Pimecrolimus

Description

Pimecrolimus Cream, 1%, is a topical formulation containing 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,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 an empirical formula of C43H68ClNO11 and a molecular weight of 810.47.

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, citric acid anhydrous, mono- and diglycerides, oleyl alcohol, propylene glycol, sodium cetostearyl sulfate, sodium hydroxide, stearyl alcohol, triglycerides, and water.

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 appropriate 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, 1%.

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%. Additionally, the application of the cream should be done without the use of 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 treatment in 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 this medication. It is important 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. Furthermore, this medication is not indicated for use in children under the age of 2 years. Healthcare providers are advised to monitor patients closely and consider the potential risks associated with prolonged use of this treatment.

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.

Serious warnings associated with the use of Pimecrolimus Cream, 1% include a caution regarding the long-term safety of topical calcineurin inhibitors, which 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, including Pimecrolimus Cream, 1%. Continuous long-term use of this cream should be avoided in any age group, and application should be limited to areas affected by atopic dermatitis.

Pimecrolimus Cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the cream's components. It is not indicated for use in children under 2 years of age and should not be used in immunocompromised adults and children, including those on systemic immunosuppressive medications. Additionally, treatment should be avoided on malignant or pre-malignant skin conditions, as these may present as dermatitis. The cream is also not recommended for patients with Netherton’s Syndrome or skin diseases that may increase systemic absorption.

In clinical trials involving pediatric subjects aged 2-17 years, the most common local adverse event was application site burning, reported in 10% of subjects treated with Pimecrolimus Cream, 1% 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 vehicle 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 2-17 years treated with Pimecrolimus Cream, 1%, 9 (0.8%) developed eczema herpeticum.

In infants aged 3 months 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%). Infants treated with Pimecrolimus Cream, 1% also exhibited a greater incidence of certain adverse events compared to vehicle, including 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%).

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 Cream concomitantly 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 under 2 years of age. The long-term safety and effects of Pimecrolimus Cream, 1% on the developing immune system remain unknown.

Three Phase 3 pediatric trials were conducted with 1,114 subjects aged 2 to 17 years, including 542 (49%) aged 2 to 6 years. These trials comprised two 6-week randomized vehicle-controlled studies with a subsequent 20-week open-label phase, and one vehicle-controlled safety trial lasting up to 1 year, which allowed for sequential topical corticosteroid use. In the short-term trials, 11% of subjects receiving Pimecrolimus did not complete the studies, with 1.5% discontinuing due to adverse events. In the 1-year trial, 32% of subjects did not complete the study, and 3% discontinued due to adverse events. The most common local adverse event reported in the short-term 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%, 0.8% developed eczema herpeticum.

Two Phase 3 trials included 436 infants aged 3 to 23 months. In the 6-week trial, 11% of Pimecrolimus subjects and 48% of vehicle subjects did not complete the study, with no discontinuations due to adverse events in either group. Infants treated with Pimecrolimus Cream, 1% 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 the open-label phase, infants switching from vehicle to Pimecrolimus had adverse event incidences that approached those who remained on Pimecrolimus. 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.

The systemic exposure to pimecrolimus was evaluated in 28 pediatric subjects with atopic dermatitis (20%-80% body surface area involvement) aged 8 months to 14 years. A second group of 30 subjects aged 3 to 23 months with 10%-92% body surface area involvement showed that after three weeks of twice-daily application, blood concentrations of pimecrolimus were generally low, with 65% of samples below 0.5 ng/mL. Notably, a higher proportion of detectable blood levels was observed in the pediatric population compared to adults.

Geriatric Use

Clinical trials of Pimecrolimus Cream, 1%, included nine subjects aged 65 years and older; however, the number of elderly 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, 1%, to geriatric patients. Due to the limited data available, it is advisable to closely monitor this population for any adverse effects and to consider potential differences in pharmacokinetics and pharmacodynamics that may necessitate dosage adjustments.

Pregnancy

There are no adequate and well-controlled studies with Pimecrolimus Cream, 1% in pregnant women; therefore, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pimecrolimus is classified as Pregnancy Category C.

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 rats demonstrated no maternal, reproductive, or embryofetal toxicity at the highest dose of 10 mg/kg/day (0.66X MRHD based on AUC comparisons), with no teratogenicity noted at any dose.

