Protopic Information
Protopic (Tacrolimus) Description
Protopic (Tacrolimus) Ointment contains tacrolimus, a macrolide immunosuppressant produced by . It is for topical dermatologic use only. Chemically, tacrolimus is designated as [3-[3*[(1*,3*,4*)],4*,5*,8*,9,12*,14*,15*,16*,18*,19*,26a*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10, 12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,monohydrate. It has the following structural formula:
Tacrolimus has an empirical formula of CHNO•HO and a formula weight of 822.03. Each gram of Protopic (Tacrolimus) Ointment contains (w/w) either 0.03% or 0.1% of tacrolimus in a base of mineral oil, paraffin, propylene carbonate, white petrolatum and white wax.
Protopic (Tacrolimus)
Protopic (Tacrolimus) Indications And Usage
Protopic (Tacrolimus) Ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2 to 15 years, is indicated as for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.
Protopic (Tacrolimus) Contraindications
Protopic (Tacrolimus) Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.
Protopic (Tacrolimus) 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 Protopic (Tacrolimus) Ointment.
Therefore:
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 the information above and the mechanism of action, there is a concern about potential risk with the use of topical calcineurin inhibitors, including Protopic (Tacrolimus) Ointment. 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 Protopic (Tacrolimus) Ointment. Therefore:
(See , boxed , and ).
Protopic (Tacrolimus) Precautions
The use of Protopic (Tacrolimus) Ointment should be avoided on pre-malignant and malignant skin conditions. Some malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), may mimic atopic dermatitis.
The use of tacrolimus ointment is not recommended in patients having skin conditions with a skin barrier defect where there is the potential for increased systemic absorption of tacrolimus, including but not limited to, Netherton's syndrome, lamellar ichthyosis, generalized erthroderma or cutaneous Graft Versus Host Disease. Oral application is also not recommended. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.
The use of Protopic (Tacrolimus) Ointment 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 Protopic (Tacrolimus) Ointment application and typically improve as the lesions of atopic dermatitis resolve. With Protopic (Tacrolimus) Ointment 0.1%, 90% of the skin burning events had a duration between 2 minutes and 3 hours (median 15 minutes). 90% of the pruritus events had a duration between 3 minutes and 10 hours (median 20 minutes) (see ).
Before commencing treatment with Protopic (Tacrolimus) Ointment, cutaneous bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of Protopic (Tacrolimus) Ointment 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 Protopic (Tacrolimus) Ointment may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum.
(See )
Patients using Protopic (Tacrolimus) Ointment should receive and understand the information in the Medication Guide. Please refer to the Medication Guide for providing instruction and information to the patient.
What is the most important information patients should know about Protopic (Tacrolimus) Ointment?
The safety of using Protopic (Tacrolimus) Ointment for a long period of time is not known. A very small number of people who have used Protopic (Tacrolimus) Ointment have had cancer (for example, skin or lymphoma). However, a link with Protopic (Tacrolimus) Ointment has not been shown. Because of this concern, instruct patients:
Protopic (Tacrolimus) Ointment comes in two strengths:
Advise patients to talk to their prescriber for more information.
How should Protopic (Tacrolimus) Ointment be used?
Advise patients to:
To apply Protopic (Tacrolimus) Ointment:
Advise patients:
What should patients avoid while using Protopic (Tacrolimus) Ointment?
Advise patients:
No evidence of genotoxicity was seen in bacterial (and ) or mammalian (Chinese hamster lung-derived cells) assays of mutagenicity, the CHO/HGPRT assay of mutagenicity, or clastogenicity assays performed in mice. Tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.
Oral (feed) carcinogenicity studies have been carried out with systemically administered tacrolimus in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found at daily doses up to 3 mg/kg [9X the Maximum Recommended Human Dose (MRHD) based on AUC comparisons] and 5 mg/kg (3X the MRHD based on AUC comparisons), respectively.
A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment) (26X MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment) (10X MRHD based on AUC comparisons).
In a 52-week photocarcinogenicity 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 tacrolimus ointment at ≥0.1% tacrolimus.
Reproductive toxicology studies were not performed with topical tacrolimus. In studies of oral tacrolimus no impairment of fertility was seen in male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.12X MRHD based on body surface area [BSA]) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (0.43X MRHD based on BSA), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
Protopic (Tacrolimus) Ointment is not indicated for children less than 2 years of age.
Only the lower concentration, 0.03%, of Protopic (Tacrolimus) Ointment is recommended for use as a for short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised children 2 to 15 years of age who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.
The long-term safety and effects of Protopic (Tacrolimus) Ointment on the developing immune system are unknown (see boxed , and ).
