WARNINGS
WARNING
Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established
Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including ELIDEL Cream.
Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including ELIDEL Cream, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.
- ELIDEL Cream is not indicated for use in children less than 2 years of age.
Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression.
Based on this information and the mechanism of action, there is a concern about a potential risk with the use of topical calcineurin inhibitors, including ELIDEL Cream. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including ELIDEL Cream. Therefore:
- ELIDEL Cream should not be used in immunocompromised adults and children.
- If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed (see PRECAUTIONS).
- The safety of ELIDEL Cream has not been established beyond one year of non-continuous use.
(See CLINICAL PHARMACOLOGY, WARNINGS, boxed WARNING, PRECAUTIONS, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION .)
PRECAUTIONS
General
The use of ELIDEL Cream should be avoided on malignant or pre-malignant skin conditions. Malignant or pre-malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis.
ELIDEL Cream should not be used in patients with Netherton’s Syndrome or other skin diseases where there is the potential for increased systemic absorption of pimecrolimus . The safety of ELIDEL Cream has not been established in patients with generalized erythroderma.
The use of ELIDEL Cream may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of ELIDEL Cream application and typically improve as the lesions of atopic dermatitis resolve (see ADVERSE REACTIONS).
Bacterial and Viral Skin Infections: Before commencing treatment with ELIDEL Cream, bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of ELIDEL Cream in the treatment of clinically infected atopic dermatitis.
While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi’s varicelliform eruption), treatment with ELIDEL Cream may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum.
In clinical studies, 15/1,544 (1%) cases of skin papilloma (warts) were observed in patients using ELIDEL Cream. The youngest patient was age 2 and the oldest was age 12. In cases where there is worsening of skin papillomas or they do not respond to conventional therapy, discontinuation of ELIDEL Cream should be considered until complete resolution of the warts is achieved.
Patients with L ymphadenopathy: In clinical studies, 14/1,544 (0.9%) cases of lymphadenopathy were reported while using ELIDEL Cream. These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear etiology or were known to resolve. Patients who receive ELIDEL Cream and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, ELIDEL Cream should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
Sun Exposure: During the course of treatment, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure, even while ELIDEL is not on the skin. The potential effects of ELIDEL Cream on skin response to ultraviolet damage are not known.
Immunocompromised Patients: The safety and efficacy of ELIDEL Cream in immunocompromised patients have not been studied.
Information for Patients
(See Medication Guide . )
Patients using ELIDEL Cream should receive the following information and instructions:
What is the most important information a patient should know about ELIDEL Cream?
The safety of using ELIDEL Cream for a long period of time is not known. A very small number of people who have used ELIDEL Cream have had cancer (for example, skin or lymphoma). However, a link with ELIDEL Cream use has not been shown. Because of this concern:
- A patient should not use ELIDEL Cream continuously for a long time.
- ELIDEL Cream should be used only on areas of skin that have eczema.
- ELIDEL Cream is not for use on a child under 2 years old.
How should a patient use ELIDEL Cream?
- A patient should use ELIDEL Cream exactly as prescribed.
- A patient should use ELIDEL Cream only on areas of skin that have eczema.
- A patient should use ELIDEL Cream for short periods, and if needed, treatment may be repeated with breaks in between.
- A patient should stop ELIDEL Cream when the signs and symptoms of eczema, such as itching, rash, and redness go away, or as directed by the physician.
- A patient should follow the physician’s advice if symptoms of eczema return after a treatment with ELIDEL Cream.
- A patient should contact the physician if:
- symptoms get worse with ELIDEL Cream
- the patient gets a skin infection
- symptoms do not improve after 6 weeks of treatment
To apply ELIDEL Cream:
- A patient or caregiver should wash their hands before using ELIDEL Cream. When applying ELIDEL Cream after a bath or shower, the skin should be dry.
- A patient or caregiver should apply a thin layer of ELIDEL Cream only to the affected skin areas, twice a day, as directed by the physician.
- A patient or caregiver should use the smallest amount of ELIDEL Cream needed to control the signs and symptoms of eczema.
- Caregivers applying ELIDEL Cream to a patient, or a patient who is not treating the hands should wash their hands with soap and water after applying ELIDEL Cream. This should remove any cream left on the hands.
- A patient should not bathe, shower or swim right after applying ELIDEL Cream. This could wash off the cream.
