AHFS Class:

• Immunomodulatory Agents 84:06.28

Generic Name(s):

• Tacrolimus

Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis .1

Atopic Dermatitis

Tacrolimus topical ointment is used as second-line therapy for short-term treatment and noncontinuous chronic treatment of moderate to severe atopic dermatitis (eczema) in immunocompetent adults and children 2-15 years of age1,4,6,7,8,12 who are unable to tolerate or have not responded to standard therapies (i.e., corticosteroids) or for whom standard therapies are inadvisable because of potential risks.1 Because of the potential for increased risk of malignancies, tacrolimus ointment should be used only as a second-line agent for short-term and intermittent treatment.1,12,13,14

Tacrolimus topical ointment is not indicated for use in children younger than 2 years of age.1,16

Efficacy of tacrolimus ointment in the treatment of atopic dermatitis was established in 3 randomized, double-blind, vehicle-controlled, multicenter clinical studies (2 in adults and 1 in children).1,4,6 In these clinical studies, application of tacrolimus ointment to atopic dermatitis lesions twice daily for up to 12 weeks produced substantial clinical improvement, decreased the percentage of the body surface area affected, and alleviated the signs and symptoms of the disease (e.g., pruritus, edema, erythema, excoriation, lichenification, oozing, scaling skin), with improvement usually evident within 1 week.1,4,6

Results of an analysis of pooled data from the 2 clinical studies in adults found that approximately 28, 37, or 7% of patients with moderate to severe atopic dermatitis who received the 0.03% ointment, the 0.1% ointment, or vehicle, respectively, experienced at least 90% improvement (based on the physician's global evaluation of clinical response);1,4 of the patients treated successfully (at least 90% improvement) with the 0.03 or the 0.1% ointment, 35 or 41%, respectively, relapsed within 2 weeks following the end of treatment.1 The success rate for tacrolimus 0.03% ointment was lower in patients with severe atopic dermatitis at baseline (20%), in patients with extensive (75-100%) body surface area involvement (5%), and in black patients (16%).4

In the clinical study involving children 2-15 years of age with moderate to severe atopic dermatitis, the 0.1% ointment appeared to provide no added benefit over the 0.03% ointment.1 Approximately 36, 41, or 7% of children receiving the 0.03% ointment, the 0.1% ointment, or vehicle, respectively, experienced at least 90% improvement (based on the physician's global evaluation of clinical response);6 however, 54% of the children treated successfully (at least 90% improvement) with tacrolimus 0.03% ointment relapsed within 2 weeks following the end of treatment.1

General

Tacrolimus is applied topically to the skin as a 0.03 or 0.1% ointment.1 Tacrolimus ointment is for external use only and should not be used in the eyes or ingested.1 Occlusive dressings or wrappings should not be used concomitantly.1,9 Tacrolimus ointment should be used with caution on the face or neck, large areas of the body (i.e., exceeding 50% of the total body surface area), or areas of broken skin.3,11

For the treatment of moderate to severe atopic dermatitis in adults or children 2-15 years of age, a thin layer of ointment should be applied and rubbed gently and completely into the affected areas of skin twice daily,1,9 approximately 12 hours apart.9 The minimum amount required to control symptoms should be used and application limited to areas affected with atopic dermatitis.1,12,15 Tacrolimus is applied as a 0.03 or 0.1% ointment in adults.1 Only the 0.03% ointment is labeled by the US Food and Drug Administration (FDA) for use in children 2-15 years of age.1 Improvement generally is evident within 1 week of the initiation of treatment in both adults and children.4,6,9

Treatment should be discontinued following resolution of signs and symptoms of atopic dermatitis (e.g., pruritus, rash, erythema).1,15 Patients should be reevaluated and their diagnosis confirmed if manifestations of the disease persist beyond 6 weeks.1

Tacrolimus ointment is intended for short-term and intermittent use only and should not be used continuously.1,12 The safety of noncontinuous use of topical tacrolimus ointment for longer than 1 year has not been established.1,12,16

Special Populations

No special population dosage recommendations at this time.1

Contraindications

Known hypersensitivity to tacrolimus or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Carcinogenicity

The long-term safety of topical tacrolimus therapy has not been established.1,16 Although a causal relationship has not been established, malignancies (e.g., skin cancer, lymphoma) have been reported rarely in patients treated with topical calcineurin inhibitors, including topical tacrolimus.1,16 Because of a possible increase in the risk of malignancies associated with topical tacrolimus therapy, continuous long-term use of topical tacrolimus should be avoided in patients of any age, and application limited to areas affected with atopic dermatitis.1,12,13,14 Topical tacrolimus is not indicated for use in children younger than 2 years of age, and only the lower (0.03%) strength of tacrolimus ointment is indicated for use in children 2-15 years of age.1,16

