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 PROTOPIC 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 |
|
³ 1 year |
1185 |
1349 |
2534 |
|
³ 2 years |
200 |
275 |
475 |
|
³ 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, PROTOPIC Ointment 0.03%, and PROTOPIC 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) 0.10% and 0.03% Tacrolimus Ointment Incidence Rate (%) |
|
Adult |
Pediatric |
Adult |
Pediatric |
Total |
|
Vehicle
(n=212)
% |
0.03%
Tacrolimus
Ointment
(n=210)
% |
0.10%
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 |
|
Complication Procedural |
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
‡ 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, blephartitis, bone disorder, breast neoplasm benign, bursitis, cataract NOS, chest pain, chills, colitis, conjuntival edema, constipation, cramps, cutanteous moniliasis, cystitis, dehydration, dizziness, dry eyes, dry mouth/nose, dyspnea, ear disorder, ecchymosis, edema, epistaxis, eye pain, furunculosis, gastritis, gastrointestinal disorder, hernia, hypercholerestemia, 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 PROTOPIC 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
DRUG INTERACTIONS
Formal topical drug interaction studies with PROTOPIC Ointment have not been conducted. Based on its extent of absorption, interactions of PROTOPIC 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.
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