Tacrolimus (Page 4 of 6)

Pregnancy

Teratogenic Effects:

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.

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.

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).

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.

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.

Table 2
(click image for full-size original)

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.

Table 3
(click image for full-size original)

† May be reasonably associated with the use of this drug product

‡ 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.

‡‡ Generally “warts”.

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

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.

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.

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