The concern for increased risk of malignancies is based principally on case reports of malignancies (including lymphoma and skin cancer) in children and adults receiving topical tacrolimus or pimecrolimus; the increased risk of lymphoma and skin cancer associated with prolonged systemic therapy with calcineurin inhibitors (e.g., cyclosporine, tacrolimus) in transplant patients; animal studies indicating dose-related increases in the risk of lymphoma and other malignancies (particularly of the skin) with tacrolimus and other calcineurin inhibitors, possibly secondary to immunosuppressive effects of the drug; and the known pharmacologic effects of these immunosuppressants.1,10,11,12,13,14 The potential risks and benefits of therapy should be carefully evaluated.12,13

Systemic use of tacrolimus in kidney and liver transplant patients is associated with development of lymphoma and skin cancers.1,13,14 The risk of malignancy appears to be related to dose and duration of exposure.13,14 Tacrolimus may be absorbed into systemic circulation following topical application, but concentrations generally are very low.1,14 The lowest blood tacrolimus concentration associated with systemic effects (e.g., immunosuppression) has not been determined.1

The risk associated with systemic therapy with calcineurin inhibitors is related to intensity and duration of immunosuppression.1 The potential for systemic immunosuppression with topical tacrolimus and the drug's role in the development of malignancies in humans have not been established.1,12,13,14 Long-term studies in humans are needed to determine whether topical tacrolimus is associated with an increased risk of malignancies.12,13 Until such data are available, the US Food and Drug Administration (FDA) recommends that use of topical tacrolimus be limited to the labeled indication and that the drug be reserved for use as a second-line agent for short-term and intermittent treatment.12,13

Topical tacrolimus therapy should be avoided for malignant or premalignant skin conditions (e.g., cutaneous T-cell lymphoma [CTCL]), which may appear clinically similar to dermatitis.1

Because of a potential increased risk for skin cancer, patients should be advised to limit exposure to sunlight or other UV light by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.1,3,11

General Precautions

Lymphadenopathy

Systemic immunosuppression potentially may result in the development of lymphoma.1,10,11 In clinical studies, lymphadenopathy was reported in 0.8% of patients receiving tacrolimus ointment; lymphadenopathy usually was related to infections, particularly of the skin, and resolved following appropriate antimicrobial therapy.1 Lymphadenopathy in association with malignancy also has been reported during postmarketing surveillance.14 Patients with lymphadenopathy or those with suspected or proven infectious mononucleosis should delay initiation of therapy with tacrolimus ointment until these conditions have resolved.3,11 Patients who develop lymphadenopathy while receiving tacrolimus ointment should have the etiology of their lymphadenopathy investigated.1 In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, tacrolimus ointment should be discontinued.1 Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.1

Netherton's Syndrome

Use of topical tacrolimus ointment in patients with Netherton's syndrome is not recommended because of the potential for increased systemic absorption of tacrolimus.1

Generalized Erythroderma

The safety of tacrolimus ointment in patients with generalized erythroderma has not been established.1

Dermatologic Reactions

Following topical application of tacrolimus ointment, a burning sensation (burning, stinging, soreness) or pruritus may occur at the treatment site.1 Such reactions usually improve as the lesions of atopic dermatitis resolve.1

Infectious Complications

Safety and efficacy of tacrolimus ointment for the treatment of clinically infected atopic dermatitis have not been established.1 The manufacturer recommends that bacterial or viral infections at treatment sites be resolved before initiating topical tacrolimus therapy.1

Systemic administration of tacrolimus in kidney and liver transplant patients has been associated with increased susceptibility to infection; the risk of infection is associated with the intensity and duration of immunosuppression.1,14 Use of tacrolimus ointment may be associated with an increased risk of varicella-zoster infections (chickenpox or shingles), herpes simplex virus infection, or eczema herpeticum.1

Phototoxicity

Although phototoxicity has not been reported in humans, it may be prudent to minimize or avoid natural or artificial sunlight exposure during topical tacrolimus therapy (including periods when no drug is on the skin).1 The potential effects of topical tacrolimus therapy on skin response to ultraviolet (UV) damage are not known.1

Animal photocarcinogenicity studies indicate a shortened time to skin tumor formation following chronic topical tacrolimus dosing with concurrent UV radiation exposure.1

