Pimecrolimus

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 indication applies to patients who have failed to respond adequately to other topical prescription treatments or when those treatments are not advisable.

Pimecrolimus acts as a calcineurin inhibitor immunosuppressant, providing an alternative therapeutic option for managing this condition.

No teratogenic or nonteratogenic effects have been mentioned in the available data.

Dosage and Administration

Pimecrolimus Cream, 1% should be applied as a thin layer to the affected skin twice daily. It is important to monitor the patient’s condition; if signs and symptoms persist beyond 6 weeks, a re-examination is recommended. Continuous long-term use of Pimecrolimus Cream, 1% should be avoided to minimize potential risks. Additionally, the use of occlusive dressings with this medication is not advised.

Contraindications

Pimecrolimus cream, 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream.

Warnings and Precautions

Pimecrolimus Cream, 1% is contraindicated in immunocompromised adults and children, including those receiving systemic immunosuppressive medications. It is essential to avoid treatment on malignant or pre-malignant skin conditions, as these may present as dermatitis. Additionally, the use of Pimecrolimus is not recommended for patients with Netherton’s Syndrome or other skin diseases that may lead to increased systemic absorption.

Serious Warnings

• Long-Term Safety: The long-term safety of topical calcineurin inhibitors, including Pimecrolimus, has not been established. Continuous long-term use should be avoided in all age groups, and application should be limited to areas affected by atopic dermatitis.

• Malignancy Risk: Although a causal relationship has not been definitively established, rare cases of malignancy, including skin cancers and lymphoma, have been reported in patients treated with topical calcineurin inhibitors, such as Pimecrolimus Cream, 1%.

Age Restrictions

Pimecrolimus Cream, 1% is not indicated for use in children under 2 years of age.

Side Effects

Patients using Pimecrolimus Cream, 1% may experience a range of adverse reactions. The following outlines the commonly reported adverse reactions, warnings, and additional important notes regarding the use of this medication.

Commonly Reported Adverse Reactions (≥1%)

• Application site burning

• Headache

• Nasopharyngitis

• Cough

• Influenza

• Pyrexia

• Viral infection

Serious Warnings

• WARNING: The long-term safety of topical calcineurin inhibitors has not been established. Although a causal relationship has not been confirmed, rare cases of malignancy (e.g., skin cancer and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Pimecrolimus Cream, 1%.

Additional Adverse Reactions or Important Notes

• Continuous long-term use of Pimecrolimus Cream, 1% should be avoided in any age group, 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.

• The cream should not be used in immunocompromised adults and children, including those on systemic immunosuppressive medications.

• 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.

Pediatric Use

In clinical trials involving pediatric subjects aged 2 to 17 years, the most common local adverse event was application site burning (10% vs. 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%)

• Cough (16% vs. 11%)

In a study of 843 subjects aged 2 to 17 years treated with Pimecrolimus Cream, 1%, 9 subjects (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%)

• Diarrhea (8% vs. 0%)

Additionally, infants on Pimecrolimus Cream, 1% exhibited a greater incidence of some 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%)

• Wheezing (4% vs. 0%)

The majority of adverse events reported were mild to moderate in severity.

Drug Interactions

The potential for drug interactions with Pimecrolimus Cream, 1%, has not been systematically evaluated, particularly concerning immunizations and other medications. While low blood levels of pimecrolimus have been detected in some patients following topical application, systemic drug interactions are generally not expected; however, they cannot be entirely ruled out.

Caution is advised when administering Pimecrolimus Cream concomitantly with known inhibitors of the CYP3A enzyme family, especially in patients with widespread or erythrodermic disease. Examples of such inhibitors include erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers, and cimetidine.

Pediatric Use

Pimecrolimus Cream, 1% is not indicated for use in children less than 2 years of age. The long-term safety and effects of Pimecrolimus Cream, 1% on the developing immune system are unknown.

Efficacy and Safety in Pediatric Patients

Three Phase 3 pediatric trials were conducted involving 1,114 subjects aged 2 to 17 years, of which 542 (49%) were aged 2 to 6 years. In these short-term trials, 11% of subjects did not complete the trials, and 1.5% discontinued due to adverse events. In a one-year trial, 32% of subjects did not complete the trial, with 3% discontinuing due to adverse events. The most common local adverse event reported in pediatric subjects aged 2 to 17 was application site burning (10% vs. 13% in the vehicle group). Among 843 subjects treated with Pimecrolimus Cream, 1%, 9 (0.8%) developed eczema herpeticum.

Two Phase 3 trials were conducted involving 436 infants aged 3 months to 23 months. In a 6-week trial, 11% of Pimecrolimus subjects and 48% of vehicle subjects did not complete the trial; no subjects in either group discontinued due to adverse events. Infants treated with Pimecrolimus Cream, 1% experienced an increased incidence of several adverse events compared to vehicle, including pyrexia (32% vs. 13% vehicle), upper respiratory infections (URI) (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 and 0% of vehicle subjects discontinuing due to adverse events.

Systemic Exposure

The systemic exposure to Pimecrolimus from Pimecrolimus Cream, 1% was investigated in 28 pediatric subjects with atopic dermatitis (20% to 80% body surface area involvement) aged 8 months to 14 years. In a second group of 30 pediatric subjects aged 3 to 23 months with 10% to 92% body surface area involvement, following twice daily application for three weeks, blood concentrations of Pimecrolimus were less than 2.6 ng/mL, with 65% of blood samples having concentrations below 0.5 ng/mL.

