Tacrolimus (Page 4 of 6)

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.

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.

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