Oral studies conducted during the period of organogenesis revealed that at doses of 45 mg/kg/day in rats, indicators of embryofetal toxicity, such as post-implantation loss and reduced litter size, were observed, although no malformations were noted. In rabbits, no maternal toxicity or embryotoxicity was observed at 20 mg/kg/day (3.9X MRHD based on AUC comparisons), the highest dose tested. However, maternal toxicity, embryolethality, and fetotoxicity were noted at 45 mg/kg/day in a second oral study in rats, with a slight increase in skeletal variations indicative of delayed skeletal ossification. No teratogenicity was observed at any dose in this study.

In a peri- and postnatal developmental study in rats, Pimecrolimus was administered from gestational day 6 through lactational day 21 at doses up to 40 mg/kg/day. At this highest dose, only 2 of 22 females delivered live pups, while postnatal survival and development of the F1 generation were unaffected at 10 mg/kg/day (12X MRHD based on AUC comparisons).

Pimecrolimus has been shown to transfer across the placenta in both 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 the discontinuation of nursing or the discontinuation of the drug, considering the importance of the drug to the lactating mother.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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 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 monitoring vital signs, providing symptomatic treatment, and ensuring the patient's safety.

If available, consultation with a poison control center or a medical toxicologist is recommended to guide the management of the overdose effectively.

Documentation of the incident, including the substance involved, the amount taken, and the time of ingestion, is crucial for appropriate treatment and follow-up care.

Nonclinical Toxicology

In the evaluation of Pimecrolimus Cream, 1%, nonclinical studies have been conducted to assess its teratogenic and non-teratogenic effects, as well as its potential for carcinogenicity and mutagenicity.

Teratogenic effects were investigated through dermal embryofetal developmental studies in rats and rabbits. No maternal or fetal toxicity was observed at doses up to 10 mg/kg/day, 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. Additionally, no teratogenicity was noted at any dose in these studies. In an oral fertility and embryofetal developmental study in rats, no malformations were observed at 45 mg/kg/day (38X MRHD based on AUC comparisons), and no maternal toxicity, embryotoxicity, or teratogenicity was noted in the oral rabbit study at 20 mg/kg/day (3.9X MRHD). Furthermore, postnatal survival and development of the F1 generation were unaffected at 10 mg/kg/day (12X MRHD). It is important to note that Pimecrolimus was transferred across the placenta in both rat and rabbit studies.

Non-teratogenic effects were also assessed, revealing indicators of embryofetal toxicity, such as post-implantation loss and reduced litter size at 45 mg/kg/day (38X MRHD) in the rat study. Maternal toxicity, embryolethality, and fetotoxicity were observed at this dose, along with a slight increase in skeletal variations indicative of delayed skeletal ossification. Similar findings of maternal toxicity and embryotoxicity were noted at 20 mg/kg/day (12X MRHD), with a corresponding increase in skeletal variations.

In terms of carcinogenicity, a 2-year dermal study in rats indicated a statistically significant increase in the incidence of follicular cell adenoma of the thyroid in male animals across all dose groups compared to controls. Conversely, no increase in thyroid adenomas was observed in an oral carcinogenicity study in male rats at doses up to 10 mg/kg/day (66X MRHD). A mouse dermal carcinogenicity study using an ethanolic solution of pimecrolimus showed no increase in neoplasms at doses up to 4 mg/kg/day (27X MRHD). However, lymphoproliferative changes, including lymphoma, were noted in a 13-week repeat dose dermal toxicity study in mice at 25 mg/kg/day (47X MRHD). An oral carcinogenicity study in mice revealed a statistically significant increase in lymphoma incidence in high-dose animals. Additionally, a significant increase in benign thymoma incidence was observed in male and female rats treated with 10 mg/kg/day of pimecrolimus.

A 39-week oral toxicology study in monkeys demonstrated a dose-dependent increase in immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus, with IRLD occurring at the lowest dose of 15 mg/kg/day (31X MRHD). A partial recovery from IRLD was noted upon cessation of dosing.

In vitro genotoxicity assessments, including the Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration tests in V79 Chinese hamster cells, along with an in vivo mouse micronucleus test, indicated no evidence of mutagenic or clastogenic potential for Pimecrolimus.

