Pimecrolimus

Description

Pimecrolimus cream, 1%, is a topical formulation containing pimecrolimus, an immunosuppressant derived from the 33-epi-chloro-derivative of the macrolactam ascomycin. The chemical structure of pimecrolimus is defined as (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo22.3.1.04,9octacos-18-ene-2,3,10,16-tetraone, with a molecular formula of C43H68ClNO11 and a molecular weight of 810.47 g/mol.

Pimecrolimus appears as a white to off-white fine crystalline powder, exhibiting solubility in methanol and ethanol, while being insoluble in water. Each gram of pimecrolimus cream, 1%, contains 10 mg of pimecrolimus incorporated into a cream base that includes benzyl alcohol, cetyl alcohol, cetostearyl alcohol (type A), citric acid anhydrous, medium-chain triglycerides, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium hydroxide, stearyl alcohol, and water.

Uses and Indications

Pimecrolimus cream, 1%, is indicated as a calcineurin inhibitor immunosuppressant 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.

There are no teratogenic or nonteratogenic effects associated with the use of pimecrolimus cream.

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 closely; 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 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 important to note that the long-term safety of topical calcineurin inhibitors, including pimecrolimus cream, 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.

To minimize potential risks, 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. Furthermore, pimecrolimus cream, 1% is not indicated for use in children under the age of 2 years. Healthcare providers are advised to monitor patients closely and consider the implications of these warnings when prescribing this medication.

Side Effects

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

In clinical trials, the incidence of certain adverse events was notably higher in patients treated with pimecrolimus cream compared to those receiving a vehicle. Specifically, in pediatric subjects aged 2 to 17 years, the following adverse reactions were reported more frequently: 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 in this age group, 9 (0.8%) developed eczema herpeticum.

In infants aged 3 to 23 months, there was an increased incidence of adverse events compared to the vehicle group, including pyrexia (32% vs. 13%), upper respiratory infection (URI) (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). Additionally, in a 6-month safety evaluation, infants treated with pimecrolimus cream exhibited a greater incidence of adverse events such as pyrexia (30% vs. 20%), URI (21% vs. 17%), cough (15% vs. 9%), hypersensitivity (8% vs. 2%), teething (27% vs. 22%), vomiting (9% vs. 4%), rhinitis (13% vs. 9%), viral rash (4% vs. 0%), rhinorrhea (4% vs. 0%), and wheezing (4% vs. 0%).

It is important to note that the long-term safety of topical calcineurin inhibitors, including pimecrolimus cream, has not been established. Although a causal relationship has not been confirmed, rare cases of malignancy, including skin cancer and lymphoma, have been reported in patients treated with these agents. Continuous long-term use of pimecrolimus cream should be avoided, and application should be limited to areas affected by atopic dermatitis.

Pimecrolimus cream, 1% 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. Treatment should also be avoided on malignant or pre-malignant skin conditions, as these may present as dermatitis. Furthermore, it is contraindicated in patients with Netherton’s Syndrome or other skin diseases that may increase systemic absorption.

Drug Interactions

Potential interactions between pimecrolimus cream, 1%, and other medications, including immunizations, have not been systematically evaluated. While systemic drug interactions are not expected due to the low blood levels of pimecrolimus detected in some patients following topical application, the possibility cannot be entirely excluded.

Caution is advised when administering pimecrolimus concurrently with known inhibitors of the CYP3A enzyme family, particularly in patients with widespread and/or erythrodermic disease. Examples of such inhibitors include erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers, and cimetidine. Monitoring for potential adverse effects or altered therapeutic efficacy is recommended in these cases.

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 less than 2 years of age. The long-term safety and effects of pimecrolimus cream on the developing immune system remain unknown.

In clinical trials, three Phase 3 studies were conducted involving 1,114 pediatric subjects aged 2 to 17 years, with 542 (49%) of these subjects aged 2 to 6 years. In the short-term trials, 11% of subjects treated with pimecrolimus did not complete the studies, with 1.5% discontinuing due to adverse events. In a one-year trial, 32% of pimecrolimus subjects did not complete the study, and 3% discontinued due to adverse events. The most common local adverse event reported in these trials was application site burning, occurring in 10% of pimecrolimus subjects compared to 13% in the vehicle group. Among 843 subjects aged 2 to 17 years treated with pimecrolimus cream, 1% developed eczema herpeticum at a rate of 0.8%.

