Protopic: Package Insert and Label Information (Page 2 of 3)

PRECAUTIONS

General

The use of PROTOPIC 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 PROTOPIC Ointment in patients with Netherton’s Syndrome or other skin diseases where there is the potential for increased systemic absorption of tacrolimus is not recommended. The safety of PROTOPIC Ointment has not been established in patients with generalized erythroderma.

The use of PROTOPIC 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 Ointment application and typically improve as the lesions of atopic dermatitis resolve. With PROTOPIC 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 ADVERSE REACTIONS).

Bacterial and Viral Skin Infections

Before commencing treatment with PROTOPIC Ointment, cutaneous bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of PROTOPIC 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 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.

Patients with Lymphadenopathy

In clinical studies, 112/13494 (0.8%) cases of lymphadenopathy were reported and were usually related to infections (particularly of the skin) and noted to resolve upon appropriate antibiotic therapy. Of these 112 cases, the majority had either a clear etiology or were known to resolve. Transplant patients receiving immunosuppressive regimens (e.g., systemic tacrolimus) are at increased risk for developing lymphoma; therefore, patients who receive PROTOPIC Ointment 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, PROTOPIC Ointment should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Sun Exposure

During the course of treatment, patients should minimize or avoid natural or artificial sunlight exposure, even while PROTOPIC is not on the skin. It is not known whether PROTOPIC Ointment interferes with skin response to ultraviolet damage.

Immunocompromised Patients

The safety and efficacy of PROTOPIC Ointment in immunocompromised patients have not been studied.

Renal Insufficiency

Rare post-marketing cases of acute renal failure have been reported in patients treated with PROTOPIC Ointment. Systemic absorption is more likely to occur in patients with epidermal barrier defects especially when PROTOPIC is applied to large body surface areas. Caution should also be exercised in patients predisposed to renal impairment.

Information for Patients

(See Medication Guide)

Patients using PROTOPIC 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 Ointment?

The safety of using PROTOPIC Ointment for a long period of time is not known. A very small number of people who have used PROTOPIC Ointment have had cancer (for example, skin or lymphoma). However, a link with PROTOPIC Ointment has not been shown. Because of this concern, instruct patients:

  • Do not use PROTOPIC Ointment continuously for a long time.
  • Use PROTOPIC Ointment only on areas of skin that have eczema.
  • Do not use PROTOPIC Ointment on a child under 2 years old.

PROTOPIC Ointment comes in two strengths:

  • Only PROTOPIC Ointment 0.03% is for use on children aged 2 to 15 years.
  • Either PROTOPIC Ointment 0.03% or 0.1% can be used by adults and children 16 years and older.

Advise patients to talk to their prescriber for more information.

How should PROTOPIC Ointment be used?

Advise patients to:

  • Use PROTOPIC Ointment exactly as prescribed.
  • Use PROTOPIC Ointment only on areas of skin that have eczema.
  • Use PROTOPIC Ointment for short periods, and if needed, treatment may be repeated with breaks in between.
  • Stop PROTOPIC Ointment when the signs and symptoms of eczema, such as itching, rash, and redness go away, or as directed.
  • Follow their doctor’s advice if symptoms of eczema return after treatment with PROTOPIC Ointment.
  • Call their doctor if:
    • Their symptoms get worse with PROTOPIC Ointment.
    • They get an infection on their skin.
    • Their symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema.

To apply PROTOPIC Ointment:

Advise patients:

  • Wash their hands before applying PROTOPIC.
  • Apply a thin layer of PROTOPIC Ointment twice daily to the areas of skin affected by eczema.
  • Use the smallest amount of PROTOPIC Ointment needed to control the signs and symptoms of eczema.
  • If they are a caregiver applying PROTOPIC Ointment to a patient, or if they are a patient who is not treating their hands, wash their hands with soap and water after applying PROTOPIC. This should remove any ointment left on the hands.
  • Do not bathe, shower, or swim right after applying PROTOPIC. This could wash off the ointment.
  • Moisturizers can be used with PROTOPIC Ointment. Make sure they check with their doctor first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If they use moisturizers, apply them after PROTOPIC Ointment.

What should patients avoid while using PROTOPIC Ointment?

Advise patients:

  • Do not use ultraviolet light therapy, sun lamps, or tanning beds during treatment with PROTOPIC Ointment.
  • Limit sun exposure during treatment with PROTOPIC Ointment even when the medicine is not on their skin. If patients need to be outdoors after applying PROTOPIC Ointment, wear loose fitting clothing that protects the treated area from the sun. Doctors should advise what other types of protection from the sun patients should use.
  • Do not cover the skin being treated with bandages, dressings or wraps. Patients can wear normal clothing.
  • Avoid getting PROTOPIC Ointment in the eyes or mouth. Do not swallow PROTOPIC Ointment. Patients should call their doctor if they swallow PROTOPIC Ointment.
Drug Interactions

Formal topical drug interaction studies with PROTOPIC Ointment have not been conducted. Based on its extent of absorption, interactions of PROTOPIC Ointment with systemically administered drugs are unlikely to occur but cannot be ruled out (see CLINICAL PHARMACOLOGY). The concomitant administration of known CYP3A4 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

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo 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/m2 /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.