Overall, while Pimecrolimus Cream, 1% has shown no teratogenic effects at tested doses, there are indications of non-teratogenic embryofetal toxicity and potential carcinogenic effects in specific studies, warranting careful consideration of its use, particularly in pregnant women.

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. The long-term safety of Pimecrolimus Cream, 1% remains uncertain, and it is advised that patients do not use the cream continuously for extended periods.

Patients are also advised to limit sun exposure during treatment with Pimecrolimus Cream, 1%, even when the medication is not actively applied to the skin. The effects of ultraviolet light exposure on the skin while using Pimecrolimus Cream, 1% are not well understood.

The most frequently reported side effect at the site of application is a burning sensation or warmth, which is typically mild to moderate in intensity, occurring during the initial days of treatment and generally resolving within a few days. Additionally, some individuals may experience viral skin infections, such as cold sores, chickenpox, shingles, or warts, as well as swollen lymph nodes. Patients are encouraged to contact their healthcare provider if symptoms worsen or do not improve after six weeks of treatment.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Medication Guide) prior to using Pimecrolimus Cream, 1%. It is important to inform patients that Pimecrolimus Cream, 1% may cause serious side effects, and the long-term safety of this medication has not been established. Although a very small number of individuals using Pimecrolimus Cream, 1% have developed cancer (such as skin cancer or lymphoma), a direct link to the use of this cream has not been confirmed. Therefore, patients should be cautioned against using Pimecrolimus Cream, 1% continuously for extended periods.

Patients should be instructed to apply Pimecrolimus Cream, 1% only to areas of skin affected by eczema and to avoid its use on children under 2 years of age. Additionally, patients should refrain from using sun lamps, tanning beds, or undergoing ultraviolet light therapy while being treated with Pimecrolimus Cream, 1%. It is crucial to emphasize that this cream is for topical use only and should not come into contact with the eyes, nose, mouth, vagina, or rectum.

Patients should limit sun exposure during treatment, even when the cream is not applied to the skin. If outdoor activity is necessary after application, patients should wear loose-fitting clothing to protect the treated areas from sun exposure. Healthcare providers should discuss additional sun protection measures with patients.

Patients should avoid covering the treated skin with bandages, dressings, or wraps, although normal clothing is acceptable. Pimecrolimus Cream, 1% should be used for short periods, with the possibility of repeating treatment after breaks as needed. Patients should wash their hands before application and ensure that the skin is dry when applying the cream after bathing or showering.

A thin layer of Pimecrolimus Cream, 1% should be applied only to the affected areas of skin twice daily, as directed by the healthcare provider. Patients should use the smallest amount necessary to control the signs and symptoms of eczema. They should also be advised not to bathe, shower, or swim immediately after application, as this may wash off the cream.

Patients may use moisturizers in conjunction with Pimecrolimus Cream, 1%, but should consult their healthcare provider regarding suitable products. Given that the skin of patients with eczema can be very dry, maintaining good skin care practices is essential. If moisturizers are used, they should be applied after Pimecrolimus Cream, 1%.

Patients should be instructed to contact their healthcare provider if their symptoms worsen or do not improve after six weeks of treatment. It is imperative to reiterate that Pimecrolimus Cream, 1% should not be used continuously for long durations.

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°C to 30°C (59°F to 86°F) as defined by USP Controlled Room Temperature guidelines. It is imperative that the product is not frozen to maintain its integrity and efficacy.

Additional Clinical Information

Patients using Pimecrolimus Cream, 1% should be counseled to avoid long-term use of topical calcineurin inhibitors and to limit application to areas affected by atopic dermatitis. It is important for patients to resolve any bacterial or viral infections at treatment sites prior to starting therapy. Additionally, minimizing or avoiding exposure to natural or artificial sunlight during treatment is recommended. Patients who experience lymphadenopathy should have the underlying cause investigated and monitored for resolution.

In clinical trials, adverse events included 15 cases (1%) of skin papilloma and 14 cases (0.9%) of lymphadenopathy among 1544 subjects treated with Pimecrolimus Cream, 1%. The lymphadenopathy cases were typically associated with infections and resolved with appropriate antibiotic treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)