Tacrolimus (topical)

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# Overview
Tacrolimus (topical) is an immunosuppressive agent that is FDA approved for the treatment of moderate to severe atopic dermatitis, prophylaxis of cardiac transplant rejection, liver transplant rejection, renal transplant rejection.   Common adverse reactions include peripheral edema, alopecia, persistent erythema of skin, pruritus, rash, constipation, diarrhea, nausea, vomiting, anemia, leukocytosis, thrombocytopenia, headache, insomnia, paresthesia, and tremor.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Apply thin layer of 0.03% or 0.1% ointment TOPICALLY to affected areas twice daily; re-examine within 6 weeks if signs and symptoms do not improve.
- Dosing Information
- (Prograf(R)) initial, 0.01 mg/kg/day IV as a continuous infusion; wait at least 6 hours after transplant to initiate therapy; switch to oral therapy as soon as tolerated.
- (Prograf(R)) initial, 0.075 mg/kg/day ORALLY in 2 divided doses (given every 12 hours); wait at least 6 hours after transplant to initiate therapy AND at least 8 to 12 hours if converting from IV to oral; titrate dose based on clinical response, serum levels, and tolerability.
- (Prograf(R)) adjunctive adrenal corticosteroid therapy is recommended early posttransplant.
- Prograf(R)initial dose: 0.075 mg/kg/day orally in 2 divided doses given every 12 hours, administered no sooner than 6 hours after transplant. Oral therapy preferred over IV therapy; if IV required, convert to oral as soon as tolerated (usually 2 to 3 days), and give the first dose 8 to 12 hours after discontinuing the infusion
- Dose titration: Based on clinical assessment of rejection and tolerability. Monitoring of whole blood trough concentrations considered essential for evaluation of rejection, toxicity, dose adjustments, and compliance; recommended whole blood trough concentration 10 to 20 nanograms/mL (ng/mL) at 1 to 3 months and 5 to 15 ng/mL at 4 months and thereafter.
- Maintenance dose: Lower doses may be used.
- Concomitant medications: Adjunctive adrenal corticosteroid therapy recommended early posttransplant.
- Dosing Information
- (Prograf(R)) initial, 0.03 to 0.05 mg/kg/day IV as a continuous infusion; wait at least 6 hours after transplant to initiate therapy; switch to oral therapy as soon as tolerated.
- Liver transplant rejection; Prophylaxis: (Prograf(R)) initial, 0.1 to 0.15 mg/kg/day ORALLY in 2 divided doses (given every 12 hours); wait at least 6 hours after transplant to initiate therapy AND, if converting from IV to oral, wait at least 8 to 12 hours after discontinuing the IV infusion; titrate dose based on clinical response, serum levels, and tolerability.
- Liver transplant rejection; Prophylaxis: (Prograf(R)) adjunctive adrenal corticosteroid therapy is recommended early posttransplant.
- Dosing Information
- Renal transplant rejection; Prophylaxis: (Astagraf XL(R) with basiliximab induction) initial, 0.15 mg/kg/day ORALLY once daily in morning, administer prior to or within 48 hours of transplant completion; may delay until renal function has recovered; titrate dose based on clinical response and tolerability to target whole blood trough levels of 5 to 17 nanograms/mL (ng/mL) on days 1 to 60, and 4 to 12 ng/mL during months 3 to 12; concomitant use with mycophenolate mofetil and corticosteroids is recommended.
- Renal transplant rejection; Prophylaxis: (Astagraf XL(R) without induction) preoperative dose, 0.1 mg/kg/day ORALLY once, administer within 12 hours prior to reperfusion; postoperative dosing, 0.2 mg/kg/day ORALLY once daily in the morning; administer first postoperative dose not less than 4 hours after the preoperative dose and within 12 hours after reperfusion; titrate dose based on clinical response and tolerability to target whole blood trough levels of 6 to 20 nanograms/mL (ng/mL) on days 1 to 60, and 6 to 14 ng/mL during months 3 to 12; concomitant use with mycophenolate mofetil and corticosteroids is recommended.
- Renal transplant rejection; Prophylaxis: (Prograf(R)) initial, 0.03 to 0.05 mg/kg/day IV as a continuous infusion; wait at least 6 hours after transplant to initiate therapy AND, if converting from IV to oral, wait at least 8 to 12 hours after discontinuing the IV infusion; switch to oral therapy as soon as tolerated.
- Renal transplant rejection; Prophylaxis: (Prograf(R) in combination with azathioprine), initial, 0.2 mg/kg/day ORALLY in 2 divided daily doses (given every 12 hours); administer within 24 hours of transplant to initiate therapy but delay until renal function has recovered; titrate dose based on clinical response, serum levels, and tolerability.
- Renal transplant rejection; Prophylaxis: (Prograf(R) in combination with mycophenolate mofetil/interleukin-2-receptor antagonist), initial, 0.1 mg/kg/day ORALLY in 2 divided daily doses (given every 12 hours); administer within 24 hours of transplant to initiate therapy but delay until renal function has recovered; titrate dose based on clinical response, serum levels, and tolerability.
- Renal transplant rejection; Prophylaxis: (Prograf(R) adjunctive adrenal corticosteroid therapy is recommended early posttransplant.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (topical) in adult patients.

