Tacrolimus (Protopic)
برای این دارو، اطلاعات عمومی (فارسی) یافت نشد . برای افزودن اطلاعات فارسی به این دارو کلیک نمایید.
Tacrolimus (Protopic)

PROTOPIC®
(tacrolimus) Ointment 0.03% and Ointment 0.1%

See BOXED WARNING concerning long-term safety of topical calcineurin inhibitors

DRUG DESCRIPTION

PROTOPIC (tacrolimus) Ointment contains tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It is for topical dermatologic use only. Chemically, tacrolimus is designated as [3S[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy3-[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-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,monohydrate. It has the following structural formula:

PROTOPIC® (tacrolimus) Structural Formula Illustration

Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Each gram of PROTOPIC 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.

What are the possible side effects of tacrolimus topical (Protopic)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using tacrolimus and call your doctor at once if you have a serious side effect such as:

  • severe stinging, burning, itching, or soreness where the medicine is applied;
  • swollen glands;
  • redness or crusting around your hair follicles; or
  • signs of a skin infection (redness, swelling, itching, oozing).

Less serious side effects may include:

  • mild burning,...

Read All Potential Side Effects and See Pictures of Protopic »

What are the precautions when taking tacrolimus (Protopic)?

Before using tacrolimus, tell your doctor or pharmacist if you are allergic to it; or to other macrolide medications (e.g., sirolimus, erythromycin, clarithromycin, azithromycin); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: swollen lymph nodes (e.g., lymphadenopathy, mononucleosis), use of light therapy (e.g., UVA or UVB), skin or other cancers.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: skin infections (e.g., herpes, shingles), other skin...

Read All Potential Precautions of Protopic »

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

PROTOPIC Ointment, both 0.03% and 0.1% for adults, and only 0.03% for children aged 2 to 15 years, is indicated as second-line therapy 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 Ointment is not indicated for children younger than 2 years of age (see BOXED WARNING, WARNINGS and PRECAUTIONS: Pediatric Use).

DOSAGE AND ADMINISTRATION

Adult

PROTOPIC Ointment 0.03% and 0.1%
  • Apply a thin layer of PROTOPIC (tacrolimus) Ointment to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve.
  • If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis.
  • Continuous long-term use of topical calcineurin inhibitors, including PROTOPIC Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of PROTOPIC Ointment under occlusion, which may promote systemic exposure, has not been evaluated. PROTOPIC Ointment should not be used with occlusive dressings.

Pediatric – For Children 2-15 Years

PROTOPIC Ointment 0.03%
  • Apply a thin layer of PROTOPIC (tacrolimus) Ointment, 0.03% to the affected skin twice daily. The minimum amount should be rubbed in gently and completely to control signs and symptoms of atopic dermatitis. Stop using when signs and symptoms of atopic dermatitis resolve.
  • If signs and symptoms (e.g. itch, rash, and redness) do not improve within 6 weeks, patients should be re-examined by their healthcare provider to confirm the diagnosis of atopic dermatitis.
  • Continuous long-term use of topical calcineurin inhibitors, including PROTOPIC Ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of PROTOPIC Ointment under occlusion, which may promote systemic exposure, has not been evaluated. PROTOPIC Ointment should not be used with occlusive dressings.

HOW SUPPLIED

PROTOPIC® (tacrolimus) Ointment 0.03%

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

PROTOPIC® (tacrolimus) Ointment 0.1%

NDC 0469-5202-30 Product Code 520230
30 gram laminate tube
NDC 0469-5202-60 Product Code 520260
60 gram laminate tube

Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

Marketed by: Astellas Pharma US, Inc. Deerfield, IL 60015-2548. Manufactured by: Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 9300809, Japan. Revised: 11/2011

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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
< 1 year 4682 4481 9163
≥ 1 year 1185 1349 2534
≥ 2 years 200 275 475
≥ 3 years 118 182 300