Two Phase 3 trials were conducted involving 436 infants aged 3 to 23 months. In a 6-week trial, 11% of pimecrolimus subjects and 48% of vehicle subjects did not complete the study; however, no subjects in either group discontinued due to adverse events. Infants treated with pimecrolimus cream exhibited an increased incidence of several adverse events compared to the vehicle group, including pyrexia (32% vs. 13%), upper respiratory infections (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). In the 6-month safety data, 16% of pimecrolimus subjects and 35% of vehicle subjects discontinued early, with 1.5% of pimecrolimus subjects discontinuing due to adverse events.

In terms of systemic exposure, pimecrolimus cream was studied in 28 pediatric subjects with atopic dermatitis (20% to 80% body surface area involvement) aged 8 months to 14 years. A second group of 30 pediatric subjects aged 3 to 23 months with 10% to 92% body surface area involvement showed that following twice daily application for three weeks, blood concentrations of pimecrolimus were less than 2.6 ng/mL, with 65% of samples having concentrations below 0.5 ng/mL.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were included in Phase 3 trials of pimecrolimus cream, 1%, with a total of nine subjects participating. However, the clinical trials did not enroll a sufficient number of geriatric patients to adequately assess the efficacy and safety of the treatment in this population.

Due to the limited data available, caution is advised when prescribing pimecrolimus cream, 1% to elderly patients. Healthcare providers should consider potential differences in pharmacokinetics and pharmacodynamics in this age group, as well as the possibility of increased sensitivity to treatment. Monitoring for adverse effects and therapeutic response is recommended to ensure the safety and effectiveness of the therapy in geriatric patients.

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.

Pimecrolimus is classified as a Pregnancy Category C medication. In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed at the highest practicable doses tested (10 mg/kg/day) in both rats and rabbits, which corresponds 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. The cream was applied topically for 6 hours per day during the organogenesis period in these studies.

A second dermal embryofetal development study in rats indicated that no maternal, reproductive, or embryo-fetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66X MRHD based on AUC comparisons), the highest dose evaluated. No teratogenicity was observed at any dose in this study.

Oral studies conducted in rats and rabbits during the organogenesis period revealed that while no malformations were noted at high doses (up to 45 mg/kg/day in rats and 20 mg/kg/day in rabbits), maternal toxicity and embryofetal toxicity indicators were observed at the highest doses. Specifically, in rats, post-implantation loss and reduced litter size were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons), while no maternal toxicity or teratogenicity was observed at 20 mg/kg/day in rabbits.

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

An oral peri- and post-natal developmental study in rats indicated 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 not affected at 10 mg/kg/day (12X MRHD based on AUC comparisons).

Pimecrolimus has been shown to transfer across 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, lactating mothers should make a decision regarding the continuation of breastfeeding or the discontinuation of the drug. This decision should take into account the importance of the drug to the 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 information regarding overdosage, healthcare professionals are advised to exercise caution and adhere to general principles of management in cases of suspected overdose.

It is essential to monitor the patient closely for any potential symptoms that may arise from an overdose. Symptoms can vary widely depending on the substance involved and the individual patient's response.

In the event of an overdose, immediate medical attention should be sought. Healthcare providers should implement supportive care measures, which may include maintaining airway patency, providing supplemental oxygen, and monitoring vital signs.

Additionally, it is recommended to consult local poison control centers or relevant toxicology resources for guidance on specific management protocols and antidotes, if applicable.

Documentation of the incident, including the substance involved, estimated dose, and time of exposure, is crucial for effective management and follow-up care.

Nonclinical Toxicology

An oral fertility and embryofetal developmental study in rats demonstrated that administration of pimecrolimus at a dose of 45 mg/kg/day resulted in estrus cycle disturbances, post-implantation loss, and a reduction in litter size, corresponding to 38 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparisons. No effects on fertility were observed in female rats at a dose of 10 mg/kg/day (12X MRHD), nor in male rats at the highest tested dose of 45 mg/kg/day (23X MRHD). 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 noted in female rats at 10 mg/kg/day (5X MRHD) or in male rats at 2 mg/kg/day (0.7X MRHD).

In a 39-week oral toxicology study in monkeys, pimecrolimus doses of 15 mg/kg/day, 45 mg/kg/day, and 120 mg/kg/day were associated with a dose-dependent increase in immunosuppressive-related lymphoproliferative disorder (IRLD) linked to lymphocryptovirus, a monkey strain related to human Epstein-Barr virus. This condition mirrors post-transplantation lymphoproliferative disease (PTLD) observed in human transplant patients undergoing chronic systemic immunosuppressive therapy, with both IRLD and PTLD having the potential to progress to lymphoma, contingent on dose and duration of treatment. Additionally, a dose-dependent increase in opportunistic infections, indicative of systemic immunosuppression, was noted. The no observed adverse effect level (NOAEL) for IRLD and opportunistic infections was not established, with IRLD occurring at the lowest dose of 15 mg/kg/day (31X MRHD) and partial recovery noted upon cessation of dosing.

