Pimecrolimus

D11A - Other dermatological preparations ATC D11AH02 Small molecule approved 2001 Topical Natural product Black-box warning

JFDA label: Elidel Cream

⚠ Black-Box Warning

Appropriate use:
Malignancy:
Pediatrics:

Mechanism of Action

Inhibitor of Peptidyl-prolyl cis-trans isomerase FKBP1A — FK506-binding protein 1A inhibitor

Target	Action	Gene / class
Peptidyl-prolyl cis-trans isomerase FKBP1A efficacy	INHIBITOR	FKBP1A

Indications

Approved

Atopic dermatitis

Off-label

Intertriginous and facial psoriasis
Oral lichen planus
Vitiligo

Contraindications

Source: Lexicomp

Hypersensitivity to pimecrolimus or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Very Common fever · Headache

Renal and urinary disorders (1)

Common Dysmenorrhea

Immune system disorders (1)

Common Hypersensitivity

Gastrointestinal disorders (7)

Common abdominal pain · constipation · Diarrhea · gastroenteritis · nausea · toothache · vomiting

Skin and subcutaneous tissue disorders (8)

Common acne vulgaris · Folliculitis · herpes simplex dermatitis · impetigo · molluscum contagiosum · skin infection · urticaria · warts

Musculoskeletal and connective tissue disorders (2)

Common Arthralgia · back pain

Ear and labyrinth disorders (2)

Common Otic infection · otitis media

Infections and infestations (6)

Very Common Influenza

Common bacterial infection · herpes simplex infection · staphylococcal infection · varicella · Viral infection

General disorders and administration site conditions (5)

Very Common application site reaction · Local burning

Common Local irritation · local pruritus · localized erythema

Respiratory, thoracic and mediastinal disorders (7)

Very Common bronchitis · cough · Nasopharyngitis · upper respiratory tract infection

Common pharyngitis · Sore throat · tonsillitis

Other (2)

Common Conjunctivitis · eye infection

Dosing

Source: Lexicomp

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 2009) 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)

(For additional information see "Pimecrolimus: Pediatric drug information") Atopic dermatitis (mild-to-moderate): Children ≥2 years and Adolescents: Topical: Refer to adult dosing.

Refer to adult dosing.

Warnings & Precautions

Source: Lexicomp

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

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

Use of pimecrolimus in children 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

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.

Pregnancy & Lactation

Pregnancy

FDA category C

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

Lactation

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.

Chemistry & Properties

Formula	C43H68ClNO11
Molecular weight	810.47 g/mol
IUPAC name	(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone
CAS	137071-32-0
PubChem CID	6509979
InChIKey	`KASDHRXLYQOAKZ-XDSKOBMDSA-N`
logP	5.72 (XLogP 3.8)
Polar surface area	158.13 Å²
H-bond acceptors / donors	11 / 2
Drug-likeness (QED)	0.15
Lipinski violations	3

SMILES

CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@H](Cl)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.558 h
Volume of distribution	1.0 L/kg
Protein binding	92.7%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Elidel Cream	Cream 1 %	15 g tube pack varies	Khoury Drug Store	14.240
Elidel Cream	Cream 1 %	30 g tube pack varies	Khoury Drug Store	26.040