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-Blind, Phase 3 Studies
12-Week Adjusted Incidence Rate (%)
Open-Label Studies (up to 3 years) 0.1% and 0.03%
Tacrolimus Ointment Incidence Rate (%)
Adult Pediatric Adult Pediatric Total
Vehicle
(n=212)
%
0.03% Tacrolimus Ointment
(n=210)
%
0.1% Tacrolimus Ointment
(n=209)
%
Vehicle
(n=116)
%
0.03% Tacrolimus Ointment
(n=118)
%
(n=4682)
%
(n=4481)
%
(n=9163)
%
Skin Burning† 26 46 58 29 43 28 20 24
Pruritus† 37 46 46 27 41 25 19 22
Flu-like symptoms† 19 23 31 25 28 22 34 28
Allergic Reaction 8 12 6 8 4 9 13 11
Skin Erythema 20 25 28 13 12 12 7 9
Headache† 11 20 19 8 5 13 9 11
Skin Infection 11 12 5 14 10 9 16 12
Fever 4 4 1 13 21 2 14 8
Infection 1 1 2 9 7 6 10 8
Cough Increased 2 1 1 14 18 3 10 6
Asthma 4 6 4 6 6 4 13 8
Herpes Simplex 4 4 4 2 0 4 3 3
Eczema Herpeticum 0 1 1 0 2 0 0 0
Pharyngitis 3 3 4 11 6 4 12 8
Accidental Injury 4 3 6 3 6 6 8 7
Pustular Rash 2 3 4 3 2 2 7 5
Folliculitis† 1 6 4 0 2 4 2 3
Rhinitis 4 3 2 2 6 2 4 3
Otitis Media 4 0 1 6 12 2 11 6
Sinusitis† 1 4 2 8 3 6 7 6
Diarrhea 3 3 4 2 5 2 4 3
Urticaria 3 3 6 1 1 3 4 4
Lack of Drug Effect 1 1 0 1 1 6 6 6
Bronchitis 0 2 2 3 3 4 4 4
Vomiting 0 1 1 7 6 1 4 3
Maculopapular Rash 2 2 2 3 0 2 1 1
Rash† 1 5 2 4 2 2 3 3
Abdominal Pain 3 1 1 2 3 1 3 2
Fungal Dermatitis 0 2 1 3 0 2 4 3
Gastroenteritis 1 2 2 3 0 2 4 3
Alcohol Intolerance† 0 3 7 0 0 4 0 2
Acne† 2 4 7 1 0 3 2 3
Sunburn 1 2 1 0 0 2 1 1
Skin Disorder 2 2 1 1 4 2 2 2
Conjunctivitis 0 2 2 2 1 3 3 3
Pain 1 2 1 0 1 2 1 2
Vesiculobullous Rash† 3 3 2 0 4 2 1 1
Lymphadenopathy 2 2 1 0 3 1 2 1
Nausea 4 3 2 0 1 2 1 2
Skin Tingling† 2 3 8 1 2 2 1 1
Face Edema 2 2 1 2 1 1 1 1
Dyspepsia† 1 1 4 0 0 2 2 2
Dry Skin 7 3 3 0 1 1 1 1
Hyperesthesia† 1 3 7 0 0 2 0 1
Skin Neoplasm Benign‡‡ 1 1 1 0 0 1 2 2
Back Pain† 0 2 2 1 1 3 0 2
Peripheral Edema 2 4 3 0 0 2 0 1
Varicella Zoster/Herpes Zoster† ‡ 0 1 0 0 5 1 2 2
Contact Dermatitis 1 3 3 3 4 2 2 2
Asthenia 1 2 3 0 0 1 0 1
Pneumonia 0 1 1 2 0 1 3 2
Eczema 2 2 2 0 0 1 0 1
Insomnia 3 4 3 1 1 2 0 1
Exfoliative Dermatitis 3 3 1 0 0 0 1 0
Dysmenorrhea 2 4 4 0 0 2 1 1
Periodontal Abscess 1 0 1 0 0 1 1 1
Myalgia† 0 3 2 0 0 2 1 1
Cyst† 0 1 3 0 0 1 0 1
Cellulitis 1 1 1 0 0 1 1 1
Exacerbation of Untreated Area 1 0 1 1 0 1 1 1
Procedural Complication 1 0 0 1 0 1 1 1
Hypertension 0 0 1 0 0 2 0 1
Tooth Disorder 0 1 1 1 0 2 1 1
Arthralgia 1 1 3 2 0 2 1 2
Depression 1 2 1 0 0 1 0 1
Paresthesia 1 3 3 0 0 2 1 2
Alopecia 0 1 1 0 0 1 1 1
Urinary Tract Infection 0 0 1 0 0 2 1 2
Ear Pain 1 0 1 0 1 0 1 1
† May be reasonably associated with the use of this drug product
‡ 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.
‡‡ Generally “warts”.

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

Infections

Bullous impetigo, osteomyelitis, septicemia

Neoplasms

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

Renal

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

Skin

Rosacea, application site edema

Read the Protopic (tacrolimus) Side Effects Center for a complete guide to possible side effects »

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.

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

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 Ointment.

Therefore:

  • Continuous long-term use of topical calcineurin inhibitors, including PROTOPIC Ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.
  • PROTOPIC Ointment is not indicated for use in children less than 2 years of age. Only 0.03% PROTOPIC Ointment is indicated for use in children 2-15 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 the information above and the mechanism of action, there is a concern about potential risk with the use of topical calcineurin inhibitors, including PROTOPIC 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 Ointment. Therefore:

  • PROTOPIC Ointment 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: General).
  • The safety of PROTOPIC Ointment has not been established beyond one year of non-continuous use.

(See CLINICAL PHARMACOLOGY, BOXED WARNING, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

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 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 erythroderma 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 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 The Patient

(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.

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.

Pregnancy

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 ( < 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.

