NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been performed to evaluate the carcinogenic potential of Picato(R) gel or ingenol mebutate. The effects of ingenol mebutate on fertility have not been evaluated.Ingenol mebutate was negative in the Ames test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test, but positive in the Syrian hamster embryo (SHE) cell transformation assay.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Topical overdosing of Picato gel could result in an increased incidence of local skin reactions.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 0.47 Tube Carton 0.015%. NDC 50222-502-47 Rx onlyPicato(R) (ingenol mebutate) gel0.015%For Topical Use on Face or Scalp Only Not for Oral, Ophthalmic, or Intravaginal Use3 Unit Dose Tubes Net Wt. 0.47 in each tubeMust be refrigerated. PRINCIPAL DISPLAY PANEL 0.47 Tube Carton 0.015%.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Actinic keratosis is not condition generally seen within the pediatric population. The safety and effectiveness of Picato gel for actinic keratosis in patients less than 18 years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamics of Picato gel is unknown.

ADVERSE REACTIONS SECTION.

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)] 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 LEO Pharma Inc. at 1-877-494-4536 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 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 Picato gel in 499 subjects with actinic keratosis, including 274 subjects exposed to Picato gel field treatment (skin area of 25 cm2 in the face or scalp regions) at concentration of 0.015% once daily for consecutive days, and 225 subjects exposed to Picato gel field treatment (skin area of 25 cm2 in the trunk or extremities regions) at concentration of 0.05% once daily for 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 scale of to 4. grade of represented no reaction present in the treated area, and grade of indicated 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)Picato gel, 0.015% once daily for daysSkin reactions Any Gradea BaselineGrade Picato gel(n=274)Vehicle (n=271)Picato gel(n=274)Vehicle(n=271)Erythema258 (94%)69 (25%)66 (24%)0 (0%)Flaking/Scaling233 (85%)67 (25%)25 (9%)0 (0%)Crusting220 (80%)46 (17%)16 (6%)0 (0%)Swelling217 (79%)11 (4%)14 (5%)0 (0%)Vesiculation/Pustulation154 (56%)1 (0%)15 (5%)0 (0%)Erosion/Ulceration87 (32%)3 (1%)1 (0%)0 (0%)aMild (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)Picato(R) gel, 0.05% once daily for daysSkin reactionsAny Gradea BaselineGrade 4Picato gel(n=225)Vehicle(n=232)Picato gel(n=225)Vehicle(n=232)Erythema207 (92%)43 (19%)34 (15%)0 (0%)Flaking/Scaling203 (90%)44 (19%)18 (8%)0 (0%)Crusting167 (74%)23 (10%)8 (4%)0 (0%)Swelling143 (64%)13 (6%)7 (3%)0 (0%)Vesiculation/Pustulation98 (44%)2 (1%)3 (1%)0 (0%)Erosion/Ulceration58 (26%)6 (3%)2 (1%)0 (0%)aMild (grade 1), Moderate (grade 2-3) or Severe (grade 4).Local skin reactions typically occurred within day of treatment initiation, peaked in intensity up to week following completion of treatment, and resolved within weeks for areas treated on the face and scalp, and within weeks for areas treated on the trunk and extremities.Adverse reactions that occurred in >=2% of subjects treated with Picato gel and at higher frequency than the vehicle are presented in Table and Table 4. Table 3. Adverse reactions occurring in >= 2% of subjects treated with Picato gel and at higher frequency than vehicle (face/scalp trials) Face/ScalpAdverse ReactionsPicato gel, 0.015%(N=274)Vehicle(N=271)Application Site Pain42 (15%)1 (0%)Application Site Pruritus22 (8%)3 (1%)Application Site Infection7 (3%)0 (0%)Periorbital Edema7 (3%)0 (0%)Headache6 (2%)3 (1%) Table 4. Adverse reactions occurring in >= 2% of subjects treated with Picato(R) gel and at higher frequency than vehicle (trunk/extremities trials) Trunk/ExtremitiesAdverse ReactionsPicato gel, 0.05%(N=225)Vehicle(N=232)Application Site Pruritus18 (8%)0 (0%)Application Site Irritation8 (4%)1 (0%)Nasopharyngitis4 (2%)2 (1%)Application Site Pain5 (2%)0 (0%)Less common adverse reactions in subjects treated with Picato gel included: eyelid edema, eye pain, conjunctivitis.A total of 108 subjects treated with Picato 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 Picato gel.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of Picato (ingenol mebutate) gel, 0.015% and 0.05%. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been performed to evaluate the carcinogenic potential of Picato(R) gel or ingenol mebutate. The effects of ingenol mebutate on fertility have not been evaluated.Ingenol mebutate was negative in the Ames test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test, but positive in the Syrian hamster embryo (SHE) cell transformation assay.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action by which Picato gel induces cell death in treating AK lesions is unknown.. 12.2 Pharmacodynamics. The pharmacodynamics of Picato gel is unknown.. 