Tacrolimus

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 ).

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 to 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.

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

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, 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 May be reasonably associated with the use of this drug product 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 Generally “warts”. 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 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. 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 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, …

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.

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 FcɛRI on Langerhans cells.

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 an empirical 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 with all- rac -α-tocopherol, paraffin, propylene carbonate, white petrolatum with butylhydroxytoluene, and white wax. Chemical Structure

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.

HOW SUPPLIED Tacrolimus ointment 0.03% NDC 16729-421-10 30 gram laminate tube NDC 16729-421-12 60 gram laminate tube 16729-421-01 100 gram laminate tube Tacrolimus ointment 0.1% NDC 16729-422-10 30 gram laminate tube NDC 16729-422-12 60 gram laminate tube NDC 16729-422-01 100 gram laminate tube Store at 25°C (77°F): excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature.] Manufactured for: Accord Healthcare, Inc., 8041 Arco Corporate Drive, Suite 200, Raleigh, NC 27617, USA. Manufactured by: Intas Pharmaceuticals Limited, Plot No.:457/458-Matoda/ Plot No.191/218P-Chacharwadi, Sarkhej-Bavla Highway, Taluka - Sanand, Matoda, Ahmedabad, Gujarat 382210, India. 10 2400 2 6031391 Issued July 2024