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

PROTOPIC Ointment is not for oral use. Oral ingestion of PROTOPIC Ointment may lead to adverse effects associated with systemic administration of tacrolimus. If oral ingestion occurs, medical advice should be sought.

CONTRAINDICATIONS

PROTOPIC (tacrolimus) Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-α, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to down regulate the expression of FcεRI on Langerhans cells.

Pharmacokinetics

Absorption

The pooled results from three pharmacokinetic studies in 88 adult atopic dermatitis patients indicate that tacrolimus is minimally absorbed after the topical application of PROTOPIC Ointment. Peak tacrolimus blood concentrations ranged from undetectable to 20 ng/mL after single or multiple doses of 0.03% and 0.1% PROTOPIC Ointment, with 85% (75/88) of the patients having peak blood concentrations less than 2 ng/mL. In general as treatment continued, systemic exposure declined as the skin returned to normal. In clinical studies with periodic blood sampling, a similar distribution of tacrolimus blood levels was also observed in adult patients, with 90% (1253/1391) of patients having a blood concentration less than 2 ng/mL.

The absolute bioavailability of tacrolimus from PROTOPIC in atopic dermatitis patients is approximately 0.5%. In adults with an average of 53% BSA treated, exposure (AUC) of tacrolimus from PROTOPIC is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients.

Mean peak tacrolimus blood concentrations following oral administration (0.3 mg/kg/day) in adult kidney transplant (n=26) and liver transplant (n=17) patients are 24.2±15.8 ng/mL and 68.5±30.0 ng/mL, respectively. The lowest tacrolimus blood level at which systemic effects (e.g., immunosuppression) can be observed is not known.

Systemic levels of tacrolimus have also been measured in pediatric patients (see Special Populations: Pediatrics).

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a US study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year. As with other topical calcineurin inhibitors, it is not known whether tacrolimus is distributed into the lymphatic system.

Metabolism

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro . The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

The mean clearance following IV administration of tacrolimus is 0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant patients and adult liver transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg.

When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus 0.172 ± 0.088 L/hr/kg.

Special Populations

Pediatrics

In a pharmacokinetic study of 14 pediatric atopic dermatitis patients, between the ages of 2-5 years, peak blood concentrations of tacrolimus ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03% PROTOPIC Ointment, with 86% (12/14) of patients having peak blood concentrations below 2 ng/mL throughout the study.

The highest peak concentration was observed in one patient with 82% BSA involvement on day 1 following application of 0.03% PROTOPIC Ointment. The peak concentrations for this subject were 14.8 ng/mL on day 1 and 4.1 ng/mL on day 14. Mean peak tacrolimus blood concentrations following oral administration in pediatric liver transplant patients (n = 9) were 48.4 ± 27.9 ng/mL.

In a similar pharmacokinetic study with 61 enrolled pediatric patients (ages 6-12 years) with atopic dermatitis, peak tacrolimus blood concentrations ranged from undetectable to 5.3 ng/mL after single or multiple doses of 0.1% PROTOPIC Ointment, with 91% (52/57) of evaluable patients having peak blood concentrations below 2 ng/mL throughout the study period. When detected, systemic exposure generally declined as treatment continued.

In clinical studies with periodic blood sampling, a similar distribution of tacrolimus blood levels was also observed, with 98% (509/522) of pediatric patients having a blood concentration below 2 ng/mL.

Renal Insufficiency

The effect of renal insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated. The mean clearance of IV administered tacrolimus in patients with renal  was similar to that of normal volunteers. On the basis of this information dose-adjustment is not expected to be needed.dysfunction

Hepatic Insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated but dose-adjustment is not expected to be needed.

Clinical Studies

Three randomized, double-blind, vehicle-controlled, multi-center, phase 3 studies were conducted to evaluate PROTOPIC Ointment for the treatment of patients with moderate to severe atopic dermatitis. One (Pediatric) study included 351 patients 2-15 years of age, and the other two (Adult) studies included a total of 632 patients 15-79 years of age. Fifty-five percent (55%) of the patients were women and 27% were black. At baseline, 58% of the patients had severe disease and the mean body surface area (BSA) affected was 46%. Over 80% of patients had atopic dermatitis affecting the face and/or neck region. In these studies, patients applied either PROTOPIC Ointment 0.03%, PROTOPIC Ointment 0.1%, or vehicle ointment twice daily to 10% - 100% of their BSA for up to 12 weeks.

In the pediatric study, a significantly greater (p < 0.001) percentage of patients achieved at least 90% improvement based on the physician's global evaluation of clinical response (the pre-defined primary efficacy endpoint) in the PROTOPIC Ointment 0.03% treatment group compared to the vehicle treatment group, but there was insufficient evidence that PROTOPIC Ointment 0.1% provided more efficacy than PROTOPIC Ointment 0.03%.

