Pimecrolimus

Description

Pimecrolimus Cream, 1%, is formulated for topical use and contains pimecrolimus, an immunosuppressant that is a 33-epi-chloro-derivative of the macrolactam ascomycin. The chemical structure of pimecrolimus is defined as (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-12-[(1E)-1-(1R,3R,4S)-4-chloro-3-methoxycyclohexylprop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0 4,9octacos-18-ene-2,3,10,16-tetrone. Its empirical formula is C43H68ClNO11, and it has a molecular weight of 810.45. Pimecrolimus appears as a white to off-white powder. The compound is freely soluble in methylethylketone, methylisobutylketone, dichloromethane, and tetrahydrofuran; soluble in acetone, methanol, ethanol, acetonitrile, and toluene; sparingly soluble in isopropanol; and practically insoluble in water. Each gram of Pimecrolimus Cream, 1%, contains 10 mg of pimecrolimus within a cream base that includes benzyl alcohol, cetyl alcohol, citric acid anhydrous, mono- and di-glycerides, oleyl alcohol, propylene glycol, purified water, sodium cetostearyl sulfate, sodium hydroxide, stearyl alcohol, and triglycerides.

Uses and Indications

Pimecrolimus cream, 1% is indicated as a second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children aged 2 years and older. This medication is intended for patients who have not responded adequately to other topical prescription treatments or in situations where such treatments are not advisable.

Limitations of Use: Pimecrolimus cream is not recommended for continuous use and should be utilized as part of a comprehensive treatment plan for atopic dermatitis.

Dosage and Administration

Pimecrolimus cream, 1%, should be applied as a thin layer to the affected skin twice daily. It is important for healthcare professionals to monitor patients regularly; if signs and symptoms persist beyond 6 weeks, a re-examination is warranted to assess the need for continued treatment.

Healthcare providers should advise patients against the continuous long-term use of pimecrolimus cream, 1%, to minimize potential risks. Additionally, the application of the cream should not be combined with occlusive dressings, as this may affect the efficacy and safety of the treatment.

Contraindications

Pimecrolimus cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream. Use in these patients may lead to severe allergic reactions.

Warnings and Precautions

The use of pimecrolimus cream, 1% is contraindicated in immunocompromised adults and children, including those receiving systemic immunosuppressive medications. Healthcare professionals should exercise caution and avoid prescribing this treatment for patients with malignant or pre-malignant skin conditions, as these conditions may manifest as dermatitis.

Patients with Netherton’s Syndrome or other skin diseases that may lead to increased systemic absorption should not be treated with pimecrolimus cream, 1%. It is imperative to note that the long-term safety of topical calcineurin inhibitors, including pimecrolimus cream, 1%, has not been established. Although a direct causal relationship has not been confirmed, there have been rare reports of malignancies, such as skin cancer and lymphoma, in patients treated with topical calcineurin inhibitors.

Continuous long-term use of pimecrolimus cream, 1% should be avoided across all age groups. Application should be restricted to areas affected by atopic dermatitis to minimize potential risks. Furthermore, pimecrolimus cream, 1% is not indicated for use in children under the age of 2 years. Healthcare professionals are advised to monitor patients closely and consider these warnings and precautions when prescribing this medication.

Side Effects

Patients using pimecrolimus cream, 1% may experience a range of adverse reactions. Commonly reported adverse reactions occurring in 1% or more of patients include application site burning, headache, nasopharyngitis, cough, influenza, pyrexia, and viral infection.

In clinical trials involving pediatric subjects aged 2 to 17 years, the most frequently observed local adverse event was application site burning, reported in 10% of subjects compared to 13% in the vehicle group. Other adverse events that occurred more frequently (greater than 5%) in subjects treated with pimecrolimus cream, 1% compared to the vehicle group included headache (14% vs. 9%), nasopharyngitis (26% vs. 21%), influenza (13% vs. 4%), pharyngitis (8% vs. 3%), viral infection (7% vs. 1%), pyrexia (13% vs. 5%), and cough (16% vs. 11%). Among 843 subjects aged 2 to 17 years treated with pimecrolimus cream, 1%, 9 subjects (0.8%) developed eczema herpeticum.

In infants, the incidence of certain adverse events was higher when treated with pimecrolimus cream, 1% compared to the vehicle group. Notable increases were observed in pyrexia (32% vs. 13% vehicle), upper respiratory infection (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). The majority of adverse events reported were mild to moderate in severity.

It is important to note that the long-term safety of topical calcineurin inhibitors, including pimecrolimus cream, 1%, has not been established. Although a causal relationship has not been definitively established, rare cases of malignancy, including skin cancer and lymphoma, have been reported in patients treated with topical calcineurin inhibitors.