Four studies were conducted involving a total of about 4,400 patients 2-15 years of age: one 12-week randomized vehicle-controlled study and three open-label safety studies of one to three years duration. About 2,500 of these patients were 2 to 6 years of age.
The most common adverse events from these studies associated with Protopic (Tacrolimus) Ointment application in pediatric patients were skin burning and pruritus (see ). In addition to skin burning and pruritus, the less common events (
In an open-label study, immune response to a 23-valent pneumococcal polysaccharide vaccine was assessed in 23 children 2 to 12 years old with moderate to severe atopic dermatitis treated with tacrolimus ointment 0.03%. Protective antibody titers developed in all patients. Similarly, in a seven-month, double-blind trial, the vaccination response to meningococcal serogroup C was equivalent in children 2 to 11 years old with moderate to severe atopic dermatitis treated with tacrolimus ointment 0.03% (n=121), a hydrocortisone ointment regimen (n=111), or normal children (n=44).
Protopic (Tacrolimus) Adverse Reactions
No phototoxicity and no photoallergenicity were detected in clinical studies with 12 and 216 normal volunteers, respectively. One out of 198 normal volunteers showed evidence of sensitization in a contact sensitization study.
In three 12 week randomized vehicle-controlled studies and four safety studies, 655 and 9,163 patients respectively, were treated with Protopic (Tacrolimus) Ointment. The duration of follow-up for adult and pediatric patients in the safety studies is tabulated below.
The following table depicts the adjusted incidence of adverse events pooled across the 3 identically designed 12-week controlled studies for patients in vehicle, Protopic (Tacrolimus) Ointment 0.03%, and Protopic (Tacrolimus) Ointment 0.1% treatment groups. The table also depicts the unadjusted incidence of adverse events in four safety studies, regardless of relationship to study drug.
Other adverse events which occurred at an incidence between 0.2% and less than 1% in clinical studies in the above table include: abnormal vision, abscess, anaphylactoid reaction, anemia, anorexia, anxiety, arthritis, arthrosis, bilirubinemia, blepharitis, bone disorder, breast neoplasm benign, bursitis, cataract NOS, chest pain, chills, colitis, conjunctival edema, constipation, cramps, cutaneous moniliasis, cystitis, dehydration, dizziness, dry eyes, dry mouth/nose, dyspnea, ear disorder, ecchymosis, edema, epistaxis, eye pain, furunculosis, gastritis, gastrointestinal disorder, hernia, hypercholesterolemia, hypertonia, hypothyroidism, joint disorder, laryngitis, leukoderma, lung disorder, malaise, migraine, moniliasis, mouth ulceration, nail disorder, neck pain, neoplasm benign, oral moniliasis, otitis externa, photosensitivity reaction, rectal disorder, seborrhea, skin carcinoma, skin discoloration, skin hypertrophy, skin ulcer, stomatitis, tendon disorder, thinking abnormal, tooth caries, sweating, syncope, tachycardia, taste perversion, unintended pregnancy, vaginal moniliasis, vaginitis, valvular heart disease, vasodilatation, and vertigo.
Protopic (Tacrolimus) Dosage And Administration
Protopic (Tacrolimus) Ointment 0.03% and 0.1%
The safety of Protopic (Tacrolimus) Ointment under occlusion, which may promote systemic exposure, has not been evaluated. Protopic (Tacrolimus) Ointment should not be used with occlusive dressings.
Protopic (Tacrolimus) Ointment 0.03%
The safety of Protopic (Tacrolimus) Ointment under occlusion, which may promote systemic exposure, has not been evaluated. Protopic (Tacrolimus) Ointment should not be used with occlusive dressings.
Protopic (Tacrolimus) How Supplied
NDC 0469-5201-30 Product Code 520130
30 gram laminate tube
NDC 0469-5201-60 Product Code 520160
60 gram laminate tube
NDC 0469-5201-11 Product Code 520111
100 gram laminate tube
NDC 0469-5202-30 Product Code 520230
30 gram laminate tube
NDC 0469-5202-60 Product Code 520260
60 gram laminate tube
NDC 0469-5202-11 Product Code 520211
100 gram laminate tube
Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
Astellas Pharma US, Inc.
Deerfield, IL 60015-2548
Astellas Pharma Tech Co., Ltd., Toyama Technology Center, 2-178 Kojin-machi, Toyama city, Toyama 930-0809, Japan
Revised: November 2011
11J082-PRT-SPL
Protopic (Tacrolimus)
Protopic (Tacrolimus) Principal Display Panel
Protopic (Tacrolimus) Principal Display Panel
