Pimecrolimus

P

Class: Skin and Mucous Membrane Agents, Miscellaneous
VA Class: DE900
Chemical Name: (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS) - 3 - [(1E) - 2 - [(1R,3R,4S) - 4 - Chloro - 3 - methoxycyclohexyl] - 1 - methyl - ethenyl] - 8 - ethyl - 5,6,8,11,12,13,14,15,16,17,18,19,24,26,26a - hexadecahydro - 5,19 - dihydroxy - 14,16 - dimethoxy - 4,10,12,18 - tetramethyl - 15,19 - epoxy - 3H - pyrido[2,1 - c][1,4]oxaazacyclotricosine - 1,17,20,21(4H,23H) - tetrone
Molecular Formula: C43H68ClNO11
CAS Number: 137071-32-0
Brands: Elidel

Long-term safety of topical pimecrolimus not established.a c

Malignancies (e.g., skin cancers, lymphoma) reported rarely in patients treated with topical calcineurin inhibitors, including pimecrolimus; causal relationship not established.a c

Avoid continuous long-term use of topical pimecrolimus; limit application to areas affected by atopic dermatitis.a c (See Carcinogenicity under Cautions.)

Not indicated for use in children <2 years of age.a c

Introduction

Immunosuppressive agent; derivative of ascomycin (a macrolactam); structurally related to tacrolimus.1 3 4 6 7

Uses for Pimecrolimus Atopic Dermatitis

Second-line therapy for short-term treatment and noncontinuous chronic treatment of mild to moderate atopic dermatitis (eczema) in immunocompetent adults and children ?2 years of age who are unable to tolerate or have not responded to first-line therapies (e.g., corticosteroids) or for whom first-line therapies are inadvisable.3 5 6 12 a c (See Carcinogenicity under Cautions.)

Not indicated for use in children <2 years of age.a c

Pimecrolimus Dosage and Administration Administration Topical Administration

Apply topically to the skin as a 1% cream.1 For external use only; do not use in the eyes or ingest.1

Apply in thin layers to affected areas of skin.a

Use minimum amount required to control symptoms;12 limit application to areas affected with atopic dermatitis.a (See Carcinogenicity under Cautions.)

Do not use occlusive dressings or wrappings.1

Dosage Pediatric Patients Atopic Dermatitis Topical

Children ?2 years of age: Apply to affected areas twice daily.1

Treatment effects usually evident within 15 days; erythema and infiltration or papulation generally reduced within 8 days.1 3 4 Discontinue treatment following resolution of signs and symptoms (e.g., pruritus, rash, erythema).a If manifestations persist beyond 6 weeks, reexamine patient and confirm diagnosis.a

Adults Atopic Dermatitis Topical

Apply to affected areas twice daily.1

Treatment effects usually evident within 15 days; erythema and infiltration or papulation generally reduced within 8 days.1 3 4 Discontinue treatment following resolution of signs and symptoms (e.g., pruritus, rash, erythema).a If manifestations persist beyond 6 weeks, reexamine patient and confirm diagnosis.a

Prescribing Limits Pediatric Patients Atopic Dermatitis Topical

For short-term and intermittent use only; avoid continuous long-term use.12 a Safety of noncontinuous use for >1 year not established.12 a c (See Carcinogenicity under Cautions.)

Adults Atopic Dermatitis Topical

For short-term and intermittent use only; avoid continuous long-term use.12 a Safety of noncontinuous use for >1 year not established.12 a c (See Carcinogenicity under Cautions.)

Cautions for Pimecrolimus Contraindications

Known hypersensitivity to pimecrolimus or any ingredient in the formulation.1

Warnings/Precautions Warnings Carcinogenicity

Possible increased risk of malignancies.12 13 14 a (See Boxed Warning.)