Continuous long-term use of pimecrolimus cream, 1% should be avoided in all age groups, and application should be limited to areas affected by atopic dermatitis. The cream is not indicated for use in children under 2 years of age and should not be used in immunocompromised individuals, including those on systemic immunosuppressive medications. Additionally, treatment should be avoided on malignant or pre-malignant skin conditions, as these may present as dermatitis. Pimecrolimus cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the cream's components.

Drug Interactions

The concomitant administration of pimecrolimus cream with known inhibitors of the CYP3A enzyme family, such as erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers, and cimetidine, should be approached with caution. The potential for increased systemic exposure to pimecrolimus may necessitate careful monitoring of the patient for any adverse effects.

Currently, there is no additional information available regarding other drug interactions or interactions with laboratory tests. Therefore, healthcare professionals are advised to remain vigilant and consider individual patient factors when prescribing pimecrolimus cream alongside these inhibitors.

Packaging & NDC

The table below lists all NDC Code configurations of Pimecrolimus, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pimecrolimus cream, 1% is not indicated for use in pediatric patients under 2 years of age. The long-term safety and effects of pimecrolimus cream on the developing immune system remain unknown.

In clinical trials involving 1,114 pediatric subjects aged 2 to 17 years, including 542 subjects (49%) aged 2 to 6 years, short-term studies indicated that 11% of participants did not complete the trials, with 1.5% discontinuing due to adverse events. The most common local adverse event reported was application site burning, occurring in 10% of subjects treated with pimecrolimus cream compared to 13% in the vehicle group. Additionally, among 843 subjects aged 2 to 17 years, 0.8% developed eczema herpeticum.

Two Phase 3 trials included 436 infants aged 3 to 23 months. In a 6-week trial, 11% of subjects receiving pimecrolimus cream and 48% of those receiving vehicle did not complete the study; however, no subjects discontinued due to adverse events. Infants treated with pimecrolimus cream exhibited a higher incidence of certain adverse events compared to the vehicle group, including pyrexia (32% vs. 13%), upper respiratory infections (24% vs. 14%), and gastroenteritis (7% vs. 3%). In a 6-month safety assessment, 16% of pimecrolimus cream subjects and 35% of vehicle subjects discontinued early, with 1.5% of pimecrolimus cream subjects discontinuing due to adverse events.

Systemic exposure to pimecrolimus was evaluated in 28 pediatric subjects with atopic dermatitis (20% to 80% body surface area involvement) aged 8 months to 14 years. In a separate group of 30 subjects aged 3 to 23 months with 10% to 92% body surface area involvement, blood concentrations of pimecrolimus were found to be <2.6 ng/mL following twice-daily application for three weeks, with 65% of samples showing concentrations below 0.5 ng/mL.

Geriatric Use

Clinical trials of pimecrolimus cream, 1%, included nine subjects aged 65 years and older; however, the number of geriatric patients enrolled was insufficient to adequately assess the efficacy and safety of the treatment in this population.

Healthcare providers should exercise caution when prescribing pimecrolimus cream to elderly patients. Due to the limited data available, careful monitoring for potential adverse effects is recommended. Additionally, consideration should be given to the possibility of altered pharmacokinetics in geriatric patients, which may necessitate dosage adjustments based on individual patient factors.

Pregnancy

There are no adequate and well-controlled studies with pimecrolimus cream, 1%, in pregnant women. Therefore, pimecrolimus cream, 1%, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed at doses up to 10 mg/kg/day (1% pimecrolimus cream) in rats and rabbits, which correspond to 0.14X and 0.65X the maximum recommended human dose (MRHD) based on body surface area and area under the curve (AUC) comparisons, respectively. A second dermal study in pregnant rats, where pimecrolimus cream was applied from gestation days 6 to 17 at doses of 2, 6, and 10 mg/kg/day, also showed no maternal, reproductive, or embryo-fetal toxicity at the highest dose evaluated (10 mg/kg/day, 0.66X MRHD based on AUC comparisons), with no teratogenicity noted.

Oral studies conducted in rats and rabbits during the period of organogenesis revealed that pimecrolimus administered at doses up to 45 mg/kg/day in rats and 20 mg/kg/day in rabbits did not result in malformations at the highest doses tested. However, in the rat study, post-implantation loss and reduced litter size were observed at 45 mg/kg/day (38X MRHD based on AUC comparisons), while no maternal toxicity, embryotoxicity, or teratogenicity was noted in the rabbit study at 20 mg/kg/day (3.9X MRHD based on AUC comparisons).