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women. The experience with PROTOPIC Ointment when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

Reproduction studies were carried out with systemically administered tacrolimus in rats and rabbits. Adverse effects on the fetus were observed mainly at oral dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.04X-0.12X MRHD based on BSA) during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (0.04X-0.12X MRHD based on BSA) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

No reduction in male or female fertility was evident.

There are no adequate and well-controlled studies of systemically administered tacrolimus in pregnant women. Tacrolimus is transferred across the placenta. The use of systemically administered tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. PROTOPIC Ointment should be used during pregnancy only if the potential benefit to the mother justifies a potential risk to the fetus.

Nursing Mothers

Although systemic absorption of tacrolimus following topical applications of PROTOPIC Ointment is minimal relative to systemic administration, it is known that tacrolimus is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tacrolimus, 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

PROTOPIC Ointment is not indicated for children less than 2 years of age.

Only the lower concentration, 0.03%, of PROTOPIC Ointment is recommended for use as a second-line therapy 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 Ointment on the developing immune system are unknown (see boxed WARNING , WARNINGS and INDICATIONS and USAGE).

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 Ointment application in pediatric patients were skin burning and pruritus (see ADVERSE REACTIONS). In addition to skin burning and pruritus, the less common events (less than 5%) of varicella zoster (mostly chicken pox), and vesiculobullous rash were more frequent in patients treated with PROTOPIC Ointment 0.03% compared to vehicle. In the open-label safety studies, the incidence of adverse events, including infections, did not increase with increased duration of study drug exposure or amount of ointment used. In about 4,400 pediatric patients treated with PROTOPIC Ointment, 24 (0.5%) were reported with eczema herpeticum. Since the safety and efficacy of PROTOPIC Ointment have not been established in pediatric patients below 2 years of age, its use in this age group is not recommended.

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).

Geriatric Use

Four hundred and four (404) patients ≥ 65 years old received PROTOPIC Ointment in phase 3 studies. The adverse event profile for these patients was consistent with that for other adult patients.

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 Ointment. The duration of follow-up for adult and pediatric patients in the safety studies is tabulated below.

Duration of Follow-up in Four Open-label Safety Studies
Time on Study Adult Pediatrics Total
less than 1 year468244819163
greater than or equal to 1 year118513492534
greater than or equal to 2 years200275475
greater than or equal to 3 years118182300

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 Ointment 0.03%, and PROTOPIC 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.

Incidence of Treatment Emergent Adverse Events
12-Week, Randomized, Double-Blink, Phase 3 Studies Open-Label Studies (up to 3 years) 0.1% and 0.03% Tacrolimus 12-Week Adjusted Incidence Rate (%) Ointment Incidence Rate (%)
Adult Pediatric Adult Pediatric Total
Vehicle(n=212)%0.03%TacrolimusOintment(n=210)%0.1%TacrolimusOintment(n=209)%Vehicle(n=116)%0.03%TacrolimusOintment(n=118)%(n-4682)%(n=4481)%(n=9163)%
Skin Burning*2646582943282024
Pruritus*3746462741251922
Flue-likesymptoms*1923312528223428
Allergic Reaction81268491311
Skin Erythema20252813121279
Headache*1120198513911
Skin Infection11125141091612
Fever44113212148
Infection112976108
Cough Increased21114183106
Asthma464664138
Herpes Simplex44420433
EczemaHerpeticum01102000
Pharyngitis3341164128
Accidental Injury43636687
Pustular Rash23432275
Folliculitis*16402423
Rhinitis43226243
Otis Media4016122116
Sinusitis*14283676
Diarrhea33425243
Urticaria33611344
Lack of DrugEffect11011666
Bronchitis02233444
Vomiting01176143
MaculopapularRash22230211
Rash*15242233
Abdominal Pain31123132
Fungal Dermatitis02130243
Gastroentesritis12230243
AlcoholIntolerance*03700402
Acne*24710323
Sunburn12100211
Skin Disorder22114222
Conjunctivitis02221333
Pain12101212
VesiculobullousRash*33204211
Lymphadenopathy22103121
Nausea43201212
Skin Tingling*23812211
Face Edema22121111
Dyspepsia*11400222
Dry Skin73301111
Hypersthesia*13700201
Skin NeoplasmBenign †11100122
Back Pain*02211302
Peripheral Edema24300201
Varicella Zoster/HerpesZoster *‡01005122
Contact Dermatitis13334222
Asthena12300101
Pneumonia01120132
Eczema22200101
Insomnia34311201
Exfoliative Dermatitis33100010
Dysmenorrhea24400211
PeriodontalAbscess10100111
Myalgia*03200211
Cyst*01300101
Cellulitis11100111
Exacerbation ofUntreated Area10110111
ProceduralComplication10010111
Hypertension00100201
Tooth Disorder01110211
Arthralgia11320212
Depression12100101
Paresthesia13300212
Alopecia01100111
Urinary Tract Infection00100212
Ear Pain10101011

† Generally “warts”.
‡ All the herpes zoster cases in the pediatric 12-week study and the majority of cases in the open-label pediatric studies were reported as chicken pox.

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.

Post-Marketing Events

The following adverse reactions have been identified during postapproval use of PROTOPIC Ointment. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CNS

Seizures

Neoplasms

Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma

Infections

Bullous impetigo, osteomyelitis, septicemia

Renal

Acute renal failure in patients with or without Netherton’s syndrome, renal impairment

Skin

Rosacea

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