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 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
|
less than 1 year |
4682 |
4481 |
9163 |
greater than or equal to 1 year |
1185 |
1349 |
2534 |
greater than or equal to 2 years |
200 |
275 |
475 |
greater than or equal to 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-Blink, Phase 3 Studies Open-Label Studies (up to 3 years) 0.1% and 0.03% Tacrolimus 12-Week Adjusted Incidence Rate (%) 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
|
Flue-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
|
Otis 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
|
Gastroentesritis
|
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
|
Hypersthesia*
|
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
|
Asthena
|
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.
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
|
REPORTS OF SUSPECTED PROTOPIC SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Protopic. The information is not vetted and should not be considered as verified clinical evidence.
Possible Protopic side effects / adverse reactions in 31 year old male
Reported by a health professional (non-physician/pharmacist) from Canada on 2011-11-02
Patient: 31 year old male weighing 67.0 kg (147.4 pounds)
Reactions: Abdominal Discomfort, Nausea, Headache
Adverse event resulted in: disablity
Suspect drug(s):
Protopic
Other drugs received by patient: Cold Cream; Elocon
Possible Protopic side effects / adverse reactions in 47 year old female
Reported by a health professional (non-physician/pharmacist) from France on 2011-11-22
Patient: 47 year old female
Reactions: Superinfection, Mycosis Fungoides, Dermatitis Exfoliative, Septic Shock
Adverse event resulted in: death
Suspect drug(s):
Protopic
Other drugs received by patient: Neoral
Possible Protopic side effects / adverse reactions in 12 year old male
Reported by a physician from Portugal on 2011-11-23
Patient: 12 year old male weighing 45.0 kg (99.0 pounds)
Reactions: Dermatitis Atopic, B-Cell Lymphoma, Upper Limb Fracture, Tooth Extraction, Mycosis Fungoides, Condition Aggravated
Suspect drug(s):
Protopic
Other drugs received by patient: Hydroxyzine; Corticosteroids, Dermatological Preparations; Emollients and Protectives
|