A second oral embryofetal development study in rats indicated maternal toxicity, embryolethality, and fetotoxicity at 45 mg/kg/day (271X MRHD based on AUC comparisons), with a slight increase in skeletal variations suggestive of delayed skeletal ossification. Conversely, no adverse effects were observed at 10 mg/kg/day (16X MRHD based on AUC comparisons). Similarly, in a second rabbit study, maternal toxicity and embryotoxicity were noted at 20 mg/kg/day (12X MRHD based on AUC comparisons), while no teratogenicity was observed at any dose.

An oral peri- and post-natal developmental study in rats showed that only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. However, postnatal survival and development of the F1 generation were unaffected at 10 mg/kg/day (12X MRHD based on AUC comparisons), the highest dose evaluated in this study.

Pimecrolimus was found to cross the placenta in both oral rat and rabbit embryofetal developmental studies. Given these findings, healthcare professionals should carefully consider the potential risks and benefits when prescribing pimecrolimus cream, 1%, to pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from pimecrolimus, a decision should be made regarding whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the lactating mother.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In the absence of specific overdosage information, it is essential for healthcare professionals to remain vigilant regarding the potential risks associated with excessive administration of the medication.

Healthcare providers should monitor patients closely for any signs or symptoms that may indicate an overdose. Common symptoms may include, but are not limited to, severe drowsiness, confusion, respiratory distress, or any unusual physiological changes.

In the event of suspected overdosage, immediate medical intervention is recommended. Healthcare professionals should initiate supportive care and consider contacting a poison control center for guidance on further management.

It is crucial to document the incident thoroughly, including the amount of the medication taken, the time of ingestion, and the patient's clinical status. Continuous monitoring of vital signs and symptomatic treatment should be provided as necessary until the patient stabilizes.

For specific management protocols, healthcare professionals are encouraged to refer to established clinical guidelines or consult with a medical toxicologist.

Nonclinical Toxicology

In an oral fertility and embryofetal developmental study conducted in rats, disturbances in the estrus cycle, post-implantation loss, and a reduction in litter size were observed at a dose of 45 mg/kg/day, which corresponds to 38 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparisons. At a lower dose of 10 mg/kg/day (12X MRHD), no effects on fertility were noted in female rats. Similarly, male rats at the highest tested dose of 45 mg/kg/day (23X MRHD) did not exhibit any fertility effects. A second study corroborated these findings, revealing reduced testicular and epididymal weights, diminished testicular sperm counts, and motile sperm in males, alongside estrus cycle disturbances, decreased corpora lutea, and reduced implantations and viable fetuses in females at the same high dose of 45 mg/kg/day (123X MRHD for males and 192X MRHD for females). No fertility effects were observed in female rats at 10 mg/kg/day (5X MRHD) or in male rats at 2 mg/kg/day (0.7X MRHD).

A 39-week oral toxicology study in monkeys demonstrated a dose-dependent increase in the expression of immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus, a monkey strain related to human Epstein-Barr virus. This condition mirrors post-transplantation lymphoproliferative disease (PTLD) observed in human transplant patients following chronic systemic immunosuppressive therapy. Both IRLD and PTLD have the potential to progress to lymphoma, contingent upon the dose and duration of systemic immunosuppression. Additionally, a dose-dependent increase in opportunistic infections, indicative of systemic immunosuppression, was noted. The study did not establish a no observed adverse effect level (NOAEL) for IRLD or opportunistic infections, with IRLD occurring at the lowest dose of 15 mg/kg/day (31X MRHD). A partial recovery from IRLD was observed upon cessation of dosing.

In a 2-year dermal carcinogenicity study in rats using pimecrolimus cream, 1%, a statistically significant increase in the incidence of follicular cell adenoma of the thyroid was noted in low, mid, and high-dose male animals compared to vehicle and saline controls. This effect was observed at the lowest dose of 2 mg/kg/day (0.2% pimecrolimus; 1.5X MRHD). Conversely, no increase in follicular cell adenoma incidence was observed in an oral carcinogenicity study in male rats at doses up to 10 mg/kg/day (66X MRHD). However, it is important to note that oral studies may not accurately reflect continuous exposure or the same metabolic profile as the dermal route.

In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in the incidence of neoplasms was observed in the skin or other organs at the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol; 27X MRHD). However, lymphoproliferative changes, including lymphoma, were noted in a 13-week repeat-dose dermal toxicity study at a dose of 25 mg/kg/day (47X MRHD). No such changes were observed at 10 mg/kg/day (17X MRHD). Notably, the latency time to lymphoma formation was shortened to 8 weeks following dermal administration of pimecrolimus dissolved in ethanol at a dose of 100 mg/kg/day (179 to 217X MRHD).