Malignancies (including lymphoma and skin cancers) reported rarely in children and adults receiving topical pimecrolimus.12 13 14 a Concerns also based on case reports of malignancies (including lymphoma and skin cancers) in patients (including transplant patients) receiving prolonged systemic treatment with calcineurin inhibitors (e.g., cyclosporine, tacrolimus);a animal studies indicating dose-related increases in the risk of lymphoma and other malignancies with pimecrolimus and other calcineurin inhibitors;12 13 14 a and known pharmacologic effects of these immunosuppressants.a 12 13 14

Animal studies using topically or orally administered pimecrolimus in 3 species (mouse, rat, monkey) indicate increased risk of lymphoma and other malignancies (possibly due to immunosuppression10 12 14 );a risk appears to be related to dose and duration of exposure.12 13 14 a

Risk associated with systemic therapy is related to intensity and duration of immunosuppression.a The potential for systemic immunosuppression with topical pimecrolimus and the drug’s role in the development of malignancies in humans have not been established.12 13 14 a Long-term studies in humans are needed to determine whether topical pimecrolimus is associated with an increased risk of malignancies.12 13 Until such data are available, FDA recommends limiting use to the labeled indication, reserving the drug for use as a second-line agent for short-term and intermittent treatment.12 13 (See Atopic Dermatitis under Uses, see Immunocompromised Patients under Cautions, and see Dosage and Administration.) Carefully evaluate potential risks and benefits of therapy.12 13

Avoid use for malignant or premalignant skin conditions (e.g., cutaneous T-cell lymphoma [CTCL]), which may appear clinically similar to dermatitis.a

General Precautions Lymphadenopathy

Lymphadenopathy reported; usually related to infections and resolves following appropriate anti-infective therapy.1 Also reported in association with malignancy.14 Investigate etiology if lymphadenopathy develops.1 Discontinue pimecrolimus in the absence of a clear etiology or in the presence of acute infectious mononucleosis.a Monitor patients with lymphadenopathy to ensure that it resolves.1

Netherton’s Syndrome

Not recommended for use in patients with Netherton’s syndrome because of the potential for increased systemic absorption of pimecrolimus.1

Generalized Erythroderma

Safety in patients with generalized erythroderma has not been established.a

Dermatologic Reactions

Mild to moderate sensation of warmth and/or burning, stinging, soreness, and pruritus at the treatment site may occur within 1–5 days of initiating therapy.a b Reactions usually last no more than 5 days and improve as the lesions of atopic dermatitis resolve.1

Infectious Complications

Clinical infections (e.g., bacterial, viral) at treatment sites should be resolved before initiating pimecrolimus therapy.1 Safety and efficacy not established for treatment of clinically infected atopic dermatitis.1

Possible increased risk of varicella-zoster infections (chickenpox or shingles), herpes simplex virus infection, or eczema herpeticum.1

Skin papilloma and/or warts may occur.1 If skin papilloma worsens or is unresponsive to conventional therapy, consider discontinuing pimecrolimus until complete resolution of the warts is achieved.1

Septic arthritis reported in infants ?1 year of age during clinical trials; however, causality not established.a

Phototoxicity

Although phototoxicity not reported in humans, it may be prudent to minimize or avoid natural or artificial sunlight exposure during pimecrolimus therapy (including periods when no drug is on skin).1 Potential effects on skin response to ultraviolet (UV) damage are not known.a

Animal photocarcinogenicity studies indicate shortened time to skin tumor formation following chronic topical pimecrolimus dosing with concurrent UV radiation exposure.1

Immunocompromised Patients

Safety and efficacy not established and not recommended for use in immunocompromised adults or children.1 12 13 14 a

Specific Populations Pregnancy

Category C.1

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established and not recommended for use in children <2 years of age.1 12 a c

Increased incidence of upper respiratory tract infections in infants <24 months of age receiving pimecrolimus compared with those receiving placebo.12 Possible increased incidence of upper respiratory symptoms and/or infections in infants 3–23 months of age compared with older children; relationship to treatment not known.1

Long-term effects on the developing immune system in infants and children are not known.12 13 14 a