Immunocompromised Patients

Tacrolimus ointment should not be used in immunocompromised adults or children.1,12,13,14 Safety and efficacy of topical tacrolimus ointment have not been established in such patients.1

Renal Effects

Acute renal failure has been reported rarely in patients receiving topical tacrolimus.1 The risk of systemic absorption is increased in patients with epidermal barrier defects, especially following topical application of the drug to large body surface areas.1

Topical tacrolimus ointment should be used with caution in patients predisposed to renal impairment.1

Specific Populations

Pregnancy

Category C.1

Lactation

Tacrolimus is distributed into milk following systemic administration.10 Not known whether tacrolimus is distributed into milk following topical application to skin.11 Discontinue nursing or drug, taking into account the importance of the drug to the woman.1

African Americans

In adult African Americans, efficacy of tacrolimus 0.03% ointment was similar to that of vehicle;4 tacrolimus 0.1% ointment appears to be effective.1,4,11

Pediatric Use

Safety and efficacy not established in children younger than 2 years of age.1,16 Not recommended for use in children younger than 2 years of age.1,16 Not recommended for use in immunocompromised children.1,12,13,14

When topical tacrolimus therapy is indicated in immunocompetent children 2-15 years of age, only the 0.03% ointment should be used.1,16

Blood concentrations of tacrolimus in children receiving topical therapy with the drug occasionally have been in the concentration range achieved with systemic therapy.14 Long-term effects on the developing immune system in infants and children are not known.1,12,13,14

Geriatric Use

No substantial differences in safety relative to younger adults.1

Common Adverse Effects

Adverse effects occurring in 20% or more of patients include burning sensation, pruritus, flu-like symptoms, skin erythema, and headache in adults1,5 and burning sensation, pruritus, and flu-like symptoms in pediatric patients.1,6 Adverse local effects are most common during the first few days of therapy with tacrolimus ointment and generally improve as the lesions of atopic dermatitis heal.1 Burning sensation or pruritus usually lasts a median of 15 minutes (range: 2 minutes to 3 hours) or 20 minutes (range: 3 minutes to 10 hours), respectively.1

No formal drug interaction studies have been performed to date.1

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors of cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., erythromycin, azole antifungal agents, calcium-channel blocking agents, cimetidine) in patients with widespread and/or erythrodermic disease.1

Vaccines

Protective antibody titers to pneumococcal 23-valent polysaccharide vaccine were achieved following vaccination of a limited number of children 2-12 years of age with moderate to severe atopic dermatitis treated with the topical tacrolimus 0.03% ointment.1 The immune response to meningococcal serogroup C was similar in children 2-11 years of age with moderate to severe atopic dermatitis treated with topical tacrolimus 0.03% ointment, in those treated with topical hydrocortisone, and in healthy children.1

Description

Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis .1 Tacrolimus is commercially available for topical use as a 0.03 or 0.1% ointment.1 The exact mechanism(s) of action of tacrolimus in the treatment of atopic dermatitis has not been elucidated but appears to involve inhibition of the activation of T cells.1,2 Tacrolimus also has been shown to inhibit release of mediators from skin mast cells and basophils and to downregulate the expression of high-affinity receptors for immunoglobulin E (IgE) on Langerhans cells.1,2 Although tacrolimus is not genotoxic and does not interact directly with DNA, the drug may impair local immunosurveillance.14

Following single or multiple applications of tacrolimus 0.3% ointment (not commercially available in the US) to atopic dermatitis lesions in adults or children 5-11 years of age, tacrolimus was not appreciably absorbed into systemic circulation (e.g., the apparent systemic bioavailability was less than 0.5%).2,3,11 Use of tacrolimus ointment on the face or neck, large areas of the body (i.e., >50% of the total body surface area), or areas of broken skin theoretically may increase systemic exposure to the drug. 3,11 The lowest blood tacrolimus concentration at which systemic effects can be observed is as yet unknown.1 Tacrolimus does not appear to accumulate systemically following intermittent topical application of the ointment for periods up to 1 year.1 Following systemic administration, tacrolimus is extensively metabolized in the liver and in the GI tract, principally via oxidation by cytochrome P-450 3A (CYP3A) isoenzymes.10,11

Advice to Patients

Importance of reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.1,15 Importance of informing clinicians of other medical conditions, including Netherton's syndrome, skin infections (e.g., chickenpox, herpes), or weakened immune system.1,15 Advise patients that tacrolimus is for external use on the affected skin only.1,15 Importance of patients or caregivers washing their hands before and after application if hands are not an area for treatment.1,15 Advise patients not to bathe, shower, or swim immediately after application.1,15 Importance of avoiding contact with the eyes.1,15 Importance of not swallowing tacrolimus; contact clinician if swallowed.1,15 Importance of following the clinician's advice regarding use of other topical preparations; importance of maintaining good skin care practices; apply moisturizers (if used) after tacrolimus.1,15