In both adult studies, a significantly greater (p < 0.001) percentage of patients achieved at least 90% improvement based on the physician's global evaluation of clinical response in the PROTOPIC Ointment 0.03% and PROTOPIC Ointment 0.1% treatment groups compared to the vehicle treatment group. There was evidence that PROTOPIC Ointment 0.1% may provide more efficacy than PROTOPIC Ointment 0.03%. The difference in efficacy between PROTOPIC Ointment 0.1% and 0.03% was particularly evident in adult patients with severe disease at baseline, adults with extensive BSA involvement, and black adults. Response rates for each treatment group are shown below by age groups. Because the two adult studies were identically designed, the results from these studies were pooled in this table.

Global Improvement over Baseline at the End-Of-Treatment in Three Phase 3 Studies

Physician's Global Evaluation of Clinical Response (% Improvement) Pediatric Study (2-15 Years of Age) Adult Studies
Vehicle Ointment
N= 116
PROTOPIC Ointment 0.03%
N = 117
Vehicle Ointment
N = 212
PROTOPIC Ointment 0.03%
N = 211
PROTOPIC Ointment 0.1%
N = 209
100% 4 (3%) 14 (12%) 2 (1%) 21 (10%) 20 (10%)
90% 8 (7%) 42 (36%) 14 (7%) 58 (28%) 77 (37%)
75% 18(16%) 65 (56%) 30 (14%) 97 (46%) 117 (56%)
50% 31 (27%) 85 (73%) 42 (20%) 130 (62%) 152 (73%)

A statistically significant difference in the percentage of adult patients with ≥ 90% improvement was achieved by week 1 for those treated with PROTOPIC Ointment 0.1%, and by week 3 for those treated with PROTOPIC Ointment 0.03%. A statistically significant difference in the percentage of pediatric patients with ≥ 90% improvement was achieved by week 2 for those treated with PROTOPIC Ointment 0.03%.

In adult patients who had achieved ≥ 90% improvement at the end of treatment, 35% of those treated with PROTOPIC Ointment 0.03% and 41% of those treated with PROTOPIC Ointment 0.1%, regressed from this state of improvement at 2 weeks after end-of-treatment. In pediatric patients who had achieved ≥ 90% improvement, 54% of those treated with PROTOPIC Ointment 0.03% regressed from this state of improvement at 2 weeks after end-oftreatment. Because patients were not followed for longer than 2 weeks after end-of-treatment, it is not known how many additional patients regressed at periods longer than 2 weeks after cessation of therapy.

In both PROTOPIC Ointment treatment groups in adults and in the PROTOPIC Ointment 0.03% treatment group in pediatric patients, a significantly greater improvement compared to vehicle (p < 0.001) was observed in the secondary efficacy endpoints of percent body surface area involved, patient evaluation of pruritus, erythema, edema, excoriation, oozing, scaling, and lichenification. The following two graphs depict the time course of improvement in the percent body surface area affected in adult and in pediatric patients as a result of treatment.

Figure 1 : Adult Patients Body Surface Area Over Time

Figure 2 : Pediatric Patients Body Surface Area Over Time

Pediatric Patients Body Surface Area Over Time - Illustration

The following two graphs depict the time course of improvement in erythema in adult and in pediatric patients as a result of treatment.

Figure 3 :Adult Patients Mean Erythema Over Time

Adult Patients Mean Erythema Over Time - Illustration

Figure 4 :Pediatric Patients Mean Erythema Over Time

Pediatric Patients Mean Erythema Over Time - Illustration

The time course of improvement in the remaining secondary efficacy variables was similar to that of erythema, with improvement in lichenification slightly slower.

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

MEDICATION GUIDE

PROTOPIC®
[pro-TOP-ik]
(tacrolimus) Ointment 0.03% Ointment 0.1%

Read the Medication Guide every time you or a family member gets PROTOPIC Ointment. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. If you have questions about PROTOPIC Ointment, ask your doctor or pharmacist.

What is the most important information I 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:

  • Do not use PROTOPIC Ointment continuously for a long time.
  • Use PROTOPIC Ointment only on areas of your 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.

Talk to your doctor for more information.

What is PROTOPIC Ointment?

PROTOPIC Ointment is a prescription medicine used on the skin (topical) to treat eczema (atopic dermatitis). PROTOPIC Ointment is in a class of medicines called topical calcineurin inhibitors. It is for adults and children 2 years of age and older who do not have a weakened immune system. PROTOPIC Ointment is used on the skin for short periods, and if needed, treatment may be repeated with breaks in between.

PROTOPIC Ointment is for use after other prescription medicines have not worked for you, or if your doctor recommends that other prescription medicines should not be used.

Who should not use PROTOPIC Ointment?

PROTOPIC Ointment should not be used:

  • on children younger than 2 years of age.
  • if you are allergic to PROTOPIC Ointment or anything in it. See the end of this Medication Guide for a complete list of ingredients.