- A patient can use moisturizers with ELIDEL Cream. They should be sure to check with the physician first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important they keep up good skin care practices. If a patient uses moisturizers, he or she should apply them after ELIDEL Cream.
What should a patient avoid while using ELIDEL Cream?
- A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet light therapy during treatment with ELIDEL Cream.
- A patient should limit sun exposure during treatment with ELIDEL Cream even when the medicine is not on the skin. If a patient needs to be outdoors after applying ELIDEL Cream, the patient should wear loose fitting clothing that protects the treated area from the sun. The physician should advise the patient about other types of protection from the sun.
- A patient should not cover the skin being treated with bandages, dressings or wraps. A patient can wear normal clothing.
- A patient should not use ELIDEL Cream in the eyes. If ELIDEL Cream gets in the eyes, a patient should rinse them with cold water.
- A patient should not swallow ELIDEL Cream and should contact the physician if they do.
Drug Interactions
Potential interactions between ELIDEL and other drugs, including immunizations, have not been systematically evaluated. Due to low blood levels of pimecrolimus detected in some patients after topical application, systemic drug interactions are not expected, but cannot be ruled out. The concomitant administration of known CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year rat dermal carcinogenicity study using ELIDEL Cream, 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 control male animals. Follicular cell adenoma of the thyroid was noted in the dermal rat carcinogenicity study at the lowest dose of 2 mg/kg/day [0.2% pimecrolimus cream; 1.5X the Maximum Recommended Human Dose (MRHD) based on AUC comparisons]. No increase in the incidence of follicular cell adenoma of the thyroid was noted in the oral carcinogenicity study in male rats up to 10 mg/kg/day (66X MRHD based on AUC comparisons). However, oral studies may not reflect continuous exposure or the same metabolic profile as by the dermal route. In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed in the skin or other organs up to the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27X MRHD based on AUC comparisons. However, lymphoproliferative changes (including lymphoma) were noted in a 13 week repeat dose dermal toxicity study conducted in mice using pimecrolimus in an ethanolic solution at a dose of 25 mg/kg/day (47X MRHD based on AUC comparisons). No lymphoproliferative changes were noted in this study at a dose of 10 mg/kg/day (17X MRHD based on AUC comparison). 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/kg/day (179-217X MRHD based on AUC comparisons).
In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in the incidence of lymphoma was noted in high dose male and female animals compared to vehicle control male and female animals. Lymphomas were noted in the oral mouse carcinogenicity study at a dose of 45 mg/kg/day (258-340X MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse oral carcinogenicity study at a dose of 15 mg/kg/day (60-133X MRHD based on AUC comparisons). In an oral (gavage) rat carcinogenicity study, a statistically significant increase in the incidence of benign thymoma was noted in 10 mg/kg/day pimecrolimus treated male and female animals compared to vehicle control treated male and female animals. In addition, a significant increase in the incidence of benign thymoma was noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day pimecrolimus treated male animals compared to vehicle control treated male animals. No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1 mg/kg/day male animals (1.1X MRHD based on AUC comparisons) and at a dose of 5 mg/kg/day for female animals (21X MRHD based on AUC comparisons).
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 (40 weeks of treatment followed by 12 weeks of observation) with the ELIDEL Cream vehicle 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.
A 39-week oral monkey toxicology study was conducted with pimecrolimus doses of 15, 45 and 120 mg/kg/day. A dose dependent increase in expression of immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus (a monkey strain of virus related to human Epstein Barr virus) was observed. IRLD in monkeys mirrors what has been noted in human transplant patients after chronic systemic immunosuppressive therapy, post transplantation lymphoproliferative disease (PTLD), after treatment with chronic systemic immunosuppressive therapy. Both IRLD and PTLD can progress to lymphoma, which is dependent on the dose and duration of systemic immunosuppressive therapy. A dose dependent increase in opportunistic infections (a signal of systemic immunosuppression) was also noted in this monkey study. A no observed adverse effect level (NOAEL) for IRLD and opportunistic infections was not established in this study. IRLD occurred at the lowest dose of 15 mg/kg/day for 39 weeks [31X the Maximum Recommended Human Dose (MRHD) of ELIDEL Cream based on AUC comparisons] in this study. A partial recovery from IRLD was noted upon cessation of dosing in this study.
A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test revealed no evidence for a mutagenic or clastogenic potential for the drug.
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/kg/day dose (38X MRHD based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (12X MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 45 mg/kg/day (23X MRHD based on AUC comparisons), which was the highest dose tested in this study.
