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warnings and cautions
5 WARNINGS AND PRECAUTIONS Ophthalmic Adverse Reactions. Eye disorders, including severe eye pain, chemical conjunctivitis, corneal burn, eyelid edema, eyelid ptosis, periorbital edema can occur after exposure. Avoid accidental transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, flush eyes with water and seek medical care. ( 5.1 ) Non-Melanoma Skin Cancer. Cases of non-melanoma skin cancer have been reported after treatment with Ingenol Mebutate Gel. Monitor patients with risk factors for skin cancer. ( 5.3 ) Local Skin Reactions. Local skin reactions can occur including severe reactions (e.g., vesiculation/pustulation, erosion/ulceration). Administration of Ingenol Mebutate Gel is not recommended until skin is healed from any previous drug or surgical treatment. ( 5.4 ) 5.1 Ophthalmic Adverse Reactions Eye disorders, including severe eye pain, chemical conjunctivitis, corneal burn, eyelid edema, eyelid ptosis, periorbital edema can occur after exposure [ see Adverse Reactions (6) ]. To avoid transfer of the drug into the eyes and to the periocular area during and after application, patients should wash hands well after applying Ingenol Mebutate Gel. If accidental exposure occurs, the area should be flushed with water and the patient should seek medical care as soon as possible. 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and allergic contact dermatitis, have been reported postmarketing. If anaphylactic or other clinically significant hypersensitivity reactions occur, discontinue Ingenol Mebutate Gel immediately and institute appropriate medical therapy. 5.3 Non-Melanoma Skin Cancer Non-melanoma skin cancers have been reported in patients treated with Ingenol Mebutate Gel. Cases of rapidly growing squamous cell carcinoma have been reported in the treatment area within a few weeks after treatment completion. Counsel patients on the potential risk and monitor closely those patients with risk factors for skin cancer. 5.4 Local Skin Reactions Severe skin reactions in the treated area, including erythema, crusting, swelling, vesiculation/postulation, and erosion/ulceration, can occur after topical application of Ingenol Mebutate Gel [ see Adverse Reactions (6) ]. Administration of Ingenol Mebutate Gel is not recommended until the skin is healed from any previous drug or surgical treatment.
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: • Ophthalmic Adverse Reaction [ see Warnings and Precautions (5.1) ] • Hypersensitivity Reactions [ see Warnings and Precautions (5.2) ] • Non-Melanoma Skin Cancer [ see Warnings and Precautions (5.3) ] The most common adverse reactions (≥2 %) are local skin reactions, application site pain, application site pruritus, application site irritation, application site infection, periorbital edema, nasopharyngitis and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure to ingenol mebutate gel in 499 subjects with actinic keratosis, including 274 subjects exposed to ingenol mebutate gel field treatment (skin area of 25 cm 2 in the face or scalp regions) at a concentration of 0.015% once daily for 3 consecutive days, and 225 subjects exposed to ingenol mebutate gel field treatment (skin area of 25 cm 2 in the trunk or extremities regions) at a concentration of 0.05% once daily for 2 consecutive days. Local skin reactions, including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration were assessed within the selected treatment area and graded by the investigator on a scale of 0 to 4. A grade of 0 represented no reaction present in the treated area, and a grade of 4 indicated a marked and severe skin reaction that extended beyond the treated area. Table 1. Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area during the 57 Days Post Treatment Period (face/scalp trials) Face and Scalp (N=545) Ingenol Mebutate Gel, 0.015% once daily for 3 days Skin reactions Any Grade a > Baseline Grade 4 Ingenol Mebutate Gel (N=274) Vehicle (N=271) Ingenol Mebutate Gel (N=274) Vehicle (N=271) Erythema 258 (94%) 69 (25%) 66 (24%) 0 (0%) Flaking/Scaling 233 (85%) 67 (25%) 25 (9%) 0 (0%) Crusting 220 (80%) 46 (17%) 16 (6%) 0 (0%) Swelling 217 (79%) 11 (4%) 14 (5%) 0 (0%) Vesiculation/Pustulation 154 (56%) 1 (0%) 15 (5%) 0 (0%) Erosion/Ulceration 87 (32%) 3 (1%) 1 (0%) 0 (0%) a Mild (grade 1), Moderate (grade 2-3) or Severe (grade 4). Table 2. Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area during the 57 Days Post Treatment Period (trunk/extremities trials) Trunk and Extremities (N=457) Ingenol Mebutate Gel, 0.05% once daily for 2 days Skin reactions Any Grade a > Baseline Grade 4 Ingenol Mebutate Gel (N=225) Vehicle (N=232) Ingenol Mebutate Gel (N=225) Vehicle (N=232) Erythema 207 (92%) 43 (19%) 34 (15%) 0 (0%) Flaking/Scaling 203 (90%) 44 (19%) 18 (8%) 0 (0%) Crusting 167 (74%) 23 (10%) 8 (4%) 0 (0%) Swelling 143 (64%) 13 (6%) 7 (3%) 0 (0%) Vesiculation/Pustulation 98 (44%) 2 (1%) 3 (1%) 0 (0%) Erosion/Ulceration 58 (26%) 6 (3%) 2 (1%) 0 (0%) a Mild (grade 1), Moderate (grade 2-3) or Severe (grade 4). Local skin reactions typically occurred within 1 day of treatment initiation, peaked in intensity up to 1 week following completion of treatment, and resolved within 2 weeks for areas treated on the face and scalp, and within 4 weeks for areas treated on the trunk and extremities. Adverse reactions that occurred in ≥2% of subjects treated with ingenol mebutate gel and at a higher frequency than the vehicle are presented in Table 3 and Table 4. Table 3. Adverse reactions occurring in ≥ 2% of subjects treated with ingenol mebutate gel and at higher frequency than vehicle (face/scalp trials) Face/Scalp Adverse Reactions Ingenol Mebutate Gel, 0.015% (N=274) Vehicle (N=271) Application Site Pain 42 (15%) 1 (0%) Application Site Pruritus 22 (8%) 3 (1%) Application Site Infection 7 (3%) 0 (0%) Periorbital Edema 7 (3%) 0 (0%) Headache 6 (2%) 3 (1%) Table 4. Adverse reactions occurring in ≥ 2% of subjects treated with ingenol mebutate gel and at higher frequency than vehicle (trunk/extremities trials) Trunk/Extremities Adverse Reactions Ingenol Mebutate Gel, 0.05% (N=225) Vehicle (N=232) Application Site Pruritus 18 (8%) 0 (0%) Application Site Irritation 8 (4%) 1 (0%) Nasopharyngitis 4 (2%) 2 (1%) Application Site Pain 5 (2%) 0 (0%) Less common adverse reactions in subjects treated with ingenol mebutate gel included: eyelid edema, eye pain, conjunctivitis. A total of 108 subjects treated with ingenol mebutate gel on the face/scalp and 38 subjects treated on the trunk/extremities were followed for 12 months. Results from these studies did not change the safety profile of ingenol mebutate gel. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ingenol mebutate gel, 0.015% and 0.05%. 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. Eye disorders: chemical conjunctivitis, corneal burn Immune system disorders: hypersensitivity, Stevens-Johnson syndrome Infections: herpes zoster Skin and Subcutaneous disorders: non-melanoma skin cancer, allergic contact dermatitis, application site pigmentation changes, application site scarring