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 pimecrolimus.

In a 2-year rat dermal carcinogenicity study, a statistically significant increase in the incidence of follicular cell adenoma of the thyroid was observed in low, mid, and high dose male rats compared to vehicle and saline controls, with the lowest dose of 2 mg/kg/day (0.2% pimecrolimus cream; 1.5X MRHD) showing this effect. Conversely, no increase in follicular cell adenoma incidence was noted in an oral carcinogenicity study in male rats at doses up to 10 mg/kg/day (66X MRHD). However, 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 neoplasm incidence 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), with no such changes at 10 mg/kg/day (17X MRHD). The latency time to lymphoma formation was shortened to 8 weeks following dermal administration of pimecrolimus at a dose of 100 mg/kg/day (179-217X MRHD).

In an oral (gavage) carcinogenicity study in mice, a statistically significant increase in lymphoma incidence was noted in high dose male and female animals at 45 mg/kg/day (258-340X MRHD), while no drug-related tumors were observed at 15 mg/kg/day (60-133X MRHD). An oral (gavage) rat carcinogenicity study revealed a statistically significant increase in benign thymoma incidence in male and female rats treated with 10 mg/kg/day compared to controls, and a significant increase was also noted in male rats at 5 mg/kg/day. No drug-related tumors were observed at 1 mg/kg/day (1.1X MRHD) in male rats or at 5 mg/kg/day in female rats (21X MRHD).

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 UV radiation exposure. No additional effect on tumor development was noted with the inclusion of pimecrolimus in the vehicle cream beyond the vehicle effect.

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 these cancers has not been established.

Serious side effects may occur with the use of pimecrolimus cream, 1%. The most frequently reported side effect at the site of application is a burning sensation or warmth, typically mild to moderate in intensity, occurring during the initial days of treatment and generally resolving within a few days.

Other commonly reported side effects include headache, symptoms of the common cold (such as stuffy nose, sore throat, and cough), influenza-like symptoms, fever, and viral infections. Some individuals may experience viral skin infections, including cold sores, chicken pox, shingles, or warts, as well as swollen lymph nodes.

Patients are advised to inform their healthcare provider if they experience a skin infection or any side effect, such as swollen glands, that is bothersome or persistent. This summary does not encompass all potential side effects associated with pimecrolimus cream, 1%. For further information, patients should consult their doctor or pharmacist. Side effects may also be reported to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients using pimecrolimus cream, 1% should be informed about the potential for serious side effects associated with its use. Healthcare providers should emphasize that the long-term safety of pimecrolimus cream, 1% has not been established, and while a very small number of users have reported cases of cancer, a direct link has not been confirmed. Therefore, patients should be advised against the continuous long-term use of this medication.

Pimecrolimus cream, 1% is intended for application only on areas of skin affected by eczema and is not recommended for use in children under 2 years of age. Patients should be cautioned to avoid sun lamps, tanning beds, and ultraviolet light therapy during treatment. Additionally, they should limit sun exposure even when the cream is not applied, and if they need to be outdoors after application, they should wear loose-fitting clothing to protect the treated areas. Healthcare providers should discuss other sun protection measures with patients.

Patients should be instructed not to cover the treated skin with bandages, dressings, or wraps, although normal clothing is acceptable. It is crucial to remind patients that pimecrolimus cream, 1% is 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.

Patients should use pimecrolimus cream, 1% for short periods, with the possibility of repeating treatment after breaks as needed. 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 their physician, using the smallest amount necessary to manage eczema symptoms.

Patients should also be advised not to bathe, shower, or swim immediately after applying pimecrolimus cream, 1%, as this may wash away the medication. While moisturizers can be used in conjunction with pimecrolimus cream, patients should consult their physician to determine which products are appropriate. Maintaining good skin care practices is essential, and if moisturizers are used, they should be applied after the pimecrolimus cream.

Storage and Handling

The product is supplied in accordance with the following specifications. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP guidelines. It is imperative that the product is not exposed to freezing temperatures to maintain its integrity and efficacy.

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 restricted 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 therapies.

Clinicians should ensure that any bacterial or viral infections at the treatment sites are resolved prior to initiating therapy. If patients do not show improvement in their atopic dermatitis symptoms within 6 weeks, a re-evaluation of their condition is necessary. The safety of pimecrolimus cream has not been established for use beyond one year of non-continuous application. Additionally, patients developing lymphadenopathy should have the cause investigated, and the cream should be discontinued if no clear etiology is found or if acute infectious mononucleosis is present. It is also advisable for patients 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 Actavis Pharma, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)