Protopic topical

Pronunciation

Generic Name: Tacrolimus topical
Class: Skin and Mucous Membrane Agents, Miscellaneous
Chemical Name: [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
CAS Number: 109581-93-3

Warning(s)

  • Long-term safety of topical tacrolimus not established.a c

  • Malignancies (e.g., skin cancers, lymphoma) reported rarely in patients treated with topical calcineurin inhibitors, including tacrolimus; causal relationship not established.a c

  • Avoid continuous long-term use of topical tacrolimus; limit application to areas affected by atopic dermatitis.a c (See Carcinogenicity under Cautions.)

  • Topical tacrolimus is not indicated for use in children <2 years of age; only the 0.03% ointment is indicated for use in children 2–15 years of age.a c

Introduction

Immunosuppressive agent; macrolide produced by Streptomyces tsukubaensis.1

Uses for Protopic

Atopic Dermatitis

Second-line therapy for short-term and noncontinuous chronic treatment of moderate to severe atopic dermatitis (eczema) in immunocompetent adults and children 2–15 years of age who are unable to tolerate or have not responded to first-line therapies or for whom first-line therapies are inadvisable.4 6 7 8 13 14 a (See Carcinogenicity under Cautions.)

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Not indicated for use in children <2 years of age.a c

Protopic Dosage and Administration

Administration

Topical Administration

Apply topically to the skin as a 0.03 or 0.l% ointment.a

For external use only; do not use in the eyes or ingest.a

Apply in thin layers;1 rub gently and completely into affected areas of skin.1

Use minimum amount required to control symptoms;12 a b limit application to areas affected with atopic dermatitis.a b (See Carcinogenicity under Cautions.)

Use with caution on the face or neck, large areas of the body (i.e., >50% of the total body surface area), or areas of broken skin.3 11 (See Absorption under Pharmacokinetics.)

Do not use occlusive dressings or wrappings.1 9

Dosage

Pediatric Patients

Atopic Dermatitis
Topical

Children 2–15 years of age: Apply 0.03% ointment to affected areas twice daily,1 9 approximately 12 hours apart.9

Adolescents ≥16 years of age: Apply 0.03 or 0.l% ointment to affected areas twice daily,1 9 b approximately 12 hours apart.9

Discontinue treatment following resolution of signs and symptoms (e.g., pruritus, rash, erythema).a b If manifestations persist beyond 6 weeks, reexamine patient and confirm diagnosis.a

Adults

Atopic Dermatitis
Topical

Apply 0.03 or 0.l% ointment to affected areas twice daily,1 9 approximately 12 hours apart.9

Discontinue treatment following resolution of signs and symptoms (e.g., pruritus, rash, erythema).a b If manifestations persist beyond 6 weeks, reexamine patient and confirm diagnosis.a

Prescribing Limits

Pediatric Patients

Atopic Dermatitis
Topical

For short-term and intermittent use only; avoid continuous long-term use.12 a Safety of noncontinuous use for >1 year not established.12 a c (See Carcinogenicity under Cautions.)

Adults

Atopic Dermatitis
Topical

For short-term and intermittent use only; avoid continuous long-term use.12 a Safety of noncontinuous use for >1 year not established.12 a c (See Carcinogenicity under Cautions.)

Special Populations

Hepatic Impairment

No dosage adjustment appears necessary; effect of hepatic impairment on the pharmacokinetics of topical tacrolimus has not been evaluated.a

Renal Impairment

No dosage adjustment appears necessary.a Effect of renal impairment on the pharmacokinetics of topical tacrolimus has not been evaluated;a following IV administration of tacrolimus, elimination in patients with renal dysfunction is similar to that in healthy individuals.a

Cautions for Protopic

Contraindications

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

Warnings/Precautions

Warnings

Carcinogenicity

Possible increased risk of malignancies.12 13 14 a (See Boxed Warning.)

Malignancies (including lymphoma and skin cancers) reported rarely in children and adults receiving topical tacrolimus.12 13 14 a Concerns also based on case reports of malignancies (including lymphoma and skin cancers) in patients (including transplant patients) receiving prolonged systemic therapy with calcineurin inhibitors (e.g., cyclosporine, tacrolimus);a 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 due to immunosuppression;1 10 11 12 13 14 a and known pharmacologic effects of these immunosuppressants.a 12 13 14

Systemic administration of tacrolimus in kidney and liver transplant patients is associated with development of lymphoma and skin cancers.13 14 a Risk 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.14 a The lowest blood tacrolimus concentration associated with systemic effects (e.g., immunosuppression) has not been determined.a (See Absorption under Pharmacokinetics.)

