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 ).

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

ADVERSE REACTIONS 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.

Duration of Follow-up in Four Open-label Safety Studies Time on Study Adult Pediatrics Total < 1 year 4682 4481 9163 ≥ 1 year 1185 1349 2534 ≥ 2 years 200 275 475 ≥ 3 years 118 182 300 The following table depicts the adjusted incidence of adverse events pooled across the 3 identically designed 12-week controlled studies for patients in vehicle, and 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.

Incidence of Treatment Emergent Adverse Events 12-Week, Randomized, Double-Blind, Phase 3 Studies 12-Week Adjusted Incidence Rate (%) Open-Label Studies (up to 3 years) 0.1% and 0.03% Tacrolimus Ointment Incidence Rate (%) Adult Pediatric Adult Pediatric Total Vehicle (n=212) % 0.03% Tacrolimus Ointment (n=210) % 0.1% Tacrolimus Ointment (n=209) % Vehicle (n=116) % 0.03% Tacrolimus Ointment (n=118) % (n=4682) % (n=4481) % (n=9163) % Skin Burning* 26 46 58 29 43 28 20 24 Pruritus* 37 46 46 27 41 25 19 22 Flu-like symptoms* 19 23 31 25 28 22 34 28 Allergic Reaction 8 12 6 8 4 9 13 11 Skin Erythema 20 25 28 13 12 12 7 9 Headache* 11 20 19 8 5 13 9 11 Skin Infection 11 12 5 14 10 9 16 12 Fever 4 4 1 13 21 2 14 8 Infection 1 1 2 9 7 6 10 8 Cough Increased 2 1 1 14 18 3 10 6 Asthma 4 6 4 6 6 4 13 8 Herpes Simplex 4 4 4 2 0 4 3 3 Eczema Herpeticum 0 1 1 0 2 0 0 0 Pharyngitis 3 3 4 11 6 4 12 8 Accidental Injury 4 3 6 3 6 6 8 7 Pustular Rash 2 3 4 3 2 2 7 5 Folliculitis* 1 6 4 0 2 4 2 3 Rhinitis 4 3 2 2 6 2 4 3 Otitis Media 4 0 1 6 12 2 11 6 Sinusitis* 1 4 2 8 3 6 7 6 Diarrhea 3 3 4 2 5 2 4 3 Urticaria 3 3 6 1 1 3 4 4 Lack of Drug Effect 1 1 0 1 1 6 6 6 Bronchitis 0 2 2 3 3 4 4 4 Vomiting 0 1 1 7 6 1 4 3 Maculopapular Rash 2 2 2 3 0 2 1 1 Rash* 1 5 2 4 2 2 3 3 Abdominal Pain 3 1 1 2 3 1 3 2 Fungal Dermatitis 0 2 1 3 0 2 4 3 Gastroenteritis 1 2 2 3 0 2 4 3 Alcohol Intolerance* 0 3 7 0 0 4 0 2 Acne* 2 4 7 1 0 3 2 3 Sunburn 1 2 1 0 0 2 1 1 Skin Disorder 2 2 1 1 4 2 2 2 Conjunctivitis 0 2 2 2 1 3 3 3 Pain 1 2 1 0 1 2 1 2 Vesiculobullous Rash* 3 3 2 0 4 2 1 1 Lymphadenopathy 2 2 1 0 3 1 2 1 Nausea 4 3 2 0 1 2 1 2 Skin Tingling* 2 3 8 1 2 2 1 1 Face Edema 2 2 1 2 1 1 1 1 Dyspepsia* 1 1 4 0 0 2 2 2 Dry Skin 7 3 3 0 1 1 1 1 Hyperesthesia* 1 3 7 0 0 2 0 1 Skin Neoplasm Benign† 1 1 1 0 0 1 2 2 Back Pain* 0 2 2 1 1 3 0 2 Peripheral Edema 2 4 3 0 0 2 0 1 Varicella Zoster/ Herpes Zoster*‡ 0 1 0 0 5 1 2 2 Contact Dermatitis 1 3 3 3 4 2 2 2 Asthenia 1 2 3 0 0 1 0 1 Pneumonia 0 1 1 2 0 1 3 2 Eczema 2 2 2 0 0 1 0 1 Insomnia 3 4 3 1 1 2 0 1 Exfoliative Dermatitis 3 3 1 0 0 0 1 0 Dysmenorrhea 2 4 4 0 0 2 1 1 Periodontal Abscess 1 0 1 0 0 1 1 1 Myalgia* 0 3 2 0 0 2 1 1 Cyst* 0 1 3 0 0 1 0 1 Cellulitis 1 1 1 0 0 1 1 1 Exacerbation of Untreated Area 1 0 1 1 0 1 1 1 Procedural Complication 1 0 0 1 0 1 1 1 Hypertension 0 0 1 0 0 2 0 1 Tooth Disorder 0 1 1 1 0 2 1 1 Arthralgia 1 1 3 2 0 2 1 2 Depression 1 2 1 0 0 1 0 1 Paresthesia 1 3 3 0 0 2 1 2 Alopecia 0 1 1 0 0 1 1 1 Urinary Tract Infection 0 0 1 0 0 2 1 2 Ear Pain 1 0 1 0 1 0 1 1 * May be reasonably associated with the use of this drug product † Generally “warts”.

‡ All the herpes zoster cases in the pediatric 12-week study and the majority of cases in the open-label pediatric studies were reported as chicken pox.

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.

Post-Marketing Events The following adverse reactions have been identified during postapproval use of tacrolimus 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 Netherton's syndrome, renal impairment Skin Rosacea, application site edema