Professional Information
Pimecrolimus (Topical)
VA CLASSIFICATION
Primary: DE900
Commonly used brand name(s): Elidel.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Immunomodulator (topical) —
Indications
Accepted
Dermatitis, atopic, mild to moderate (treatment)—Pimecrolimus cream is indicated for short-term and intermittent long-term therapy in the treatment of non-immunocompromised patients 2 years of age and older with mild to moderate atopic dermatitis, in whom the use of alternative, conventional therapies are deemed inappropriate or inadequate.{01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
810.47{01}
Solubility
Pimecrolimus is soluble in methanol and ethanol and insoluble in water.{01}
Mechanism of action/Effect:
The mechanism of action of pimecrolimus in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. Also, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/lgE.{01}
Protein binding:
High (74 to 87%)—plasma proteins {01}
Biotransformation:
Following the administration of a single oral radiolabeled dose of pimecrolimus, numerous circulating O-demethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin.{01}
Peak blood concentration:
Blood—Range from undetectable (less than 0.5 ng per mL) to less than 2 ng per mL.{01}
Elimination:
Following single oral radiolabeled administration— 78.4% was recovered in the feces as metabolites. Less than 1% of the radioactivity found in the feces was due to unchanged pimecrolimus.{01}
Precautions to Consider
Carcinogenicity/Tumorigenicity
A two year dermal carcinogenicity study in rats showed a statistically significant increase in the incidence of follicular cell adenoma of the thyroid in low, mid and high doses of pimecrolimus in male rats. Follicular cell adenoma of the thyroid was found at the lowest dose of 2 mg per kg of body weight per day. In an oral carcinogenicity study in male rats, no increase in the incidence of follicular cell adenoma was found at doses up to 10 mg per kg of body weight per day. However, oral studies may not reflect continuous exposure or the same metabolic profile as the dermal route.{01}
In a dermal carcinogenicity study in mice using pimecrolimus in an ethanolic solution, there was no increase noted in the incidence of neoplasms in the skin or other organs up to the highest dose of 4 mg per kg of body weight per day. However, in a 13 week repeat dose dermal toxicity study in mice using pimecrolimus in an ethanolic solution at a dose of 25 mg per kg of body weight per day lymphoproliferative changes, including lymphoma, were found. Lymphoproliferative changes were not found in this study at doses of 10 mg per kg of body weight per day. However, the latency time to lymphoma formation was shortened to 8 weeks after dermal administration of pimecrolimus dissolved in ethanol at a dose of 100 mg per kg of body weight per day.{01}
In an oral (gavage) carcinogenicity study in mice, a significant increase in the incidence of lymphoma was noted in high dose male and female animals compared to vehicle control animals. Lymphomas were noted in the oral mouse carcinogenicity study at a dose of 45 mg per kg of body weight per day. No drug-related tumors were noted in this study at a dose of 15 mg per kg of body weight per day. In an oral (gavage) carcinogenicity study in rats, a significant increase in the incidence of benign thymoma was found in male and female rats treated with pimecrolimus at doses of 10 mg per kg of body weight per day compared to vehicle control animals. An increase in the incidence of benign thymoma was also noted in another oral (gavage) rat carcinogenicity study in 5 mg per kg of body weight per day pimecrolimus treated male rats compared to vehicle control treated male rats. No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1 mg per kg of body weight per day in male animals.{01}
In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation with the vehicle cream alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, pimecrolimus, to the vehicle cream.{01}
Mutagenicity
No evidence for a mutagenic or clastogenic potential for pimecrolimus was revealed in a battery of in vitro genotoxicity tests, including the Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test.{01}
Pregnancy/Reproduction
Fertility—
An oral fertility and embryofetal developmental study in rats revealed estrus cycle disturbances, post-implantation loss and reduction in litter size at the 45 mg per kg of body weight per day dose. No effect on fertility in female rats was noted at 10 mg per kg of body weight per day. No effect on fertility in male rats was noted at 45 mg per kg of body weight per day, which was the highest dose tested in this study.{01}
Pregnancy—