Risk associated with systemic therapy is related to intensity and duration of immunosuppression.a The potential for systemic immunosuppression with topical tacrolimus and the drug’s role in the development of malignancies in humans have not been established.12 13 14 a 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, FDA recommends limiting use to the labeled indication, reserving the drug for use as a second-line agent for short-term and intermittent treatment.12 13 (See Atopic Dermatitis under Uses, see Immunocompromised Patients under Cautions, and see Dosage and Administration.) Carefully evaluate potential risks and benefits of therapy.12 13

Avoid use for malignant or premalignant skin conditions (e.g., cutaneous T-cell lymphoma [CTCL]), which may appear clinically similar to dermatitis.a

General Precautions

Lymphadenopathy

Lymphadenopathy reported; usually related to infections and resolves following appropriate anti-infective therapy.1 Also reported in association with malignancy.14 Investigate etiology if lymphadenopathy develops.1 Discontinue tacrolimus in the absence of a clear etiology or in the presence of acute infectious mononucleosis.a Monitor patients with lymphadenopathy to ensure that it resolves.1

Netherton’s Syndrome

Not recommended for use in patients with Netherton’s syndrome because of the potential for increased systemic absorption of tacrolimus.1

Generalized Erythroderma

Safety in patients with generalized erythroderma has not been established.1

Dermatologic Reactions

Possible burning sensation (burning, stinging, soreness) or pruritus at the treatment site within the first few days of initiating therapy.1 Reactions usually improve as the lesions of atopic dermatitis resolve.1

Infectious Complications

Clinical infections (e.g., bacterial, viral) at treatment sites should be cleared before initiating tacrolimus therapy.1 a Safety and efficacy not established for treatment of clinically infected atopic dermatitis.1

Possible increased risk of varicella-zoster infections (chickenpox or shingles), herpes simplex virus infection, or eczema herpeticum.1

Systemic administration of tacrolimus in kidney and liver transplant patients associated with increased susceptibility to infection.14

Phototoxicity

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

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

Immunocompromised Patients

Safety and efficacy not established and not recommended for use in immunocompromised adults or children.12 13 14 a

Renal Effects

Acute renal failure reported rarely in patients receiving topical tacrolimus.a Increased risk of systemic absorption in patients with epidermal barrier defects, especially following topical application to large body surface areas.a

Use with caution in patients predisposed to renal impairment.a

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into milk following topical administration.11 Discontinue nursing or the drug.1

Blacks

0.03% ointment is ineffective; use the 0.1% ointment.1 4 11

Pediatric Use

Safety and efficacy not established and not recommended for use in children <2 years of age.1 a c

Use only the 0.03% ointment when topical tacrolimus is indicated in immunocompetent children 2–15 years of age.a c (See Atopic Dermatitis under Uses.)

Long-term effects on the developing immune system in infants and children are not known.12 13 14 a

Not recommended for use in immunocompromised children.12 13 14 a

Geriatric Use

No substantial differences in safety relative to younger adults.1

Renal Impairment

Use with caution in patients predisposed to renal impairment.a (See Renal Effects.)

Common Adverse Effects

Burning sensation, pruritus, flu-like symptoms, skin erythema, headache.1 5 6

Interactions for Protopic

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

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors of CYP3A4 isoenzyme in patients with widespread and/or erythrodermic disease.1

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles

Potential interaction (inhibition of tacrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Calcium-channel blocking agents

Potential interaction (inhibition of tacrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Cimetidine

Potential interaction (inhibition of tacrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Erythromycin

Potential interaction (inhibition of tacrolimus metabolism) in patients with widespread and/or erythrodermic disease (which may increase systemic absorption)1

Caution advised in patients with widespread and/or erythrodermic disease1

Meningococcal vaccine

Responses to meningococcal serogroup C similar in children 2–11 years of age with moderate to severe atopic dermatitis treated with topical tacrolimus (0.03%), those treated with topical hydrocortisone, and in healthy childrena

