application to involved areas. Discontinue use when symptoms have resolved; re-evaluate if symptoms persist >6 weeks.

Oral lichen planus (off-label use): Topical: Apply twice daily for 1 month (Passeron 2007; Swift 2005; Volz 2008)

Psoriasis (off-label use): Topical: Apply twice daily (Gribetz 2004; Menter 2009b)

Vitiligo (off-label use): Topical: Apply twice daily for 6 months. Treatment beyond 12 months may be useful; long-term safety has not been established. (Esfandiarpour 2009; Stinco 2009; Taieb 2013)

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Atopic dermatitis (mild-moderate): Children ≥2 years and Adolescents: Topical: Apply a thin layer to affected area twice daily; limit application to affected areas only; discontinue therapy when symptoms have resolved; re-evaluate patient if symptoms persist >6 weeks.

Use: Labeled Indications

Atopic dermatitis: Second-line therapy for short-term and noncontinuous long-term treatment of mild to moderate atopic dermatitis in nonimmunocompromised patients 2 years and older who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Intertriginous and facial psoriasisLevel of Evidence [A, G]

Data from a double-blind, randomized, vehicle-controlled study support the use of pimecrolimus in the treatment of inverse psoriasis. In patients with this condition, pimecrolimus was effective, safe, and well-tolerated ^Ref.

Based on the American Academy of Dermatology guidelines of care for the management of psoriasis and psoriatic arthritis, pimecrolimus for the treatment of intertriginous and facial psoriasis is effective and recommended in the management of this condition. Access Full Off-Label Monograph

Oral lichen planusLevel of Evidence [B]

Data from short-term controlled trials demonstrate that topical pimecrolimus is effective in improving clinical symptoms of oral lichen planus and may be considered an alternative therapy for patients who do not respond to topical steroids. Access Full Off-Label Monograph

VitiligoLevel of Evidence [C, G]

Data from a meta-analysis and randomized, controlled trials suggest that pimecrolimus may be effective in the management of vitiligo ^Ref.

European Dermatology Forum consensus guidelines support the use of topical calcineurin inhibitors as first-line therapy for patients with vitiligo; use should be limited to the head and neck regions ^Ref. Access Full Off-Label Monograph

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

American Academy of Dermatology, Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis; Sec. 3, Management and Treatment of Psoriasis with Topical Therapies, April 2009

Administration: Topical

Apply a thin layer to affected skin. Limit application to areas of involvement. Do not use with occlusive dressings. Burning at the application site is most common in first few days but improves over time. Discontinue use when symptoms have resolved; re-evaluate if symptoms persist >6 weeks. Moisturizers may be applied after use of pimecrolimus cream. Wash hands before and after use.

Oral lichen planus (off-label use): Apply to affected oral mucosa, cover with a thin layer of gauze to delay dilution with saliva (Volz 2008). Eating, drinking, or chewing gum was not allowed for 30 minutes after application (Passeron 2007).

Administration: Pediatric

Topical: Apply a thin layer of cream over affected area; limit application to areas of involvement; do not use with occlusive dressings. Burning at the application sites is common in the first few days of treatment and improves as atopic dermatitis improves. Discontinue use when symptoms have resolved. Avoid contact with eyes, nose, mouth and with cut, scraped, or infected skin areas. Wash hands with soap and water prior to and after cream application. If applying cream after a bath or shower, make sure skin is dry. Moisturizers may be applied after use of pimecrolimus cream.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Pimecrolimus may cause carcinogenicity and has a structural or toxicity profile similar to existing hazardous agents. Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends double gloving, a protective gown, and (if liquid that could splash) eye/face protection for administration of a topical product; if there is potential for inhalation, respiratory protections is recommended (NIOSH 2016).

Storage/Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat eczema.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Skin irritation

• Stinging

• Itching or soreness

• Common cold symptoms

• Flu-like symptoms

• Sensation of warmth

• Headache

• Stuffy nose

• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection

• Skin infection

• Swollen glands

• Night sweats

• Excessive weight loss

• Warts

• Cold sores

• Skin ulcers

• Skin growths

• Mole changes

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088587.pdf, must be dispensed with this medication.

