Label: TACROLIMUS ointment

FOR DERMATOLOGIC USE ONLY
NOT FOR OPHTHALMIC USE

Rx Only

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

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 C44H69NO12∙H2O 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 with all-rac-α-tocopherol, paraffin, propylene carbonate, white petrolatum with butylhydroxytoluene, and white wax.

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.

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.

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).

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

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 WARNING, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

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 Tacrolimus 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, Tacrolimus Ointment 0.03%, and Tacrolimus 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, neoplasm benign, oral moniliasis, otitis externa, photosensitivity reaction, rectal disorder, seborrhea, skin carcinoma, skin discoloration, skin hypertrophy, skin ulcer, stomatitis, tendon disorder, thinking abnormal, tooth caries, sweating, syncope, tachycardia, taste perversion, unintended pregnancy, vaginal moniliasis, vaginitis, valvular heart disease, vasodilatation, and vertigo.

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.

Manufactured by:
LEO Laboratories Ltd.
285 Cashel Road
Dublin 12, Ireland

Distributed by:
Padagis
Allegan, MI 49010
www.padagis.com

Revised: 12/2022

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

What is the most important information I should know about Tacrolimus Ointment?

The safety of using Tacrolimus Ointment for a long period of time is not known. A very small number of people who have used Tacrolimus Ointment have had cancer (for example, skin or lymphoma). However, a link with Tacrolimus Ointment has not been shown. Because of this concern:

• Do not use Tacrolimus Ointment continuously for a long time.
• Use Tacrolimus Ointment only on areas of your skin that have eczema.
• Do not use Tacrolimus Ointment on a child under 2 years old.

Tacrolimus Ointment comes in two strengths:

• Only Tacrolimus Ointment 0.03% is for use on children aged 2 to 15 years.
• Either Tacrolimus Ointment 0.03% or 0.1% can be used by adults and children 16 years and older.

Talk to your doctor for more information.

What is Tacrolimus Ointment?

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

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

Who should not use Tacrolimus Ointment?

Tacrolimus Ointment should not be used:

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

What should I tell my doctor before starting Tacrolimus Ointment?

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

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

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

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

How should I use Tacrolimus Ointment?

• Use Tacrolimus Ointment exactly as prescribed.
• Use Tacrolimus Ointment only on areas of your skin that have eczema.
• Use Tacrolimus Ointment for short periods, and if needed, treatment may be repeated with breaks in between.
• Stop Tacrolimus Ointment when the signs and symptoms of eczema, such as itching, rash, and redness go away, or as directed by your doctor.
• Follow your doctor's advice if symptoms of eczema return after treatment with Tacrolimus Ointment.
• Call your doctor if :
  • your symptoms get worse with Tacrolimus Ointment.
  • you get an infection on your skin.
  • your symptoms do not improve after 6 weeks of treatment. Sometimes other skin diseases can look like eczema.

To apply Tacrolimus Ointment:

• Wash your hands before applying Tacrolimus Ointment.
• Apply a thin layer of Tacrolimus Ointment twice daily to the areas of skin affected by eczema.
• Use the smallest amount of Tacrolimus Ointment needed to control the signs and symptoms of eczema.
• If you are a caregiver applying Tacrolimus Ointment to a patient, or if you are a patient who is not treating your hands, wash your hands with soap and water after applying Tacrolimus Ointment. This should remove any ointment left on the hands.
• Do not bathe, shower, or swim right after applying Tacrolimus Ointment. This could wash off the ointment.
• You can use moisturizers with Tacrolimus Ointment. Make sure you check with your doctor first about the products that are right for you. Because the skin of patients with eczema can be very dry, it is important to keep up good skin care practices. If you use moisturizers, apply them after Tacrolimus Ointment.

What should I avoid while using Tacrolimus Ointment?

• Do not use ultraviolet light therapy, sun lamps, or tanning beds during treatment with Tacrolimus Ointment.
• Limit sun exposure during treatment with Tacrolimus Ointment even when the medicine is not on your skin. If you need to be outdoors after applying Tacrolimus Ointment, wear loose fitting clothing that protects the treated area from the sun. Ask your doctor what other types of protection from the sun you should use.
• Do not cover the skin being treated with bandages, dressings or wraps. You can wear normal clothing.
• Avoid getting Tacrolimus Ointment in the eyes or mouth. Do not swallow Tacrolimus Ointment. If you do, call your doctor.

What are the possible side effects of Tacrolimus Ointment?

Please read the first section of this Medication Guide.

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

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

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

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

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

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

How should I store Tacrolimus Ointment?

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

General advice about Tacrolimus Ointment

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

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

Your doctor or pharmacist can give you information about Tacrolimus Ointment that is written for health care professionals. For more information, you can call Perrigo at 1-866-634-9120.

What are the ingredients in Tacrolimus Ointment?

Active Ingredient: tacrolimus, either 0.03% or 0.1%
Inactive Ingredients: mineral oil, paraffin, propylene carbonate, white petrolatum, white wax, all-rac-α-tocopherol and butylhydroxytoluene.

Manufactured by:
LEO Laboratories Ltd.
285 Cashel Road
Dublin 12, Ireland

Distributed by:
Padagis
Allegan, MI 49010
www.padagis.com

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

Revised: 12/2022

NDC 45802-390-00

Rx Only

Tacrolimus Ointment 0.03%
Attention: Dispense with enclosed Medication Guide

30 g

Padagis™

NDC 45802-700-00

Rx Only

Tacrolimus Ointment 0.1%
Attention: Dispense with enclosed Medication Guide

30 g

Padagis™