What should I tell my doctor before starting PROTOPIC Ointment?

Before you start using PROTOPIC, you and your doctor should talk about all of your medical conditions, including if you:

  • have a skin disease called Netherton’s syndrome (a rare inherited condition).
  • have any infection on your skin including chicken pox or herpes.
  • have been told you have a weakened immune system.
  • are pregnant, breastfeeding, or planning to become pregnant.

Tell your doctor about all the medicines you take and skin products you use including prescription and nonprescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

How should I use PROTOPIC Ointment?

  • Use PROTOPIC Ointment exactly as prescribed.
  • Use PROTOPIC Ointment only on areas of your 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 by your doctor.
  • Follow your doctor’s advice if symptoms of eczema return after treatment with PROTOPIC Ointment.
  • Call your doctor if :
    • your symptoms get worse with PROTOPIC Ointment.
    • you get an infection on your skin.
    • your symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema.

To apply PROTOPIC Ointment:

  • Wash your 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 you are a caregiver applying PROTOPIC Ointment to a patient, or if you are a patient who is not treating your hands, wash your 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.
  • You can use moisturizers with PROTOPIC Ointment. Make sure you check with your doctor first about the products that are right for you. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If you use moisturizers, apply them after PROTOPIC Ointment.

What should I avoid while using PROTOPIC Ointment?

  • 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 your skin. If you need to be outdoors after applying PROTOPIC Ointment, wear loose fitting clothing that protects the treated area from the sun. Ask your doctor what other types of protection from the sun you should use.
  • Do not cover the skin being treated with bandages, dressings or wraps. You can wear normal clothing.
  • Avoid getting PROTOPIC Ointment in the eyes or mouth. Do not swallow PROTOPIC Ointment. If you do, call your doctor.

What are the possible side effects of PROTOPIC Ointment?

Please read the first section of this Medication Guide.

The most common side effects of PROTOPIC Ointment at the skin application site are stinging, burning, or itching of the skin treated with PROTOPIC. These side effects are usually mild to moderate, are most common during the first few days of treatment, and usually go away as your skin heals.

Other side effects include acne, swollen or infected hair follicles, headache, increased sensitivity of the skin to hot or cold temperatures, or flu-like symptoms such as the common cold and stuffy nose, skin tingling, upset stomach, muscle pain, swollen glands (enlarged lymph nodes), or skin infections including cold sores, chicken pox or shingles.

Talk to your doctor if you have a skin infection or if side effects (for example, swollen glands) continue or bother you.

While you are using PROTOPIC, drinking alcohol may cause the skin or face to become flushed or red and feel hot.

These are not all the side effects with PROTOPIC Ointment. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088

How should I store PROTOPIC Ointment?

  • Store PROTOPIC Ointment at room temperature (59° to 86°F). Do not leave PROTOPIC Ointment in your car in cold or hot weather. Make sure the cap on the tube is tightly closed.
  • Keep PROTOPIC Ointment and all medicines out of the reach of children.

General advice about PROTOPIC Ointment

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROTOPIC Ointment for a condition for which it was not prescribed. Do not give PROTOPIC Ointment to other people, even if they have the same symptoms you have. It may not be right for them.

This Medication Guide summarizes the most important information about PROTOPIC Ointment. If you would like more information, talk with your doctor.

Your doctor or pharmacist can give you information about PROTOPIC Ointment that is written for health care professionals. For more information, you can also visit the PROTOPIC website at www.protopic.com or call 1-800-727-7003.

What are the ingredients in PROTOPIC Ointment?

Active Ingredient: tacrolimus, either 0.03% or 0.1%
Inactive Ingredients
: mineral oil, paraffin, propylene carbonate, white petrolatum and white wax.

This Medication Guide has been approved by the U.S. Food and Drug Administration

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

MEDICATION GUIDE

PROTOPIC®
[pro-TOP-ik]
(tacrolimus) Ointment 0.03% Ointment 0.1%

Read the Medication Guide every time you or a family member gets PROTOPIC Ointment. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. If you have questions about PROTOPIC Ointment, ask your doctor or pharmacist.

What is the most important information I 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:

  • Do not use PROTOPIC Ointment continuously for a long time.
  • Use PROTOPIC Ointment only on areas of your 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.

Talk to your doctor for more information.

What is PROTOPIC Ointment?

PROTOPIC Ointment is a prescription medicine used on the skin (topical) to treat eczema (atopic dermatitis). PROTOPIC Ointment is in a class of medicines called topical calcineurin inhibitors. It is for adults and children 2 years of age and older who do not have a weakened immune system. PROTOPIC Ointment is used on the skin for short periods, and if needed, treatment may be repeated with breaks in between.

PROTOPIC Ointment is for use after other prescription medicines have not worked for you, or if your doctor recommends that other prescription medicines should not be used.

Who should not use PROTOPIC Ointment?