12.3 Pharmacokinetics. Absorption The systemic exposure to Picato gel, 0.05% was assessed in two studies in total of 16 subjects with AK, following application of approximately g of Picato gel, 0.05% to an area of 100 cm2 of the dorsal forearm once daily for two consecutive days. In these studies, the blood levels of ingenol mebutate and two of its metabolites (acyl isomers of ingenol mebutate) were measured. Blood levels of ingenol mebutate and the two metabolites were below the lower limit of quantification (0.1 ng/mL) in all the blood samples of the subjects evaluated.Drug InteractionsIn vitro studies demonstrated that [3H]-ingenol mebutate undergoes extensive metabolism in human hepatocytes.In vitro studies to assess the potential of ingenol mebutate to inhibit or induce human cytochrome P450 (CYP) enzymes demonstrated that ingenol mebutate does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 2C9, and 3A4. The estimated expected systemic exposure (< 0.1 ng/mL) following topical application of Picato(R) gel, 0.05% to AK subjects in the pharmacokinetic studies described above is negligible compared to the concentrations of ingenol mebutate evaluated in the in vitro studies.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Actinic Keratosis of the Face and Scalp. In two double-blind, vehicle-controlled, clinical trials, 547 adult subjects with AK on the face or scalp were randomized to treatment with either Picato gel, 0.015% or vehicle gel for consecutive days, followed by an week follow-up period. The trials enrolled subjects with to clinically typical, visible, discrete AK lesions within 25 cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. total of 536 subjects (98%) completed these trials. Study subjects ranged from 34 to 89 years of age (mean 64 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 85% of subjects were male, and all Picato gel-treated subjects were Caucasian.Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. Partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected treatment area. Table presents the efficacy results for each trial.Table 5. Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial Study Study Picato gel, 0.015% (N=135 Vehicle (N=134 Picato gel, 0.015% (N=142) Vehicle (N=136) CompleteClearance Rate50 (37%)3 (2%)67 (47%)7 (5%)Partial ClearanceRate (>= 75%)81 (60%)9 (7%)96 (68%)11 (8%)Table presents the response rates by anatomical location for each trial.Table 6. Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by TrialStudy 1Study Picato gel, 0.015% (N=135 Vehicle (N=134 Picato gel, 0.015%(N=142) Vehicle (N=136)Scalp4/26 (15%)0/25 (0%)9/31 (29%)1/25 (4%)Face46/109 (42%)3/109 (2%)58/111 (52%)6/111 (5%)Subjects who achieved complete clearance at Day 57 in Study and Study entered 12-month follow-up period. Based on 108 Picato gel-treated subjects who achieved complete clearance in Study and Study 2, the recurrence rate at 12 months was 54% where recurrence was defined as the percentage of subjects with any identified AK lesion in the previously treated area who achieved complete clearance at Day 57.. 14.2 Actinic Keratosis of the Trunk and Extremities. In two double-blind, vehicle-controlled clinical trials, 458 adult subjects with AK on the trunk or extremities were randomized to treatment with either Picato(R) gel, 0.05% or vehicle gel for consecutive days, followed by an week follow-up period. The trials enrolled subjects with to clinically typical, visible, discrete AK lesions within 25 cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. total of 447 subjects (98%) completed these trials. Study subjects ranged from 34 to 89 years of age (mean 66 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 62% of subjects were male, and all Picato gel-treated subjects were Caucasian.Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. The partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected treatment area. Table presents the efficacy results for each trial.Table 7. Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial Study Study Picato gel, 0.05%(N=126 Vehicle (N=129 )Picato gel, 0.05% (N=100) Vehicle (N=103)CompleteClearance Rate35 (28%)6 (5%)42 (42%)5 (5%)Partial Clearance Rate (>= 75%)56 (44%)9 (7%)55 (55%)7 (7%)Table presents the response rates by anatomical location for each trial.Table 8. Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by Trial Study Study Picato gel, 0.05% (N=126) Vehicle (N=129) Picato gel, 0.05% (N=100) Vehicle (N=103)Arm22/84 (26%)4/82 (5%) 27/59 (46%)3/67 (5%)Back of Hand4/25 (16%)0/29 (0%) 6/28 (21%)0/27 (0%)Chest8/9 (89%)1/8 (13%) 3/5 (60%)1/3 (33%)Othera 1/8 (13%)1/10 (10%) 6/8 (75%)1/6 (17%)aOther includes shoulder, back, leg.Subjects who achieved complete clearance at Day 57 in Study entered 12-month follow-up period. Based on 38 Picato(R) gel-treated subjects who achieved complete clearance in Study 4, the recurrence rate at 12 months was 50% where recurrence was defined as the percentage of subjects with any identified AK lesion in the previously treated area who achieved complete clearance at Day 57.In separate trial, in an open-label treatment period, subjects were treated for AK lesions on their face or scalp. Those subjects who did not achieve clearance at Day 57 or experienced recurrence after achieving clearance at Day 57 were randomized to receive second treatment course of Picato gel or its vehicle gel. Some subjects had treatment benefit with the second treatment course of Picato gel when evaluated weeks after the retreatment.