There are no adequate and well-controlled studies of topically administered pimecrolimus in pregnant women. Pimecrolimus should be used only if risk-benefit assessment indicates use{02} during pregnancy.{01}
Pimecrolimus crossed the placenta in oral rat and rabbit embryofetal developmental studies. In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed in topical doses up to 10 mg per kg of body weight per day of 1% pimecrolimus cream in rats and rabbits, during the period of organogenesis.{01}
A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis up to doses of 45 mg per kg of body weight per day in rats and 20 mg per kg of body weight per day in rabbits. In the absence of maternal toxicity, indicators of embryofetal toxicity, such as, post-implantation loss and reduction of litter, were noted at 45 mg per kg of body weight per day in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg per kg of body weight per day in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg per kg of body weight per day, which was the highest dose tested in this study.{01}
In an oral peri- and post-natal developmental study in rats, pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg per kg of body weight per day. Only 2 of 22 females delivered live pups at the highest dose of 40 mg per kg of body weight per day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg per kg of body weight per day.{01}
FDA Pregnancy Category C{01}
Breast-feeding
It is not known whether pimecrolimus is distributed into breast milk.{01}
Pediatrics
Use in children up to 2 years of age is not recommended. In clinical studies, infants under the age of 2 had a greater incidence of side effects. The effects of pimecrolimus on the developing immune system in infants are unknown.{01}
Pimecrolimus cream may be used by pediatric patients 2 years of age or older.{01}
Geriatrics
Appropriate studies on the relationship of age to the effects of pimecrolimus have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.{01}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Potential interactions between pimecrolimus and other drugs, including immunizations, have not been systematically evaluated. Minimal systemic absorption of topically applied pimecrolimus should preclude the potential for significant interactions with other oral medications.{01}
CYP3A inhibitors, such as:
Erythromycin
Itraconazole
Ketoconazole
Fluconazole
Calcium channel blockers or
Cimetidine (patients with widespread and/or erythrodermic disease should use pimecrolimus with caution{01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Infections, active cutaneous viral, or
» Infected atopic dermatitis (pimecrolimus cream should not be applied topically to areas of active cutaneous viral infections or to clinically infected atopic dermatitis. Before commencing treatment with pimecrolimus infections at treatment sites should be cleared. {01})
» Hypersensitivity to pimecrolimus or any of the components of the cream{01}
» Immunocompromised patients (safety and efficacy have not been established, no data to support the use of pimecrolimus{01})
» Netherton's syndrome (potential for increased systemic absorption; use of pimecrolimus is not recommended{01})
Risk-benefit should be considered when the following medical problems exist
Eczema herpeticum (Kaposi's varicelliform eruption) or
Herpes simplex virus infection or
Varicella zoster virus infection (chicken pox or shingles) (increased risk of superficial skin infections may be associated with these conditions{01})
» Lymphadenopathy or
» Mononucleosis, acute infectious (patients who develop lymphadenopathy while using pimecrolimus cream should have the etiology of their lymphadenopathy investigated; consider discontinuation of topical pimecrolimus if lymphadenopathy without a clear etiology develops or in the presence of acute infectious mononucleosis{01})
(in clinical studies there was a rare incidence (0.9%) of lymphadenopathy in patients which was usually related to ongoing infections and noted to resolve upon appropriate antibiotic therapy.{01})
Skin papilloma or
Warts (discontinuation of pimecrolimus cream should be considered if there is a worsening of skin papillomas or they do not respond to therapy{01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Monitor for resolution of symptoms of atopic dermatitis and discontinue therapy; resume treatment at first signs of recurrence.{01}
» If skin site reactions are severe or persists for more than 1 week consider discontinuation of therapy.{01}
» , If no improvement in atopic dermatitis is seen following 6 weeks of treatment or if at any time the condition worsens consider discontinuation of therapy.{01}
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Application site reaction (burning; itching; redness; skin rash; swelling or soreness at site.)