Not recommended for use in immunocompromised children.1 12 13 14

Geriatric Use

Experience insufficient to determine whether patients ?65 years of age respond differently than younger adults.1

Common Adverse Effects

Upper respiratory tract infection,1 3 b cough,1 3 b nasopharyngitis,1 b application site reactions (e.g., sensation of burning or warmth),1 3 b headache.1 3 b

Interactions for Pimecrolimus

No formal drug interaction studies have been performed.1

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors of CYP3A4 in patients with widespread and/or erythrodermic disease.1

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles

Potential interaction (inhibition of pimecrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Calcium-channel blocking agents

Potential interaction (inhibition of pimecrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Cimetidine

Potential interaction (inhibition of pimecrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Erythromycin

Potential interaction (inhibition of pimecrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Pimecrolimus Pharmacokinetics Absorption Bioavailability

Not appreciably absorbed into systemic circulation following multiple topical applications in adults or children 2–14 years of age with atopic dermatitis.1 2 3 Increased systemic absorption occurs following topical application in infants 3–23 months of age with atopic dermatitis compared with older children, possibly because of the larger surface area to body mass ratio.1 14

Occlusive dressings or wrappings may promote systemic exposure.1

Distribution Extent

Crosses placenta in rats and rabbits following oral administration.1

Plasma Protein Binding

74–87% bound to plasma proteins in vitro.1

Elimination Metabolism

Studies using oral pimecrolimus indicate absorbed drug is metabolized in the liver principally via demethylation by CYP3A isoenzymes.1 3

No evidence of skin-mediated metabolism.1

Elimination Route

Studies using oral pimecrolimus indicated absorbed drug is eliminated principally in feces as metabolites.1

Stability Storage Topical Cream

25°C (may be exposed to 15–30°C).1 Do not freeze.1

ActionsActions

Exact mechanism(s) of immunosuppressive action in the treatment of atopic dermatitis not known; appears to involve inhibition of T cell activation.1 3 7

Not genotoxic and does not interact directly with DNA; however, may impair local immunosurveillance.14

In vitro studies indicate pimecrolimus prevents release of inflammatory mediators from mast cells.1 3 7 11

Advice to Patients

Importance of reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.b

Importance of informing clinicians of other medical conditions, including Netherton’s syndrome, skin infections (e.g., chicken pox, herpes), or weakened immune system.b

Advise patients that pimecrolimus is for external use on affected areas of the skin only.a Importance of patients or caregivers washing their hands before and after application if hands are not an area for treatment.1

Importance of ensuring that the skin is completely dry before applying the drug.a Advise patients not to bathe, shower, or swim immediately after application.b

Importance of avoiding contact with the eyes; irrigate eyes with copious amounts of cool water if contact occurs.a

Importance of following the clinician’s advice regarding use of other topical preparations; importance of maintaining good skin care practices; apply moisturizers (if used) after pimecrolimus.a

Advise patients to discontinue pimecrolimus when the signs and symptoms (e.g., itching, rash, redness) of atopic dermatitis (eczema) resolve, or as directed by clinician.a Importance of following the clinician’s advice if symptoms recur after a course of treatment.a

Importance of not using the drug in children <2 years of age.a

Importance of avoiding use of bandages, dressings, or wrappings on treated skin.b

Importance of not using the drug for any disorder other than that for which it was prescribed.1

Importance of using pimecrolimus exactly as prescribed and of not using the drug continuously for a long period of time.a 1 Importance of using the minimum amount required to control signs and symptoms of atopic dermatitis; importance of using the drug for short-term or intermittent therapy (e.g., courses repeated after treatment-free intervals) only.12 13 a

Importance of reporting persistently swollen glands or any other adverse reactions to clinician.1 b Importance of notifying clinician if reaction at treatment site (e.g., warmth and/or burning) is severe or persists >1 week.1

Importance of notifying clinician if the signs and symptoms of atopic dermatitis do not improve after 6 weeks of therapy or at any time become noticeably worse.1