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Picato gel is contraindicated in patients with known hypersensitivity to ingenol mebutate or any component of the formulation. Anaphylaxis, as well as allergic reactions leading to hospitalization have been reported in postmarketing use with Picato gel [see Warnings and Precautions (5.2)].. Known hypersensitivity to ingenol mebutate or any component of the formulation. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Picato(R) (ingenol mebutate) gel, 0.015% or 0.05% is clear colorless gel for topical administration, which contains the active substance ingenol mebutate, an inducer of cell death.The chemical name of ingenol mebutate is:2-Butenoic acid, 2-methyl-, (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-1a,2,5,5a,6,9,10,10a-octahydro-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1H-2,8a-methanocyclopenta [a]cyclopropa[e]cyclodecen-6-yl ester, (2Z) -or(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H 2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl (2Z) 2-methylbut-2-enoate.The molecular formula is C25H34O6 and molecular weight is 430.5. Ingenol mebutate is represented by the following structural formula:Ingenol mebutate is white to pale yellow crystalline powder.Picato gel, 0.015% or 0.05%, contains 150 mcg or 500 mcg of ingenol mebutate, respectively, in each gram of gel consisting of isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified water.Picato gel is clear colorless gel and supplied in unit dose laminate tubes, for single use, containing nominal fill weight of 0.47 g, with deliverable weight of 0.25 g. The tubes should be discarded after single use.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For the treatment of actinic keratosis on the face or scalp Picato gel, 0.015% should be applied to the affected area once daily for consecutive days.For the treatment of actinic keratosis on the trunk or extremities Picato gel, 0.05% should be applied to the affected area once daily for consecutive days.Picato gel may be applied to the affected area, up to one contiguous skin area of approximately 25 cm2 (e.g., cm 5 cm) using one unit dose tube. After spreading evenly over the treatment area, the gel should be allowed to dry for 15 minutes. Patients should wash their hands immediately after applying Picato gel and take care not to transfer the applied drug to other areas, including the eye. Patients should avoid washing and touching the treated area for period of hours after application of Picato gel. Following this time, patients may wash the area with mild soap.Avoid transfer of Picato gel to periocular area [see Warnings and Precautions (5.1)]. Avoid application near and around the mouth and lips.For topical use only; not for oral, ophthalmic, or intravaginal use.. For application of up to one contiguous skin area of approximately 25 cm2 (5 cm 5 cm) using one unit dose tube.(2)Actinic keratosis on the face or scalp: Apply Picato gel, 0.015% to the affected area once daily for consecutive days. (2)Actinic keratosis on the trunk or extremities: Apply Picato gel, 0.05% to the affected area once daily for consecutive days. (2)Avoid transfer of Picato gel to periocular area. (2)Avoid application near and around the mouth and lips. (2)For topical use only; not for oral, ophthalmic, or intravaginal use. (2). For application of up to one contiguous skin area of approximately 25 cm2 (5 cm 5 cm) using one unit dose tube.(2). Actinic keratosis on the face or scalp: Apply Picato gel, 0.015% to the affected area once daily for consecutive days. (2). Actinic keratosis on the trunk or extremities: Apply Picato gel, 0.05% to the affected area once daily for consecutive days. (2). Avoid transfer of Picato gel to periocular area. (2). Avoid application near and around the mouth and lips. (2). For topical use only; not for oral, ophthalmic, or intravaginal use. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Picato gel contains 0.015% or 0.05% of ingenol mebutate in clear colorless gel base.. Gel, 0.015% or 0.05% (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 1165 subjects treated with Picato gel in the clinical trials, 56% were 65 years and older and, 21% were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Picato gel is clear colorless gel and is supplied in unit dose laminate tubes containing nominal fill weight of 0.47 g, with deliverable weight of 0.25 g. The tubes should be discarded after single use.Picato gel is available in dosage strengths: 0.015% or 0.05%.Dosage StrengthNumber of unit dose tubes per cartonNDC0.015 %350222-502-470.05 %250222-503-47Store Picato gel in refrigerator at 36oF 46oF (2oC 8oC); excursions permitted between 32oF 59oF (0oC 15oC) (see USP for controlled cold temperature). Protect from freezing.