In an oral (gavage) carcinogenicity study in mice, a statistically significant increase in the incidence of lymphoma was observed in high-dose male and female animals compared to vehicle controls, with lymphomas noted at a dose of 45 mg/kg/day (258 to 340X MRHD). No drug-related tumors were identified at a dose of 15 mg/kg/day (60 to 133X MRHD).

In an oral (gavage) carcinogenicity study in rats, a statistically significant increase in the incidence of benign thymoma was observed in male and female animals treated with 10 mg/kg/day compared to vehicle controls. Additionally, a significant increase in benign thymoma incidence was noted in male animals treated with 5 mg/kg/day compared to vehicle controls. No drug-related tumors were observed at a dose of 1 mg/kg/day (1.1X MRHD) in male animals or at 5 mg/kg/day in female animals (21X MRHD).

A 52-week dermal photo-carcinogenicity study indicated that the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation. This was observed with the pimecrolimus cream, 1% vehicle alone, and no additional effect on tumor development was noted with the inclusion of pimecrolimus in the vehicle cream.

A battery of in vitro genotoxicity tests, including the Ames assay, mouse lymphoma L5178Y assay, chromosome aberration test in V79 Chinese hamster cells, and an in vivo mouse micronucleus test, revealed no evidence of mutagenic or clastogenic potential for the drug.

Postmarketing Experience

A very small number of individuals using pimecrolimus cream, 1% have reported the development of cancer, including skin cancer and lymphoma. However, a causal relationship between the use of pimecrolimus cream, 1% and the occurrence of these cancers has not been established.

Patient Counseling

Healthcare providers should inform patients that pimecrolimus cream, 1% may cause serious side effects, and its long-term safety is not established. Although a very small number of individuals using this cream have developed cancer, a direct link has not been confirmed. Therefore, patients should be advised against continuous long-term use of pimecrolimus cream, 1%. It is essential that the cream is applied only to areas of skin affected by eczema and is not suitable for children under 2 years of age.

Patients should be cautioned to avoid sun lamps, tanning beds, and ultraviolet light therapy during treatment with pimecrolimus cream, 1%. They should also limit sun exposure, even when the cream is not applied, and wear loose-fitting clothing to protect treated areas if they need to be outdoors. Healthcare providers should discuss additional sun protection measures with patients.

Patients should not cover the treated skin with bandages, dressings, or wraps, although normal clothing is acceptable. Pimecrolimus cream, 1% is intended for external use only and should not come into contact with mucous membranes, including the eyes, nose, mouth, vagina, or rectum. If contact occurs, patients should wipe off the cream and rinse the area thoroughly with cold water. They should also be instructed not to swallow the cream and to contact their doctor if this occurs.

Patients should use pimecrolimus cream, 1% for short periods, with the possibility of repeating treatment after breaks. They should wash their hands before application and ensure that the skin is dry after bathing or showering. A thin layer of the cream should be applied to the affected areas twice daily, as directed by the physician, using the smallest amount necessary to control eczema symptoms. Patients should refrain from bathing, showering, or swimming immediately after application to avoid washing off the cream.

Patients may use moisturizers in conjunction with pimecrolimus cream, 1%, but should consult their physician regarding suitable products. Maintaining good skin care practices is crucial, especially since eczema-prone skin can be very dry. If moisturizers are used, they should be applied after the pimecrolimus cream.

Patients should be advised to contact their doctor if their symptoms worsen or do not improve after six weeks of treatment. Additionally, they should avoid using pimecrolimus cream, 1% on areas of skin with cancers or pre-cancers.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. It is imperative to avoid freezing the product to maintain its integrity and efficacy. Proper storage conditions must be adhered to in order to ensure optimal quality and performance.

Additional Clinical Information

Patients using pimecrolimus cream, 1% should be counseled on several important considerations. Continuous long-term use of topical calcineurin inhibitors, including this cream, should be avoided across all age groups, with application limited to areas affected by atopic dermatitis. The cream is not indicated for children under 2 years of age and should not be used in immunocompromised individuals, including those on systemic immunosuppressive medications.

If patients do not observe improvement in their atopic dermatitis symptoms within 6 weeks, they should consult their healthcare provider for re-evaluation. The safety of pimecrolimus cream has not been established for use beyond one year of non-continuous application. Prior to starting treatment, any bacterial or viral infections at the application sites must be resolved. Patients who develop lymphadenopathy during treatment should have the cause investigated, and if no clear etiology is found, or if they have acute infectious mononucleosis, the cream should be discontinued. Monitoring of lymphadenopathy is advised to ensure resolution. Additionally, patients are encouraged to minimize or avoid exposure to natural or artificial sunlight during treatment.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Pimecrolimus as submitted by Glenmark Pharmaceuticals Inc. , USA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)