Geriatric Use

In clinical trials of Pimecrolimus Cream, 1%, only nine subjects aged 65 years and older were included, which is insufficient to adequately assess the efficacy and safety of the medication in this population. Therefore, caution is advised when prescribing Pimecrolimus to elderly patients, as the available data do not provide a comprehensive understanding of its effects in this age group. Monitoring for potential adverse reactions and considering individual patient factors is recommended when treating geriatric patients with this medication.

Pregnancy

There are no adequate and well-controlled studies with pimecrolimus cream, 1%, in pregnant patients. 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 Pregnancy Category C. In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed at the highest practicable doses tested, which were 10 mg/kg/day in both rats and rabbits (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 period of organogenesis.

A second dermal study in rats, where pimecrolimus cream was applied from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day, also showed no maternal, reproductive, or embryofetal toxicity at the highest dose evaluated. No teratogenicity was noted in this study at any dose.

Oral studies conducted during the period of organogenesis indicated that at doses of 45 mg/kg/day in rats (38X MRHD based on AUC comparisons), 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, embryotoxicity, or teratogenicity were observed at the highest dose of 20 mg/kg/day (3.9X MRHD based on AUC comparisons).

Further oral studies in rats and rabbits revealed maternal toxicity, embryolethality, and fetotoxicity at higher doses (45 mg/kg/day in rats and 20 mg/kg/day in rabbits), with slight increases in skeletal variations indicative of delayed skeletal ossification. However, no adverse effects were noted at lower doses (10 mg/kg/day in rats and 6 mg/kg/day in rabbits).

An oral peri- and postnatal developmental study in rats indicated that only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day, 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 providers should carefully consider the risks and benefits when prescribing pimecrolimus to pregnant patients.

Lactation

It is not known whether pimecrolimus is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider whether to discontinue nursing or to discontinue the drug, weighing the importance of the medication to the lactating mother.

Renal Impairment

Patients with renal impairment do not have specific dosage adjustments, monitoring requirements, or safety considerations outlined for the use of Pimecrolimus cream. The available data does not provide guidance on the use of this medication in individuals with reduced kidney function. Therefore, healthcare professionals should exercise clinical judgment when prescribing Pimecrolimus to patients with renal impairment, as the lack of information necessitates careful consideration of individual patient circumstances.

Hepatic Impairment

Patients with hepatic impairment do not have specific dosage adjustments, special monitoring requirements, or precautions outlined for the use of Pimecrolimus cream. The available data does not provide any information regarding the impact of hepatic function on the pharmacokinetics or safety of this medication. Therefore, standard dosing may be considered for patients with liver problems, but clinical judgment should be exercised.

Overdosage

In the event of an overdose with Pimecrolimus cream, there is currently no specific information available regarding the symptoms or management of such an occurrence. Given the absence of detailed overdosage data, it is recommended that healthcare professionals monitor the patient for any unusual reactions or symptoms following excessive application of the cream.

In the case of suspected overdose, it is advisable to discontinue use of the product and provide supportive care as needed. Consultation with a medical professional or poison control center may be warranted to determine the appropriate course of action.

Nonclinical Toxicology

Teratogenic Effects

Pimecrolimus Cream, 1% has not been evaluated in adequate and well-controlled studies in pregnant women. Therefore, its use during pregnancy should be considered only if the potential benefit justifies the potential risk to the fetus. In dermal embryofetal developmental studies conducted in rats and rabbits, no maternal or fetal toxicity was observed at doses up to 10 mg/kg/day, with no teratogenic effects noted at any dose. However, indicators of embryofetal toxicity, such as post-implantation loss and reduced litter size, were observed at 45 mg/kg/day in rats. Maternal toxicity, embryolethality, and fetotoxicity were also noted at this higher dose. In oral fertility and embryofetal developmental studies in rats, estrus cycle disturbances, reduced testicular and epididymal weights, and decreased viable fetuses were observed at 45 mg/kg/day, while no effects on fertility were noted at lower doses.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year dermal carcinogenicity study in rats, a statistically significant increase in the incidence of follicular cell adenoma of the thyroid was observed in male animals across all dose groups. Conversely, no increase in thyroid adenomas was noted in an oral carcinogenicity study at doses up to 10 mg/kg/day. In a mouse dermal carcinogenicity study, no neoplasms were observed at doses up to 4 mg/kg/day; however, lymphoproliferative changes, including lymphoma, were noted in a 13-week repeat dose study at 25 mg/kg/day. A significant increase in lymphoma incidence was also observed in a mouse oral carcinogenicity study at 45 mg/kg/day. In an oral rat carcinogenicity study, a significant increase in benign thymoma was noted at 10 mg/kg/day.

A comprehensive battery of in vitro genotoxicity tests, including the Ames assay and mouse lymphoma assays, demonstrated no evidence of mutagenic or clastogenic potential for pimecrolimus.

Animal Toxicology

A 39-week oral toxicology study in monkeys revealed a dose-dependent increase in immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus, mirroring conditions observed in human transplant patients undergoing chronic immunosuppressive therapy. A no observed adverse effect level (NOAEL) for IRLD was not established, with IRLD occurring at the lowest dose of 15 mg/kg/day. A partial recovery from IRLD was noted upon cessation of dosing.

In summary, while pimecrolimus exhibits no significant teratogenic effects at tested doses, it has been associated with various non-teratogenic effects, including potential carcinogenicity and fertility impairment at higher doses in animal studies.

Storage and Handling

Pimecrolimus is supplied in a cream formulation. 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 important to ensure that the product does not freeze during storage.