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Picato(R) gel is indicated for the topical treatment of actinic keratosis. Picato gel is an inducer of cell death indicated for the topical treatment of actinic keratosis. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Ophthalmic Adverse ReactionsInform patients that severe eye injury can occur with Picato gel. Advise patients that Picato gel is not for ophthalmic use. Advise patients to avoid application around the eyes. If severe eye pain or other symptoms of accidental exposure occur, advise patients to flush eyes with water and seek medical care [see Warnings and Precautions (5.1)]. Hypersensitivity ReactionsInform patients that hypersensitivity reactions can occur with Picato gel. Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see Warnings and Precautions (5.2)]. Non-Melanoma Skin CancerInform patients that non-melanoma skin cancers have been reported in patients treated with Picato. Instruct patients to notify their physician if any new or changing skin lesions occur in the treatment area after treatment completion [see Warnings and Precautions (5.3)].Local Skin ReactionsInform patients that treatment with Picato gel may lead to local skin reactions [see Warnings and Precautions (5.4)].Important Administration InstructionsAdvise patients that Picato(R) gel is for external use only. Advise patients to avoid application near and around the eyes, mouth and lips.Patients should avoid inadvertent transfer of Picato gel to other areas, or to another person. Instruct patients to:allow the treated area to dry for 15 minutes after application.avoid washing and touching the treated area, or participating in activities that cause excessive sweating, for hours after treatment. Following this time, patients may wash the area with mild soap and water.keep out of the reach of children.. allow the treated area to dry for 15 minutes after application.. avoid washing and touching the treated area, or participating in activities that cause excessive sweating, for hours after treatment. Following this time, patients may wash the area with mild soap and water.. keep out of the reach of children.. LactationAdvise breastfeeding women to avoid accidental transfer of Picato gel to the nipple and areola area to prevent direct infant exposure [see Use in Specific Populations (8.2)]. Manufactured by:LEO Laboratories Ltd. (LEO Pharma)285 Cashel RoadDublin 12, Ireland Distributed by: LEO Pharma Inc.Seven Giralda FarmsMadison, NJ 07940, USAPicato(R) is registered trademark of LEO Laboratories Ltd. (C) 2020, LEO Pharma Inc. All rights reserved. March 2021.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. Instructions for Use: PICATO(R) (Pih-KAY-toe) (ingenol mebutate) gel, 0.05%Be sure that you read, understand, and follow these Instructions for Use before you use Picato(R) gel for the first time. Also read the Patient Information leaflet that comes with Picato(R) gel.Important:Always use Picato(R) gel exactly as your healthcare provider tells you. Check with your healthcare provider or pharmacist if you are not sure.Only use Picato(R) gel, 0.05% to treat actinic keratosis on your body, arms, hands or legs.Apply Picato(R) gel, 0.05% to the skin area to be treated time each day for days in row. Use new tube for each day of treatment.Avoid touching the treatment area or doing activities that cause lot of sweating for hours after applying Picato(R) gel. After hours you may wash the treatment area with mild soap and water.Do not:apply right after taking shower or less than hours before bedtime.get Picato(R) gel in, around, or near your eyes. Do not touch your eyes while you are applying Picato(R) gel. Wash your hands well with soap and water after applying it. After applying Picato(R) gel, be careful to keep Picato(R) gel on treated area from coming into contact with your eyes. Irritation may happen if you get Picato(R) gel in your eyes.If you accidentally get Picato(R) gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see the section of Patient Information leaflet section called What are the possible side effects of Picato(R) gel.get Picato(R) gel in, around, or near your lips and mouth.Applying Picato(R) gel.Step 1. Open new tube each time you use Picato(R) gel.Step 2. Remove cap from tube just before use. (See Figure A.)Figure AStep 3. Squeeze the gel from the tube onto fingertip. (See Figure B.) Only use enough gel needed to cover the affected area, as directed by your healthcare provider. One tube contains enough gel to cover skin area of about inches by inches.Figure BStep 4. Spread the gel evenly over only the skin area to be treated. Do not get in, around or near the eyes, lips, and mouth. Allow the treated area to dry for 15 minutes. (See Figure C.)Figure CStep 5. Wash your hands right away after applying Picato(R) gel. (See Figure D.) If you are treating your hands you should only wash the fingertip which you used for applying the gel.Figure DStep 6. Safely throw away (dispose of) the tube after use.Repeat the above steps for each day of treatment.To help prevent transfer of Picato(R) gel to other areas of your body or to another person, allow the treated area to dry for 15 minutes after you apply Picato(R) gel.How should store Picato(R) gelStore Picato(R) gel in refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.Picato(R) gel has an expiration date (exp) marked on the end of the tube. Do not use the gel after this date.Safely throw away used Picato(R) gel tubes in household trash.