Advise patients to discontinue tacrolimus when the signs and symptoms (e.g., itching, rash, redness) of atopic dermatitis (eczema) resolve, or as directed by their clinician.1,15 Importance of following the clinician's advice if symptoms recur after a course of treatment.1,15 Importance of not using the drug in children younger than 2 years of age.1,15 Importance of using only the 0.03% ointment in children 2-15 years of a 1,15 either the 0.03 or 0.1% ointment may be used in adults and adolescents 16 years of age or older.1,15 Importance of avoiding use of bandages, dressings, or wrappings on treated skin.1,15

Importance of not using the drug for any disorder other than that for which it was prescribed.1,15 Importance of using tacrolimus exactly as prescribed and of not using the drug continuously for a long period of time.1,15 Importance of using the minimum amount required to control signs and symptoms of atopic dermatitis; importance of using the drug for short-term or intermittent therapy (e.g., courses repeated after treatment-free intervals) only.1,12,13,15 Importance of reporting persistently swollen glands or any other adverse reactions to clinician.1,15 Importance of notifying clinician if a skin infection develops during treatment with tacrolimus.1,15 Importance of notifying clinician if the signs and symptoms of atopic dermatitis do not improve after 6 weeks of therapy or at any time become noticeably worse.1,15

Importance of avoiding or limiting exposure of unprotected skin to natural or artificial sunlight (tanning beds or UVA/B light) while using tacrolimus ointment (even when the drug is not on the skin); wear protective clothing and use a broad-spectrum sunscreen with a high protection factor.1,3,11,15

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary or herbal supplements, any other skin product, or any form of phototherapy (UVA or UVB).1,9,15 Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1,15 Importance of informing patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Astellas Pharma US, Inc. Protopic^® (tacrolimus) ointment 0.03 and 0.1% prescribing information. Deerfield, IL; 2006 Jan.

2. Bekersky I, Fitzsimmons W, Tanase A et al. Nonclinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis. J Am Acad Dermatol . 2001; 44(1 Suppl):S17-27. [PubMed 11145792]

3. Dermatologic and Ophthalmic Drugs Advisory Committee Meeting. 54th meeting. Bethesda, MD: Food and Drug Administration; 2000 Nov 16.

4. Hanifin JM, Ling MR, Langley R et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol . 2001; 44(1 Suppl):S28-38.

5. Soter NA, Fleischer AB Jr, Webster GF et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part II, safety. J Am Acad Dermatol . 2001; 44(1 Suppl):S39-46.

6. Paller A, Eichenfield LF, Leung DY et al. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol . 2001; 44(1 Suppl):S47-57.

7. Kang S, Lucky AW, Pariser D et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol . 2001; 44(1 Suppl):S58-64. [PubMed 11145796]

8. Reitamo S, Wollenberg A, Schopf E et al for the European Tacrolimus Ointment Study Group. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol . 2000; 136:999-1006. [PubMed 10926735]

9. Astellas Pharma US, Inc. Protopic^® (tacrolimus) ointment patient information. Deerfield, IL; 2005 Apr.

10. Fujisawa Healthcare, Inc. Prograf^® (tacrolimus) for injection and oral capsules prescribing information. Deerfield, IL; 1998 Oct.

11. Reviewers' comments (personal observations).

12. Anon. FDA issues public health advisory informing health care providers of safety concerns associated with the use of two eczema drugs, Elidel and Protopic. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2005 March 10. From the FDA website. Accessed on May 25, 2005. [Web]

13. Food and Drug Administration (FDA). FDA Public Health Advisory regarding potential cancer risk from use of Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. From FDA website. 2005 Mar 10. Accessed on May 25, 2005. [Web]

14. Food and Drug Administration (FDA). FDA alert for healthcare professionals regarding potential cancer risk from use of tacrolimus (marketed as Protopic). From FDA website. Accessed on May 25, 2005. [Web]

15. Astellas Pharma US, Inc. Protopic^® (tacrolimus) ointment 0.03 and 0.1% medication guide. Deerfield, IL; 2006 Jan.

16. Rico MJ. Dear health care provider letter regarding important safety information regarding Protopic^® and rare cases of malignancy reported in patients treated with topical calcineurin inhibitors. Deerfield, IL; 2006 Jan 19.