PROTOPIC Ointment should not be used:

  • on children younger than 2 years of age.
  • if you are allergic to PROTOPIC Ointment or anything in it. See the end of this Medication Guide for a complete list of ingredients.

What should I tell my doctor before starting PROTOPIC Ointment?

Before you start using PROTOPIC, you and your doctor should talk about all of your medical conditions, including if you:

  • have a skin disease called Netherton’s syndrome (a rare inherited condition).
  • have any infection on your skin including chicken pox or herpes.
  • have been told you have a weakened immune system.
  • are pregnant, breastfeeding, or planning to become pregnant.

Tell your doctor about all the medicines you take and skin products you use including prescription and nonprescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

How should I use PROTOPIC Ointment?

  • Use PROTOPIC Ointment exactly as prescribed.
  • Use PROTOPIC Ointment only on areas of your 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 by your doctor.
  • Follow your doctor’s advice if symptoms of eczema return after treatment with PROTOPIC Ointment.
  • Call your doctor if :
    • your symptoms get worse with PROTOPIC Ointment.
    • you get an infection on your skin.
    • your symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema.

To apply PROTOPIC Ointment:

  • Wash your 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 you are a caregiver applying PROTOPIC Ointment to a patient, or if you are a patient who is not treating your hands, wash your 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.
  • You can use moisturizers with PROTOPIC Ointment. Make sure you check with your doctor first about the products that are right for you. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If you use moisturizers, apply them after PROTOPIC Ointment.

What should I avoid while using PROTOPIC Ointment?

  • 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 your skin. If you need to be outdoors after applying PROTOPIC Ointment, wear loose fitting clothing that protects the treated area from the sun. Ask your doctor what other types of protection from the sun you should use.
  • Do not cover the skin being treated with bandages, dressings or wraps. You can wear normal clothing.
  • Avoid getting PROTOPIC Ointment in the eyes or mouth. Do not swallow PROTOPIC Ointment. If you do, call your doctor.

What are the possible side effects of PROTOPIC Ointment?

Please read the first section of this Medication Guide.

The most common side effects of PROTOPIC Ointment at the skin application site are stinging, burning, or itching of the skin treated with PROTOPIC. These side effects are usually mild to moderate, are most common during the first few days of treatment, and usually go away as your skin heals.

Other side effects include acne, swollen or infected hair follicles, headache, increased sensitivity of the skin to hot or cold temperatures, or flu-like symptoms such as the common cold and stuffy nose, skin tingling, upset stomach, muscle pain, swollen glands (enlarged lymph nodes), or skin infections including cold sores, chicken pox or shingles.

Talk to your doctor if you have a skin infection or if side effects (for example, swollen glands) continue or bother you.

While you are using PROTOPIC, drinking alcohol may cause the skin or face to become flushed or red and feel hot.

These are not all the side effects with PROTOPIC Ointment. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088

How should I store PROTOPIC Ointment?

  • Store PROTOPIC Ointment at room temperature (59° to 86°F). Do not leave PROTOPIC Ointment in your car in cold or hot weather. Make sure the cap on the tube is tightly closed.
  • Keep PROTOPIC Ointment and all medicines out of the reach of children.

General advice about PROTOPIC Ointment

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROTOPIC Ointment for a condition for which it was not prescribed. Do not give PROTOPIC Ointment to other people, even if they have the same symptoms you have. It may not be right for them.

This Medication Guide summarizes the most important information about PROTOPIC Ointment. If you would like more information, talk with your doctor.

Your doctor or pharmacist can give you information about PROTOPIC Ointment that is written for health care professionals. For more information, you can also visit the PROTOPIC website at www.protopic.com or call 1-800-727-7003.

What are the ingredients in PROTOPIC Ointment?

Active Ingredient: tacrolimus, either 0.03% or 0.1%
Inactive Ingredients
: mineral oil, paraffin, propylene carbonate, white petrolatum and white wax.

This Medication Guide has been approved by the U.S. Food and Drug Administration

Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Protopic Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

TACROLIMUS - TOPICAL

(tack-row-LEE-muss)

COMMON BRAND NAME(S): Protopic

WARNING: Patients have benefited from tacrolimus when it is used correctly. Long-term safety for this drug is not known at this time. There have been rare reports of cancers (e.g., skin cancer, lymphoma) in patients using tacrolimus. It is not known whether tacrolimus caused these cancers when used on the skin. Further studies to determine the long-term safety of this product are ongoing. In the unlikely event that unusual lumps, swollen glands, or growths (especially on the skin) occur, contact your doctor immediately.

The US Food and Drug Administration recommends the following: This drug should be used only if other drugs have failed or if other medications are not considered appropriate by your doctor. Tacrolimus should be used on the skin for short treatment periods only. If needed, treatment may be repeated with breaks in between. Use the smallest amount that will treat your condition properly, and apply only on the affected skin. Also, this medication should not be used in children younger than 2 years. As with all medications, discuss the risks, benefits, and proper use of this medication with your doctor.