bronchitis ( cough producing mucus; difficulty breathing; shortness of breath; tightness in chest; wheezing)
ear infection ( change in hearing; earache or pain in ear; ear drainage; fever)
influenza (chills; cough; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting)
gastroenteritis (abdominal or stomach pain; diarrhea; loss of appetite; nausea; weakness )
pharyngitis streptococcal ( body aches or pain; congestion; cough; dryness or soreness of throat; fever; hoarseness; runny nose; tender, swollen glands in neck; trouble in swallowing; voice changes)
pyrexia ( fever)
skin infection ( itching; pain; redness; swelling; tenderness; warmth on skin)
tonsillitis (congestion; fever; sore throat; swollen glands )
upper respiratory tract infection (ear congestion; nasal congestion; chills; cough; fever; sneezing, or sore throat; body aches or pain; headache; loss of voice; runny nose; unusual tiredness or weakness; difficulty in breathing)
viral infection ( chills; cough or hoarseness; fever; cold or flu-like symptoms)
{01}
Incidence less frequent
Asthma (cough; difficulty breathing; noisy breathing; shortness of breath; tightness in chest; wheezing)
bacterial infection ( chills; cough or hoarseness; fever; cold or flu-like symptoms)
chickenpox ( skin rash on face, scalp, or stomach)
dyspnea (shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
herpes simplex dermatitis (blistering, crusting, irritation, itching, or reddening of skin; swelling; fever)
hypersensitivity (fast heartbeat; fever; hives; itching; irritation; hoarseness; joint pain, stiffness or swelling; rash; redness of skin; shortness of breath; swelling of eyelids, face, lips, hands, or feet; tightness in chest; troubled breathing or swallowing; wheezing)
infection, eye (blurred vision or other change in vision; eye pain; redness of eye; sensitivity of eye to light; tearing)
laceration (tearing of skin)
molluscum contagiosum (itchy, raised, round, smooth, skin-colored bumps found on just one area of the body; oozing, thick, white fluid)
pneumonia (chest pain; cough; fever or chills; sneezing; shortness of breath; sore throat; troubled breathing; tightness in chest; wheezing)
urticaria ( hives or welts; itching; redness of skin; skin rash)
{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Application site burning
application site irritation
application site pruritus ( itching skin at site)
cough
diarrhea
folliculitis ( burning, itching, and pain in hairy areas; pus at root of hair)
headache
nasopharyngitis (stuffy or runny nose; muscle aches; unusual tiredness or weakness; fever; sore throat; headache)
sore throat
{01}
Incidence less frequent
Abdominal pain (stomach pain)
acne (blemishes on the skin; pimples)
application site erythema (flushing; redness of skin; unusually warm skin at site)
arthralgias ( pain in joints; muscle pain or stiffness; difficulty in moving)
back pain
constipation (difficulty having a bowel movement (stool))
dysmenorrhea (pain; cramps; heavy bleeding)
earache or otis media (earache, redness or swelling in ear)
epistaxis (bloody nose)
herpes simplex (burning or stinging of skin; painful cold sores or blisters on lips, nose, eyes, or genitals)
impetigo (bacterial skin infection )
loose stools
nasal congestion (stuffy nose )
nausea
rhinorrhea (runny nose)
sinus congestion (stuffy nose; headache)
sinusitis ( pain or tenderness around eyes and cheekbone; fever; stuffy or runny nose; headache; cough; shortness of breath or troubled breathing; tightness of chest or wheezing)
skin papilloma ( lump or growth on skin)
toothache
vomiting
wheezing (difficulty in breathing or troubled breathing)
{01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Treatment of overdose
No information is available about specific treatment for an overdose of pimecrolimus.{01}
Supportive care:
Treatment should be symptomatic and supportive.{01}
No incidents of accidental ingestion have been reported. If oral ingestion occurs, medical advice should be sought.{01}
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.{01}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Pimecrolimus (Topical).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to pimecrolimus or any of the components of the cream
Pregnancy—FDA Pregnancy Category C; should be used only if clearly needed during pregnancy; crosses the placenta in animals
Use in children——Safety and efficacy not established in children up to 2 years of age; may be used by pediatric patients 2 years of age or older.