Contraindications

Hypersensitivity to pimecrolimus or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Infection: Patients with atopic dermatitis are predisposed to skin infections; therapy has been associated with an increased risk of developing eczema herpeticum, varicella zoster, and herpes simplex. Do not apply to areas of active bacterial or viral infection; local infections at the treatment site should be resolved prior to therapy.

• Local symptoms: May cause local symptoms (eg, burning, pruritus, soreness, stinging) during first few days of treatment; usually self-resolving as atopic dermatitis lesions heal.

• Lymphadenopathy: May be associated with development of lymphadenopathy; possible infectious causes should be investigated. Discontinue use in patients with unknown cause of lymphadenopathy or acute infectious mononucleosis.

• Malignancy: [US Boxed Warning]: Topical calcineurin inhibitors (including pimecrolimus) have been associated with rare cases of lymphoma and skin malignancy; avoid use on malignant or premalignant skin conditions (eg, cutaneous T-cell lymphoma).

• Skin papilloma: Skin papilloma (warts) have been observed with use; discontinue use if there is worsening of skin papillomas or they do not respond to conventional treatment.

Disease-related concerns:

• Atopic dermatitis: Diagnosis should be reconfirmed if sign/symptoms do not improve within 6 weeks of treatment.

• Erythroderma: Safety not established in patients with generalized erythroderma.

• Skin diseases which may increase systemic absorption: Not recommended for use in patients with Netherton's syndrome or skin conditions which may increase the potential for systemic absorption.

Special populations:

• Immunocompromised patients: Should not be used in immunocompromised patients, including patients on concomitant systemic immunosuppressive therapy.

• Pediatric: [US Boxed Warning]: Use of pimecrolimus in children <2 years of age is not recommended, particularly since the effect on immune system development is unknown.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Other warnings/precautions:

• Appropriate use: [US Boxed Warning]: Continuous long-term use of calcineurin inhibitors (including pimecrolimus) should be avoided and application of cream should be limited to areas of involvement with atopic dermatitis. Safety of intermittent use for >1 year has not been established.

• Sun exposure: Avoid artificial or natural sunlight exposure, even when pimecrolimus is not on the skin.

* See Cautions in AHFS Essentials for additional information.

Warnings: Additional Pediatric Considerations

Clinical trial experience of 436 infants and children <2 years reported a higher incidence of detectable serum concentrations (possibly related to larger BSA:mass ratio) and infection (upper respiratory) or infection-related symptoms than comparative placebo (vehicle) group and older pediatric patients. Pimecrolimus long-term effects on the developing immune system are unknown.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies following topical application.

Breast-Feeding Considerations

It is not known if pimecrolimus is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Briggs' Drugs in Pregnancy & Lactation

• Pimecrolimus

Adverse Reactions

>10%:

Central nervous system: Headache (children and adolescents 11% to 25%; adults 7%), fever (children and adolescents 13%; adults 1%)

Infection: Influenza (3% to 13%)

Local: Local burning (adults 26%; children and adolescents 2% to 8%; tends to resolve/improve as lesions resolve), application site reaction (adults 15%; children and adolescents 2%)

Respiratory: Nasopharyngitis (infants, children, and adolescents 10% to 27%; adults 8%), upper respiratory tract infection (children and adolescents 14% to 19%; adults 4%), cough (children and adolescents 9% to 16%; adults 2%), bronchitis (children and adolescents ≤11%; adults ≤2%)

1% to 10%:

Dermatologic: Folliculitis (adults 6%; children and adolescents 1%), skin infection (5% to 6%), impetigo (4%), warts (children and adolescents ≤3%), acne vulgaris (≤2%), herpes simplex dermatitis (≤2%), molluscum contagiosum (children and adolescents ≤2%), urticaria (≤1%)

Gastrointestinal: Diarrhea (children and adolescents 1% to 8%; adults ≤2%), gastroenteritis (children and adolescents ≤7%; adults 2%), vomiting (1% to 4%), constipation (children and adolescents ≤4%), abdominal pain (≤3%), toothache (≤3%), nausea (1% to 2%)

Genitourinary: Dysmenorrhea (1% to 2%)

Hypersensitivity: Hypersensitivity (3% to 5%)

Infection: Viral infection (children and adolescents ≤7%), herpes simplex infection (≤4%), bacterial infection (1% to 2%), staphylococcal infection (1% to 2%), varicella (≤1%)