USES: This form of tacrolimus is used on the skin to treat a skin condition called eczema (atopic dermatitis) in patients who have not responded well to (or should not use) other eczema medications.

Eczema is an allergic-type condition that causes red, irritated, and itchy skin. This drug works by weakening the skin's defense (immune) system, thereby decreasing the allergic reaction and relieving the eczema. Tacrolimus belongs to a class of drugs known as topical calcineurin inhibitors (TCIs).

This medication is not recommended if you have a history of a certain rare genetic disorder (Netherton's syndrome). Also, this medication should not be used by anyone who has a weakened immune system (e.g., following an organ transplant).

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using tacrolimus and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Wash your hands with soap and water before using this medication. Apply a thin layer to the affected areas of skin, usually twice daily or as directed by your doctor. Rub the medication into the skin gently and completely. Wash your hands after using this product unless your hands are being treated. If your doctor recommends a moisturizer, apply it after this medication.

This product is for use on the skin only. Avoid getting this medication in your eyes or on the inside of your nose or mouth. If you do get the medication in those areas, flush with plenty of water. Do not apply this medication to open wounds or infected areas. Do not cover the treated area with plastic or waterproof bandages unless directed to do so by your doctor. Do not bathe, shower, or swim right after applying this medication. This could wash it off the treated area.

Use this medication exactly as directed. Your doctor may instruct you to stop using it once your eczema has cleared and to start using it again if symptoms reappear. Consult your doctor for details.

Inform your doctor if your condition does not improve after 6 weeks of using this medication or if your condition worsens at any time.

Only the weakest product should be used in children 2 to 15 years old.

Disclaimer

Protopic Consumer (continued)

SIDE EFFECTS: Stinging, burning, soreness, or itching in the area of treated skin may occur during the first few days of treatment. Headache, acne, "hair bumps" (folliculitis), stomach upset, flu-like symptoms (e.g., fever, chills, runny nose, sore throat, muscle aches), or increased sensitivity of the skin to hot/cold/pain/touch may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual tiredness, back/joint/muscle pain, appearance of any skin infections or sores (e.g., chicken pox, shingles, lip sores, tumors, warts).

Tell your doctor immediately if this rare but very serious side effect occurs: chest pain.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Protopic (tacrolimus) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using tacrolimus, tell your doctor or pharmacist if you are allergic to it; or to other macrolide medications (e.g., sirolimus, erythromycin, clarithromycin, azithromycin); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: swollen lymph nodes (e.g., lymphadenopathy, mononucleosis), use of light therapy (e.g., UVA or UVB), skin or other cancers.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: skin infections (e.g., herpes, shingles), other skin conditions, kidney disease.

This drug may make you more sensitive to the effects of alcohol. Your face or skin may flush red and feel hot. Limit alcoholic beverages.

Tacrolimus may lessen your response to a vaccine making the vaccine less effective. Do not have immunizations/vaccinations while you are using this product without the consent of your doctor. Talk with your doctor about scheduling your vaccinations before or after treatment with this product.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This drug may pass into breast milk and may have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

Disclaimer

Protopic Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove tacrolimus from your body (such as cimetidine, St. John's wort, azole antifungals including itraconazole, ketoconazole, macrolide antibiotics including clarithromycin, erythromycin, protease inhibitors including indinavir, ritonavir, calcium channel blockers including diltiazem, verapamil), ziprasidone.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medication may be harmful if swallowed. If swallowing or overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others. This drug should be used as directed for treating your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in that case.

Talk with your doctor about other ways to manage your eczema, such as using moisturizers and taking shorter baths/showers.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Protopic Patient Information Including Side Effects

Brand Names: Protopic

Generic Name: tacrolimus topical (Pronunciation: ta KROE li mus)

What is tacrolimus topical (Protopic)?

Tacrolimus is an immunosuppressant. It works by decreasing your body's immune system.

Tacrolimus topical (for the skin) is used to treat severe atopic dermatitis (ezcema).

Tacrolimus may also be used for purposes not listed in this medication guide.

What are the possible side effects of tacrolimus topical (Protopic)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using tacrolimus and call your doctor at once if you have a serious side effect such as:

  • severe stinging, burning, itching, or soreness where the medicine is applied;
  • swollen glands;
  • redness or crusting around your hair follicles; or
  • signs of a skin infection (redness, swelling, itching, oozing).

Less serious side effects may include:

  • mild burning, stinging, or itching;
  • skin redness;
  • acne;
  • cold or flu symptoms such as stuffy nose, sneezing, sore throat;
  • headache; or
  • feeling more sensitive to hot or cold temperatures.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Protopic (tacrolimus) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about tacrolimus topical (Protopic)?

You should not use tacrolimus topical if you are allergic to it.