A second oral fertility and embryofetal developmental study in rats revealed reduced testicular and epididymal weights, reduced testicular sperm counts and motile sperm for males and estrus cycle disturbances, decreased corpora lutea, decreased implantations and viable fetuses for females at 45 mg/kg/day dose (123X MRHD for males and 192X MRHD for females based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (5X MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 2 mg/kg/day (0.7X MRHD based on AUC comparisons).
Pregnancy
Teratogenic Effects: Pregnancy Category C
There are no adequate and well-controlled studies of topically administered pimecrolimus in pregnant women. The experience with ELIDEL Cream when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.
In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14X MRHD based on body surface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65X MRHD based on AUC comparisons). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits).
A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately 22 hours. 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 in this study. No teratogenicity was noted in this study at any dose.
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 (2 weeks prior to mating until gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45 mg/kg/day in rats and 20 mg/kg/day in rabbits. In the absence of maternal toxicity, indicators of embryofetal toxicity (post-implantation loss and reduction in litter size) were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9X MRHD based on AUC comparisons), which was the highest dose tested in this study.
A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days 6 – 17) at doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity were noted at 45 mg/kg/day (271X MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryolethality or fetotoxicity were noted at 10 mg/kg/day (16X MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.
A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (gestational days 7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12X MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/day (5X MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.
An oral peri- and post-natal developmental study was conducted in rats. Pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg/kg/day. Only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg/kg/day (12X MRHD based on AUC comparisons), the highest dose evaluated in this study.
Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pimecrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
ELIDEL Cream is not indicated for use in children less than 2 years of age.
The long-term safety and effects of ELIDEL Cream on the developing immune system are unknown (see WARNINGS , boxed WARNING , and INDICATIONS AND USAGE).
Three Phase 3 pediatric studies were conducted involving 1,114 patients 2-17 years of age. Two studies were 6-week randomized vehicle-controlled studies with a 20-week open-label phase and one was a vehicle-controlled (up to 1 year) safety study with the option for sequential topical corticosteroid use. Of these patients 542 (49%) were 2-6 years of age. In the short-term studies, 11% of ELIDEL patients did not complete these studies and 1.5% of ELIDEL patients discontinued due to adverse events. In the one-year study, 32% of ELIDEL patients did not complete this study and 3% of ELIDEL patients discontinued due to adverse events. Most discontinuations were due to unsatisfactory therapeutic effect.
The most common local adverse event in the short-term studies of ELIDEL Cream in pediatric patients ages 2-17 was application site burning (10% vs. 13% vehicle); the incidence in the long-term study was 9% ELIDEL vs. 7% vehicle (see ADVERSE REACTIONS). Adverse events that were more frequent (>5%) in patients treated with ELIDEL Cream compared to vehicle were headache (14% vs. 9%) in the short-term trial. 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%), and headache (25% vs. 16%) were increased over vehicle in the 1-year safety study (see ADVERSE REACTIONS). In 843 patients ages 2-17 years treated with ELIDEL Cream, 9 (0.8%) developed eczema herpeticum (5 on ELIDEL Cream alone and 4 on ELIDEL Cream used in sequence with corticosteroids). In 211 patients on vehicle alone, there were no cases of eczema herpeticum. The majority of adverse events were mild to moderate in severity.
Two Phase 3 studies were conducted involving 436 infants age 3 months-23 months. One 6-week randomized vehicle-controlled study with a 20-week open-label phase and one safety study, up to one year, were conducted. In the 6-week study, 11% of ELIDEL and 48% of vehicle patients did not complete this study; no patient in either group discontinued due to adverse events. Infants on ELIDEL Cream had an increased incidence of some adverse events compared to vehicle. In the 6-week vehicle-controlled study these adverse events included pyrexia (32% vs. 13% vehicle), URI (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). In the open-label phase of the study, for infants who switched to ELIDEL Cream from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those patients who remained on ELIDEL Cream. In the 6 month safety data, 16% of ELIDEL and 35% of vehicle patients discontinued early and 1.5% of ELIDEL and 0% of vehicle patients discontinued due to adverse events. Infants on ELIDEL Cream had a greater incidence of some adverse events as compared to vehicle. These included 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%).
Geriatric Use
Nine (9) patients ≥65 years old received ELIDEL Cream in Phase 3 studies. Clinical studies of ELIDEL did not include sufficient numbers of patients aged 65 and over to assess efficacy and safety.
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