Local: Local irritation (adults ≤6%; children and adolescents ≤1%), local pruritus (1% to 6%), localized erythema (≤2%)

Neuromuscular & skeletal: Arthralgia (≤2%), back pain (≤2%)

Ocular: Conjunctivitis (≤2% to 3%), eye infection (≤1%)

Otic: Otic infection (1% to 6%), otitis media (1% to 3%)

Respiratory: Sore throat (4% to 8%), pharyngitis (children and adolescents 1% to 8%; adults 1%), tonsillitis (children and adolescents ≤6%; adults <1%), asthma (3% to 4%), asthma aggravated (children and adolescents ≤4%), streptococcal pharyngitis (children and adolescents 3%), nasal congestion (1% to 3%), sinusitis (1% to 3%), epistaxis (≤3%), dyspnea (≤2%), flu-like symptoms (≤2%), pneumonia (≤2%), rhinitis (≤2%), rhinorrhea (children and adolescents ≤2%), viral upper respiratory tract infection (≤2%), wheezing (children and adolescents ≤1%)

Miscellaneous: Laceration (children and adolescents ≤2%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, eczema (herpeticum), eye irritation (following application near eyes), facial edema, flushing (ethanol-associated), lymphadenopathy, malignant neoplasm (basal cell carcinoma, squamous cell carcinoma, malignant melanoma, malignant lymphoma), skin discoloration

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of Pimecrolimus. Exceptions: Grapefruit Juice. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy

Immunosuppressants: Pimecrolimus may enhance the adverse/toxic effect of Immunosuppressants. Exceptions: Cytarabine (Liposomal). Risk X: Avoid combination

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Cream, External:

Elidel: 1% (30 g, 60 g, 100 g) [contains benzyl alcohol, cetyl alcohol, propylene glycol]

Generic: 1% (30 g, 60 g, 100 g)

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Cream, External:

Elidel: 1% (15 g, 30 g, 60 g, 100 g) [contains benzyl alcohol, cetyl alcohol, propylene glycol]

Anatomic Therapeutic Chemical (ATC) Classification

• D11AH02

Generic Available (US)

Yes

Pricing: US

Cream (Elidel External)

1% (per gram): $11.96

Cream (Pimecrolimus External)

1% (per gram): $10.15 - $10.72

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Penetrates inflamed epidermis to inhibit T cell activation by blocking transcription of proinflammatory cytokine genes such as interleukin-2, interferon gamma (Th1-type), interleukin-4, and interleukin-10 (Th2-type). Pimecrolimus binds to the intracellular protein FKBP-12, inhibiting calcineurin, which blocks cytokine transcription and inhibits T-cell activation. Prevents release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE.

Pharmacodynamics/Kinetics

Onset of action: Time to significant improvement: 8 days (Wellington 2001)

Absorption: Topical: Low systemic absorption; blood concentration of pimecrolimus was routinely <2 ng/mL with treatment of atopic dermatitis in adult patients (13% to 62% BSA involvement); blood concentration of pimecrolimus was <3 ng/mL in 26 pediatric patients 2 to 14 years of age with atopic dermatitis (20% to 69% BSA involvement). Detectable blood levels were observed in a higher proportion of children as compared to adults and may be due to the larger surface area to body mass ratio seen in pediatric patients (Menter 2009a).

Protein binding: 99.5%, primarily to various lipoproteins

Metabolism: Hepatic via cytochrome (CYP) P450 3A4

Half-life elimination: Terminal: Oral: 30 to 40 hours (Wellington 2001)

Time to peak, serum: Topical: 2 to 6 hours

Excretion: Feces (78.4% as metabolites; <1% as unchanged drug)

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

• Safe Handling of Hazardous Drugs

FDA Approval Date

December 14, 2001

References

<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.

Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319.[PubMed 11487763]

Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm[PubMed 6810084]

Eichenfield LF, Lucky AW, Boguniewicz M, et al, “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(4):495-504.[PubMed 11907497]

Elidel (pimecrolimus) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals; December 2017.