Importance of notifying clinician if a skin infection develops during treatment with pimecrolimus.a

Importance of avoiding or limiting exposure of unprotected skin to natural or artificial sunlight (tanning beds or UVA/B light) while using pimecrolimus cream (even when the drug is not on the skin); wear protective clothing and use a broad-spectrum sunscreen with a high protection factor.1 a

Importance of not swallowing pimecrolimus; contact clinician if swallowed.a

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary supplements, herbal supplements, any other skin product, or any form of phototherapy (UVA or UVB).1 b

Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pimecrolimus

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Cream

1%

Elidel

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Elidel 1% Cream (NOVARTIS): 100/$311.99 or 200/$596.95

Elidel 1% Cream (NOVARTIS): 30/$109.99 or 90/$300.96

Elidel 1% Cream (NOVARTIS): 60/$203.09 or 180/$586.63

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceutical Corp. Elidel (pimecrolimus) cream 1% prescribing information. East Hanover, NJ; 2004 Jul.

2. Harper J, Green A, Scott G et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol. 2001; 144:781-7. [IDIS 462842] [PubMed 11298537]

3. Novartis Pharmaceutical Corp., East Hanover, NJ: Personal communication.

4. Hebert AA, Warken KA, Cherill R. Pimecrolimus cream 1%: a new development in nonsteroid topical treatment of inflammatory skin diseases. Semin Cutan Med Surg. 2001; 20:260-7. [PubMed 11770913]

5. Van Leent EJM, Graber M, Thurston M et al. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol. 1998; 134:805-9. [IDIS 409267] [PubMed 9681343]

6. Luger T, Van Leent EJM, Graeber M et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol. 2001; 144:788-94. [IDIS 462843] [PubMed 11298538]

7. Stuetz A, Grassberger M, Meingassner JG. Pimecrolimus (Elidel, SDZ ASM 981)—preclinical pharmacologic profile and skin selectivity. Semin Cutan Med Surg. 2001; 20:233-41. [PubMed 11770910]

8. Lucky A, Marshall K, Bush C et al. Efficacy and safety of SDZ ASM 981 1% cream in the treatment of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol. 2000; 14(Suppl 1):318.

9. Lucky A, Marshall K, Bush C et al. SDZ ASM 981: efficacy and safety in children with atopic dermatitis. J Eur Acad Dermatol Venereol. 2000; 14(Suppl 1):91. [PubMed 10972092]

10. Robinson N, Singri P, Gordon KB. Safety of the new macrolide immunomodulators. Semin Cutan Med Surg. 2001; 20:242-9. [PubMed 11770911]

11. Fujisawa Healthcare, Inc. Protopic (tacrolimus) ointment prescribing information. Deerfield, IL; 2000 Dec.

12. Anon. FDA issues public health advisory informing health care providers of safety concerns associated with the use of two eczema drugs, Elidel and Protopic. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2005 March 10. From the FDA website: . Accessed on May 20, 2005.

13. Food and Drug Administration (FDA). FDA Public Health Advisory regarding potential cancer risk from use of Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. From FDA website: . 2005 Mar 10. Accessed on May 20, 2005

14. Food and Drug Administration (FDA). FDA alert for healthcare professionals regarding potential cancer risk from use of pimecrolimus (marketed as Elidel). From FDA website: . Accessed on May 20, 2005.

a. Novartis Pharmaceutical Corp. Elidel (pimecrolimus) cream 1% prescribing information. East Hanover, NJ; 2006 Jan.

b. Novartis Pharmaceutical Corp. Elidel (pimecrolimus) cream 1% medication guide. East Hanover, NJ; 2006 Jan.

c. Bess AL, Cunningham SR. Dear health care provider letter regarding important safety information regarding Elidel and rare cases of malignancy reported in patients treated with topical calcineurin inhibitors. East Hanover, NJ;2006 Jan 27.

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