Before using tacrolimus topical, tell your doctor if you have skin cancer or a skin infection (including herpes or chickenpox), Netherton's syndrome (a genetic skin disorder), a weak immune system, kidney disease, or swelling, redness, or irritation of large areas of your skin.

Tacrolimus can lower the blood cells that help your body fight infections. This can make it easier for you to get sick from a virus such as chicken pox or herpes (cold sores or shingles). Tell your doctor if you have been exposed to any illness.

Avoid sunlight, sun lamps, tanning beds, and phototherapy treatments with UVA or UVB light. If you must be outdoors, wear loose clothing over the skin areas treated with tacrolimus topical. Do not use sunscreen on treated skin unless your doctor has told you to.

Talk to your doctor if your skin condition does not improve after using tacrolimus topical for 6 weeks.

Do not use this medication on a child younger than 2 years old.

Some people have developed skin cancer or lymphoma after using tacrolimus or pimecrolimus (Elidel). However, it is not known if either of these medicines causes skin cancer or lymphoma. Talk to your doctor about your individual risk.

Side Effects Centers

Protopic Patient Information including How Should I Take

What should I discuss with my healthcare provider before using tacrolimus topical (Protopic)?

You should not use tacrolimus topical if you are allergic to it.

To make sure you can safely use tacrolimus topical, tell your doctor if you have any of these other conditions:

  • skin cancer or a skin infection (including herpes or chickenpox);
  • Netherton's syndrome (a genetic skin disorder);
  • a weak immune system (caused by disease or by using certain medicines);
  • kidney disease; or
  • swelling, redness, or irritation of large areas of your skin.

Tacrolimus can lower the blood cells that help your body fight infections. This can make it easier for you to get sick from a virus such as chicken pox or herpes (cold sores or shingles). Tell your doctor if you have been exposed to any illness.

Some people have developed skin cancer or lymphoma after using tacrolimus or pimecrolimus (Elidel). However, it is not known if either of these medicines causes skin cancer or lymphoma. Talk to your doctor about your individual risk.

FDA pregnancy category C. It is not known whether tacrolimus topical will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Tacrolimus topical can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not use tacrolimus topical on a child younger than 2 years old.

How should I use tacrolimus topical (Protopic)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

If you are using this medicine on a child younger than 16 years old, use only the 0.03% ointment. The 0.1% ointment is for adults and children who are at least 16 years old, but is too strong to use on younger children.

Wash your hands before and after using tacrolimus, unless you are using the medication to treat a hand condition.

Apply the medicine in a thin layer, only to skin areas affected by eczema. Do not cover the treated skin with a bandage.

Do not bathe, shower, or swim right after applying tacrolimus topical. Water may wash off the medicine.

You may need to use a moisturizing cream or lotion to keep your skin from getting too dry. Ask your doctor about which moisturizer to use.

Tacrolimus is not for long-term use. Stop using the medicine once your symptoms have cleared up, unless your doctor has told you otherwise.

Call your doctor if your symptoms do not improve after 6 weeks of treatment, or if they get worse while using tacrolimus.

Store at room temperature. Do not freeze. Keep ointment tube tightly closed when not in use.

Side Effects Centers

Protopic Patient Information including If I Miss a Dose

What happens if I miss a dose (Protopic)?

Apply the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose (Protopic)?

An overdose of tacrolimus topical is not expected to be dangerous. Seek emergency medical attention or call the Poison Help line at 1-800-222-1222 if anyone has accidentally swallowed the medication.

What should I avoid while using tacrolimus topical (Protopic)?

Avoid using other medications on the areas you treat with tacrolimus topical unless you doctor tells you to.

Avoid exposure to sunlight or tanning beds, and phototherapy treatments with UVA or UVB light. If you must be outdoors, wear loose clothing over the skin areas treated with tacrolimus topical. Do not use sunscreen on treated skin unless your doctor has told you to.

Drinking alcohol while you are using tacrolimus topical may cause your skin or face to feel hot and become flushed or red.

What other drugs will affect tacrolimus topical (Protopic)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied tacrolimus topical. But an interaction may occur if you apply tacrolimus over large skin areas. Tell your doctor about all other medicines you use, especially:

  • conivaptan (Vaprisol);
  • imatinib (Gleevec);
  • isoniazid (for treating tuberculosis);
  • an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), or telithromycin (Ketek);
  • antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Extina, Ketozole, Nizoral, Xolegal), or voriconazole (Vfend);
  • an antidepressant such as nefazodone;
  • heart or blood pressure medication such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others;
  • HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir);

This list is not complete and other drugs may interact with tacrolimus topical. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about tacrolimus topical.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 5.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

توزیع کنندگان این دارو
شرکت های تولید کننده یا وارد کننده دارو

دارونـــما
نوآوری برای سلامت

طراحی و اجرا M.Ramezani
ارتباط با ما Info@darunama.com