Esfandiarpour I, Ekhlasi A, Farajzadeh S, Shamsadini S. The efficacy of pimecrolimus 1% cream plus narrow-band ultraviolet B in the treatment of vitiligo: a double-blind, placebo-controlled clinical trial. J Dermatolog Treat. 2009;20(1):14-18.[PubMed 18608735]

Hanifin JM, Cooper KD, Ho VC, et al, “Guidelines of Care for Atopic DErmatitis, Developed in Accordance With the American Academy of Dermatology (AAD)/American Academy of Dermatology Association: Administrative Regulations for Evidence-Based Clinical Practice Guidelines," J Am Acad Dermatol, 2004, 50(3):391-404.[PubMed 14988682]

"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278.[PubMed 9024461]

Gribetz C, Ling M, Lebwohl M, et al, “Pimecrolimus Cream 1% in the Treatment of Intertriginous Psoriasis: A Double-Blind, Randomized Study,” J Am Acad Dermatol, 2004, 51(5):731-8.[PubMed 15523351]

Lee JH, Kwon HS, Jung HM, et al. Treatment outcomes of topical calcineurin inhibitor therapy for patients with vitiligo: a systematic review and meta-analysis. JAMA Dermatol. 2019;155(8):929-938. doi: 10.1001/jamadermatol.2019.0696[PubMed 31141108]

McCaughey C, Machan M, Bennett R, Zone JJ, Hull CM. Pimecrolimus 1% cream for oral erosive lichen planus: a 6-week randomized, double-blind, vehicle-controlled study with a 6-week open-label extension to assess efficacy and safety. J EurAcad Dermatol Venereol. 2011;25(9):1061-1067.[PubMed 21175873]

Menter A, Korman NJ, Elmets CA, et al, “Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis With Traditional Systemic Agents,” J Am Acad Dermatol, 2009a, 61(3):451-85.[PubMed 19493586]

Menter A, Korman NJ, Elmets CA, et al; American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3: guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009b;60(4):643-659.[PubMed 19217694]

Passeron T, Lacour JP, Fontas E, et al, “Treatment of Oral Erosive Lichen Planus With 1% Pimecrolimus Cream: A Double-Blind, Randomized, Prospective Trial With Measurement of Pimecrolimus Levels in the Blood,” Arch Dermatol, 2007, 143(4):472-6.[PubMed 17438179]

Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr Crit Care Med. 2009;10(2):256-259.[PubMed 19188870]

Stinco G, Piccirillo F, Forcione M, Valent F, Patrone P. An open randomized study to compare narrow band UVB, topical pimecrolimus and topical tacrolimus in the treatment of vitiligo. Eur J Dermatol. 2009;19(6):588-593.[PubMed 19651562]

Swift JC, Rees TD, Plemons JM, Hallmon WW, Wright JC. The effectiveness of 1% pimecrolimus cream in the treatment of oral erosive lichen planus. J Periodontol. 2005;76(4):627-635.[PubMed 15857105]10.1902/jop.2005.76.4.627

Taieb A, Alomar A, Böhm M, et al; Vitiligo European Task Force (VETF); European Academy of Dermatology and Venereology (EADV); Union Européenne des Médecins Spécialistes (UEMS). Guidelines for the management of vitiligo: the European Dermatology Forum consensus. Br J Dermatol. 2013;168(1):5-19.[PubMed 22860621]

US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed April 4, 2017.

Volz T, Caroli U, Lüdtke H, et al, “Pimecrolimus Cream 1% in Erosive Oral Lichen Planus -- A Prospective Randomized Double-Blind Vehicle-Controlled Study,” Br J Dermatol, 2008, 159(4):936-41.[PubMed 18647310]

Wahn U, Bos JD, Goodfield M, et al, “Efficacy and Safety of Pimecrolimus Cream in the Long-Term Management of Atopic Dermatitis in Children,” Pediatrics, 2002, 110(1 Pt 1):e2.[PubMed 12093983 ]

Wellington K, Jarvis B. Topical pimecrolimus: a review of its clinical potential in the management of atopic dermatitis. Drugs. 2002;62(5):817-840.[PubMed 11929333]

Brand Names: International

Elidel (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EE, EG, ES, FI, GB, GT, HK, HN, HR, ID, IL, IN, IS, IT, JO, KR, KW, LB, LT, LU, LV, MT, MX, MY, NI, NL, NO, NZ, PA, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TW, UA, UY, VE); Pimecroderm (EG); Pimoroyal (EG)

Last Updated 2/13/20