Other medical problems, especially active cutaneous viral infections, acute infectious mononucleosis, infected atopic dermatitis, immunocompromised patients, lymphadenopathy, or Netherton's syndrome
Proper use of this medication
Monitoring patientresolution, recurrence or worsening of symptoms; no improvement of symptoms in 6 weeks of therapy; skin site reactions persisting more than 1 week
Clinical infections at treatment sites should be cleared before initiating topical pimecrolimus treatment
Wash hands after application if hands are not an area for treatment
» Proper dosing especially no occlusive dressings
Missed dose: applying as soon as possible; not using if almost time for next scheduled dose; not doubling doses
Proper storage
Precautions while using this medication
» Importance of close monitoring by a physician
Report any adverse reactions to physician especially application site reactions and cutaneous infections
Do not use pimecrolimus cream for any disorder other than that for which it was prescribed
» Minimize or avoid prolonged{02} exposure to natural or artificial sunlight
Side/adverse effects
Signs of potential side effects, especially application site reaction, asthma, bacterial infection, bronchitis, chickenpox, dyspnea, ear infection, eye infection, hypersensitivity, gastroenteritis, herpes simplex dermatitis, influenza, laceration, molluscum contagiosum, pharyngitis streptococcal, pneumonia, pyrexia, skin infection, tonsillitis, upper respiratory tract infection, urticaria, or viral infection.
General Dosing Information
Pimecrolimus cream is for external use only and should not be used ophthalmically.{01}
Pimecrolimus cream should not be used with occlusive dressings, which may promote systemic exposure and undue local irritation{02}.{01}
Patients using pimecrolimus cream should minimize or avoid prolonged {02}natural or artificial sunlight exposure (tanning beds or UVA/B treatment).{01}
Application is allowed on all skin surfaces, including the head, neck and intertriginous areas.{01}
Patients should see a physician if an application site reaction is severe or persists for more than one week.{01}
Therapy with pimecrolimus cream should be discontinued after signs and symptoms of atopic dermatitis have resolved. {01}
If symptoms persist beyond six weeks or if at any time the condition worsens, the patient should be re-evaluated by a physician{01}.
Topical Dosage Forms
PIMECROLIMUS CREAM
Usual Adult Dose
Atopic dermatitis
Topical, 1% cream, apply a thin layer to the affected skin twice a day and rub in gently and completely. Treatment should continue for as long as signs and symptoms persist.{01}
Adult duration limits
6 weeks—If symptoms persist the patient should be re-evaluated.{01}
Usual Pediatric Dose
Up to two years of age—Safety and efficacy have not been established.{01}
Two years of age and older—See Usual adult dose{01}
Pediatric duration limits
Two years of age and older—See Adult duration limits{01}
Usual Geriatric Dose
See Usual adult dose.
Geriatric duration limits
See Adult duration limits{01}
Strength(s) usually available
U.S.—
1% (Rx) [Elidel (benzyl alcohol ) (cetyl alcohol) (citric acid) (mono- and di-glycerides) ( oleyl alcohol) (propylene glycol) (sodium cetostearyl sulphate) (sodium hydroxide) (stearyl alcohol) ( triglycerides) (water)]{01}
Canada—
Not commercially available.
Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 to 86 °F). Do not freeze.{01}
Auxiliary labeling:
• Avoid extended exposure to sunlight or tanning beds while taking this drug
• External use only
• Use sparingly and rub well into affected areas
{01}
Developed: 11/05/2002
Revised: 1/14/2003
References
- Product Information: Elidel®, pimecrolimus. Novartis, East Hanover, NJ, (PI issued 12/2001) reviewed 11/2002.
- Expert Committee comment, 12/2002.
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