Pneumococcal 23-valent polysaccharide vaccine

Protective antibody titers achieved in limited number of children 2–12 years of age with moderate to severe atopic dermatitis treated with topical tacrolimus (0.03%)a

Protopic Pharmacokinetics

Absorption

Bioavailability

Minimally absorbed into systemic circulation following topical application to the skin.a Apparent systemic bioavailability approximately 0.5%.a

Systemic absorption decreases as atopic dermatititis resolves.a

Following topical application (53% of total body surface area) in adults, systemic exposure is approximately 30-fold less than following oral administration of immunosuppressive dosages of tacrolimus in adult kidney and liver transplant patients.a

Blood concentrations in children receiving tacrolimus topically occasionally have been in the concentration range achieved with systemic therapy.14 a

Use of occlusive dressing/wrappings or on the face or neck, large areas of the body (i.e., >50% of the total body surface area), or areas of broken skin may increase systemic exposure to the drug.3 11

Distribution

Plasma Protein Binding

Approximately 99% (mainly albumin and α1-acid glycoprotein).a

Elimination

Metabolism

Studies using systemic tacrolimus indicate that the drug is extensively metabolized in the liver and in the GI tract, principally via oxidation by CYP isoenzymes.10 11 a

Elimination Route

Following oral or IV administration, eliminated principally in feces (92%); approximately 1–2% excreted unchanged in urine.a

Half-life

Following IV administration, elimination half-life of approximately 44–48 hours in healthy individuals;a similar elimination half-life (31–48 hours) following oral administration.a

Stability

Storage

Topical

Ointment

15–30°C.1

Actions

  • Exact mechanism(s) of immunosuppressive action in the treatment of atopic dermatitis not known.1

  • Inhibits T-lymphocyte cell activation; 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

  • Not genotoxic and does not interact directly with DNA; however, may impair local immunosurveillance.14

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.a b

  • Importance of informing clinicians of other medical conditions, including Netherton’s syndrome, skin infections (e.g., chicken pox, herpes), or weakened immune system.a b

  • Advise patients that tacrolimus is for external use on affected areas of the skin only.a b Importance of patients or caregivers washing their hands before and after application if hands are not an area for treatment.1

  • Advise patients not to bathe, shower, or swim immediately after application.b

  • Importance of avoiding contact with the eyes.a b

  • 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.a b

  • Advise patients to discontinue tacrolimus when the signs and symptoms (e.g., itching, rash, redness) of atopic dermatitis (eczema) resolve, or as directed by clinician.a b Importance of following the clinician’s advice if symptoms recur after a course of treatment.a b

  • Importance of not using the drug in children <2 years of age.a

  • Importance of using only the 0.03% ointment in children 2–15 years of age;a b either 0.03% or 0.1% ointment may be used in adults and adolescents ≥16 years of age.a b

  • Importance of avoiding use of bandages, dressings, or wrappings on treated skin.a b

  • Importance of not using the drug for any disorder other than that for which it was prescribed.1

  • Importance of using tacrolimus exactly as prescribed and of not using the drug continuously for a long period of time.a b 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.12 13 a b

  • Importance of reporting persistently swollen glands or any other adverse reactions to clinician.a b

  • 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.a b

  • Importance of notifying clinician if a skin infection develops during treatment with tacrolimus.a b

  • 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.3 11 a b

  • Importance of not swallowing tacrolimus; contact clinician if swallowed.a b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary supplements, herbal supplements, any other skin product, or any form of phototherapy (UVA or UVB).9 a b

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tacrolimus

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Ointment

0.03%

Protopic

Astellas

0.1%

Protopic

Astellas

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Protopic 0.03% Ointment (ASTELLAS): 30/$152.59 or 90/$440.36

Protopic 0.03% Ointment (ASTELLAS): 60/$310.00 or 180/$879.93

Protopic 0.1% Ointment (ASTELLAS): 30/$152.99 or 90/$450.95

Protopic 0.1% Ointment (ASTELLAS): 60/$308.00 or 180/$880.98

Protopic 0.1% Ointment (ASTELLAS): 100/$518.99 or 300/$1,504.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Astellas Pharma US, Inc. Protopic (tacrolimus) ointment prescribing information. Deerfield, IL; 2005 Jul.

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. [IDIS 457747] [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. [IDIS 457751] [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. [IDIS 451208] [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.

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.

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.

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

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

c. 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.

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