### NonGuideline-Supported Use
- Dosing Information
- Histocompatible Allogenic Bone Marrow Transplant:
- Study dose: Initial, 0.04 mg/kg/day as continuous IV infusion for median of 26 days; patients switched to 0.12 to 0.15 mg/kg/day orally in 2 divided doses as soon as feasible.
- Mismatched Marrow or Blood Stem Cell Transplant:
- Study dose: 0.02 mg/kg every 24 hours as continuous IV infusion initiated 3 days prior to transplant (target serum level of 5 to 10 nanograms/mL ), plus oral sirolimus 12-mg loading dose 3 days before transplant and then 4 mg/day as single morning dose (target trough level of 3 to 12 ng/mL), plus methotrexate 5 mg/m(2) given on posttransplant days 1, 3, 6, and 11. Tacrolimus and sirolimus were tapered by 33% at 9 and 17 weeks and discontinued at 26 weeks, if feasible.
- Study dose: 0.03 mg/kg/day as a continuous IV infusion from day -2 until engraftment plus methotrexate 5 mg/m(2) IV on days 1, 3, 6, and 11.

### Rejection of pancreas transplant
- Guideline dose: Initial range from 0.05 to 0.2 mg/kg/day; usually started 1, 2, or 3 days after transplant, although some centers wait until day 6 or 7; target whole blood trough level usually maintained between 10 and 20 nanograms/mL (ng/mL) for the first 3 months and may be reduced to 8 to 15 ng/mL after 3 months.

### Renal transplant rejection, Rescue

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Usual dose: Apply thin layer of 0.03% ointment to affected areas twice daily until signs and symptoms resolve; use minimum amount and rub in gently and completely; do not use occlusive dressings; re-examine within 6 weeks if signs and symptoms do not improve.
- Dosing Information
- Prograf(R): Initial dose: 0.03 to 0.05 mg/kg/day; patients without pre-existing hepatic or renal dysfunction have required higher doses than adults to achieve similar whole blood concentrations. Infusion should be started no sooner than 6 hours after transplant.
- Prograf(R): Initial dose: 0.15 to 0.2 mg/kg/day orally divided every 12 hours. Initial dose should be given no sooner than 6 hours after transplant, or 8 to 12 hours after discontinuing IV dosing. Pediatric patients without pre-existing hepatic or renal dysfunction have required higher doses than adults to achieve similar whole blood concentrations.
- Maintenance dose: Lower doses may be adequate; titrate based on clinical assessment of rejection and tolerability. Monitoring of whole blood trough concentrations is essential for evaluation of rejection, toxicity, dose adjustments, and compliance; recommended whole blood trough concentration 5 to 20 nanograms/mL at 1 to 12 months.
- Concomitant medications: Adjunctive adrenal corticosteroid therapy recommended early posttransplant.

