tacrolimus 0.03 % Topical Ointment

Generic Name: TACROLIMUS
Brand Name: Tacrolimus
  • Substance Name(s):
  • TACROLIMUS

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 tacrolimus ointment.

Therefore: • Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.

• Tacrolimus ointment is not indicated for use in children less than 2 years of age.

Only 0.03% tacrolimus 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 tacrolimus 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 tacrolimus ointment.

Therefore: • Tacrolimus 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 tacrolimus ointment has not been established beyond one year of non-continuous use.

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

DRUG INTERACTIONS

Drug Interactions Formal topical drug interaction studies with tacrolimus ointment have not been conducted.

Based on its extent of absorption, interactions of tacrolimus 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.

OVERDOSAGE

Tacrolimus ointment is not for oral use.

Oral ingestion of tacrolimus ointment may lead to adverse effects associated with systemic administration of tacrolimus.

If oral ingestion occurs, medical advice should be sought.

DESCRIPTION

Tacrolimus ointment contains tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis .

It is for topical dermatologic use only.

Chemically, tacrolimus is designated as [3 S- [3 R * [ E (1 S * ,3 S * ,4 S * )],4 S * ,5 R * ,8 S * ,9 E ,12 R * ,14 R * ,15 S * ,16 R * ,18 S * ,19 S * ,26a R * ]]-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 a molecular formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03.

Each gram of tacrolimus 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.

Structural Formula

CLINICAL STUDIES

Three randomized, double-blind, vehicle-controlled, multi-center, phase 3 studies were conducted to evaluate tacrolimus 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 tacrolimus ointment 0.03%, tacrolimus 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 tacrolimus ointment 0.03% treatment group compared to the vehicle treatment group, but there was insufficient evidence that tacrolimus ointment 0.1% provided more efficacy than tacrolimus 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 tacrolimus ointment 0.03% and tacrolimus ointment 0.1% treatment groups compared to the vehicle treatment group.

There was evidence that tacrolimus ointment 0.1% may provide more efficacy than tacrolimus ointment 0.03%.

The difference in efficacy between tacrolimus 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 Tacrolimus Ointment 0.03% N=117 Vehicle Ointment N=212 Tacrolimus Ointment 0.03% N=211 Tacrolimus Ointment 0.1% N=209 100% ≥ 90% ≥ 75% ≥ 50% 4 (3%) 8 (7%) 18 (16%) 31 (27%) 14 (12%) 42 (36%) 65 (56%) 85 (73%) 2 (1%) 14 (7%) 30 (14%) 42 (20%) 21 (10%) 58 (28%) 97 (46%) 130 (62%) 20 (10%) 77 (37%) 117 (56%) 152 (73%) A statistically significant difference in the percentage of adult patients with ≥ 90% improvement was achieved by week 1 for those treated with tacrolimus ointment 0.1%, and by week 3 for those treated with tacrolimus 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 tacrolimus ointment 0.03%.

In adult patients who had achieved ≥ 90% improvement at the end of treatment, 35% of those treated with tacrolimus ointment 0.03% and 41% of those treated with tacrolimus 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 tacrolimus 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 tacrolimus ointment treatment groups in adults and in the tacrolimus 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 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 Figure 4 – Pediatric Patients Mean Erythema Over Time The time course of improvement in the remaining secondary efficacy variables was similar to that of erythema, with improvement in lichenification slightly slower.

Figure 1 Figure 2 Figure 3 Figure 4

HOW SUPPLIED

Tacrolimus ointment 0.03% NDC 0168-0417-30 NDC 0168-0417-60 NDC 0168-0417-99 30 gram laminate tube 60 gram laminate tube 100 gram laminate tube Tacrolimus ointment 0.1% NDC 0168-0416-30 NDC 0168-0416-60 NDC 0168-0416-99 30 gram laminate tube 60 gram laminate tube 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

GERIATRIC USE

Geriatric Use Four hundred and four (404) patients ≥ 65 years old received tacrolimus ointment in phase 3 studies.

The adverse event profile for these patients was consistent with that for other adult patients.

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

Tacrolimus 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.

Tacrolimus ointment is not indicated for children younger than 2 years of age (see boxed WARNING , WARNINGS and PRECAUTIONS: Pediatric Use ).

PEDIATRIC USE

Pediatric Use Tacrolimus ointment is not indicated for children less than 2 years of age.

Only the lower concentration, 0.03%, of tacrolimus 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 tacrolimus 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 tacrolimus 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 tacrolimus 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 tacrolimus ointment, 24 (0.5%) were reported with eczema herpeticum.

Since the safety and efficacy of tacrolimus 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).

PREGNANCY

Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women.

The experience with tacrolimus 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.

Tacrolimus ointment should be used during pregnancy only if the potential benefit to the mother justifies a potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers Although systemic absorption of tacrolimus following topical applications of tacrolimus 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.

BOXED WARNING

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 tacrolimus ointment.

Therefore: • Continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.

• Tacrolimus ointment is not indicated for use in children less than 2 years of age.

Only 0.03% tacrolimus ointment is indicated for use in children 2-15 years of age.

INFORMATION FOR PATIENTS

Information for Patients (See MEDICATION GUIDE ) Patients using tacrolimus 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.

DOSAGE AND ADMINISTRATION

Adult Tacrolimus ointment 0.03% and 0.1% • Apply a thin layer of 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 tacrolimus ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of tacrolimus ointment under occlusion, which may promote systemic exposure, has not been evaluated.

Tacrolimus ointment should not be used with occlusive dressings.

PEDIATRIC – FOR CHILDREN 2-15 YEARS Tacrolimus ointment 0.03% • Apply a thin layer of 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 tacrolimus ointment should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of tacrolimus ointment under occlusion, which may promote systemic exposure, has not been evaluated.

Tacrolimus ointment should not be used with occlusive dressings.