Tacrolimus ointment

Dosage Forms & Strengths

ointment

• 0.03%
• 0.1%

Atopic Dermatitis

0.03% or 0.1% ointment: Apply thin layer to affected area q12hr; discontinue treatment when symptoms have cleared; if no improvement within 6 weeks, reassess diagnosis

Dosage Forms & Strengths

ointment

• 0.03%
• 0.1%

Atopic Dermatitis

<2 years old: Not recommended

2-15 years: 0.03% ointment: Apply thin layer to affected area q12hr

>15 years: Apply 0.03% or 0.1% ointment as thin layer to affected area q12hr; discontinue treatment when symptoms have cleared; if no improvement within 6 weeks, reassess diagnosis

Tacrolimus ointment is applied to the affected areas of skin twice daily. The 0.1% concentration of tacrolimus ointment is approved for the treatment of adults, while the 0.03% concentration is approved for the treatment of both children (ages two and older) and adults.

Ointment: 0.03% and 0.1%.

Tacrolimus should be stored at room temperature 15 C - 30 C (59 F - 86 F).

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.

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.

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:

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:

(See CLINICAL PHARMACOLOGY, boxed WARNINGS, 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, 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.

* 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

Infections

Bullous impetigo, osteomyelitis, septicemia

Neoplasms

Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma

Renal

Acute renal failure in patients with or without Netherton's syndrome, renal impairment

Skin

Rosacea, application site edema

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.