### Renal transplant rejection; Prophylaxis((16 years or older; Astagraf XL(R) only))
- Dosing Information
- Prograf(R): Experience with tacrolimus in children undergoing kidney transplant is limited.
- Astagraf XL(R): In combination with Mycophenolate and Corticosteroid Following Basiliximab Induction
- Usual dose (16 years or older): 0.15 mg/kg/day orally once daily, consistently in the morning and preferably on an empty stomach; initiate prior to or within 48 hours of transplant completion; however, may be delayed until recovery of renal function
- Dose titration: Based on clinical response, whole blood levels, and tolerability; recommended whole blood trough concentration 5 to 17 nanograms/mL (ng/mL) on days 1 to 60, and 4 to 12 ng/mL during months 3 to 12.
- In Combination with Mycophenolate and Corticosteroid Without Concomitant Induction Therapy
- Usual dose (16 years and older): 0.1 mg/kg/day orally once within 12 hours prior to reperfusion. Postoperative dosing should continue with 0.2 mg/kg/day orally once daily in the morning and preferable on an empty stomach. Begin the initial postoperative dose no less than 4 hours after the preoperative dose and within 12 hours following reperfusion.
- Dose titration: Titrate based on clinical response, whole blood levels, and tolerability; the recommended whole blood trough concentration is 6 to 20 nanograms/mL (ng/mL) on days 1 to 60, and 6 to 14 ng/mL during months 3 to 12.
- Prograf(R): Experience with tacrolimus in children undergoing kidney transplant is limited.
- Study dose: 0.3 mg/kg/day orally divided every 12 hours with adjustments based on trough concentrations.
- Study dose: In 14 children, average oral tacrolimus dose was 0.16 mg/kg/day. Doses ranging from 0.036 to 0.3 mg/kg/day, were based on clinical signs, and were targeted to a trough level of 5 to 11 nanograms/mL.
- Astagraf XL(R) extended-release capsules are not interchangeable or substitutable for Prograf(R) immediate-release capsules.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (topical) in pediatric patients.

### NonGuideline-Supported Use
- Dosing Information
- Prograf(R): Study dose: 0.15 mg/kg/day as a slow IV infusion, followed by conversion to oral therapy (0.15 mg/kg twice daily); specifics of conversion were not presented, although most patients had 1-day overlap of IV and oral therapy.
- Study dose: Initial tacrolimus infusion below 0.05 mg/kg/day may result in delay in achieving therapeutic concentrations in pediatric patients undergoing heart transplant.

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

# Warnings
- 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.
- The safety of PROTOPIC Ointment has not been established beyond one year of non-continuous use.

### 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).
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 (Kaposis 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.

# Adverse Reactions

## Clinical Trials Experience
- 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.
- 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.
- 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, benign neoplasm, 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 Nethertons syndrome, renal impairment
- Skin
- Rosacea, application site edema
OVERDOSAGE
- 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.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tacrolimus (topical) in the drug label.

# 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. 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tacrolimus (topical) in women who are pregnant.

### Labor and Delivery
- There is no FDA guidance on use of Tacrolimus (topical) during labor and delivery.

### 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.
- 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. 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).

### Geriatic 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.

### Gender
- There is no FDA guidance on the use of Tacrolimus (topical) with respect to specific gender populations.

### Race
- There is no FDA guidance on the use of Tacrolimus (topical) with respect to specific racial populations.

### Renal Impairment
- There is no FDA guidance on the use of Tacrolimus (topical) in patients with renal impairment.

### Hepatic Impairment
- There is no FDA guidance on the use of Tacrolimus (topical) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Tacrolimus (topical) in women of reproductive potentials and males.

### Immunocompromised Patients
- There is no FDA guidance one the use of Tacrolimus (topical) in patients who are immunocompromised.

# Administration and Monitoring

### 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.

### Monitoring
- There is limited information regarding Monitoring of Tacrolimus (topical) in the drug label.

# IV Compatibility
- There is limited information regarding IV Compatibility of Tacrolimus (topical) in the drug label.

# Overdosage
- There is limited information regarding Chronic Overdose of Tacrolimus (topical) in the drug label.

# 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-, 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 FcRI on Langerhans cells.

## Structure
- 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-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy-4,10, 12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido(2,1-c)(1,4) oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,monohydrate. It has the following structural formula:
- Tacrolimus has an empirical formula of C44H69NO12H2O 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.

## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Tacrolimus (topical) in the drug label.

## 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 24.215.8 ng/mL and 68.530.0 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.
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 dysfunction was similar to that of normal volunteers. On the basis of this information dose-adjustment is not expected to be needed.
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.

## Nonclinical Toxicology
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  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 ) 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.

# 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 physicians 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 physicians 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.
- 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-of-treatment. 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.
- The following two graphs depict the time course of improvement in erythema in adult and in pediatric patients as a result of treatment.
- The time course of improvement in the remaining secondary efficacy variables was similar to that of erythema, with improvement in lichenification slightly slower.

# 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
- NDC 0469-5202-11 Product Code 520211
- 100 gram laminate tube

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

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Information for Patients
- 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 doctors 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.

# Precautions with Alcohol
- Alcohol-Tacrolimus (topical) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Astagraf XL,
Hecoria,
Prograf,
Protopic.

# Look-Alike Drug Names
There is limited information regarding Tacrolimus (topical) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price