Protopic (Tacrolimus Topical) - Side Effects and Adverse Reactions

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
< 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, 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) 0.1% 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 1	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 2	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 3	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

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

Overdosage

PROTOPIC Ointment is not for oral use. Oral ingestion of PROTOPIC Ointment may lead to adverse effects associated with systemic administration of tacrolimus. If oral ingestion occurs, medical advice should be sought.