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: LEO Laboratories Ltd. (LEO Pharma)285 Cashel RoadDublin 12, IrelandDistributed by: LEO Pharma Inc.Seven Giralda FarmsMadison, NJ 07940, USAFor more information call: 1-877-494-4536.Revised: 06/2017. Always use Picato(R) gel exactly as your healthcare provider tells you. Check with your healthcare provider or pharmacist if you are not sure.. Only use Picato(R) gel, 0.05% to treat actinic keratosis on your body, arms, hands or legs.. Apply Picato(R) gel, 0.05% to the skin area to be treated time each day for days in row. Use new tube for each day of treatment.. Avoid touching the treatment area or doing activities that cause lot of sweating for hours after applying Picato(R) gel. After hours you may wash the treatment area with mild soap and water.. apply right after taking shower or less than hours before bedtime.. get Picato(R) gel in, around, or near your eyes. Do not touch your eyes while you are applying Picato(R) gel. Wash your hands well with soap and water after applying it. After applying Picato(R) gel, be careful to keep Picato(R) gel on treated area from coming into contact with your eyes. Irritation may happen if you get Picato(R) gel in your eyes.If you accidentally get Picato(R) gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see the section of Patient Information leaflet section called What are the possible side effects of Picato(R) gel.. Wash your hands well with soap and water after applying it. After applying Picato(R) gel, be careful to keep Picato(R) gel on treated area from coming into contact with your eyes. Irritation may happen if you get Picato(R) gel in your eyes.. If you accidentally get Picato(R) gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see the section of Patient Information leaflet section called What are the possible side effects of Picato(R) gel.. get Picato(R) gel in, around, or near your lips and mouth.. Store Picato(R) gel in refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.. Picato(R) gel has an expiration date (exp) marked on the end of the tube. Do not use the gel after this date.. Safely throw away used Picato(R) gel tubes in household trash.. Figure A. Figure B. Figure C. Figure D. Instructions for Use: PICATO(R) (Pih-KAY-toe) (ingenol mebutate) gel, 0.015%Be sure that you read, understand, and follow these Instructions for Use before you use Picato(R) gel for the first time. Also read the Patient Information leaflet that comes with Picato(R) gel.Important:Always use Picato(R) gel exactly as your healthcare provider tells you. Check with your healthcare provider or pharmacist if you are not sure.Only use Picato(R) gel, 0.015% to treat actinic keratosis on your face or scalp.Apply Picato(R) gel, 0.015% to the skin area to be treated time each day for days in row. Use new tube for each day of treatment.Avoid touching the treatment area or doing activities that cause lot of sweating for hours after applying Picato(R) gel. After hours you may wash the treatment area with mild soap and water.Do not:apply right after taking shower or less than hours before bedtime.get Picato(R) gel in, around, or near your eyes. Do not touch your eyes while you are applying Picato(R) gel. Wash your hands well with soap and water after applying it. After applying Picato(R) gel, be careful to keep Picato(R) gel on the treated area from coming into contact with your eyes. Irritation may happen if you get Picato(R) gel in your eyes.If you accidentally get Picato(R) gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see the section of Patient Information leaflet section called What are the possible side effects of Picato(R) gel.get Picato(R) gel in, around, or near your lips and mouth.Applying Picato(R) gel.Step 1. Open new tube each time you use Picato(R) gel.Step 2. Remove cap from tube just before use. (See Figure A.)Figure AStep 3. Squeeze the gel from the tube onto fingertip. (See Figure B.) Only use enough gel needed to cover the affected area, as directed by your healthcare provider. One tube contains enough gel to cover skin area of about inches by inches.Figure BStep 4. Spread the gel evenly over only the skin area to be treated. Do not get in, around or near the eyes, lips, and mouth. Allow the treated area to dry for 15 minutes. (See Figure C.)Figure CStep 5. Wash your hands right away after applying Picato(R) gel. (See Figure D.)Figure DStep 6. Safely throw away (dispose of) the tube after use.Repeat the above steps for each day of treatment.To help prevent transfer of Picato(R) gel to other areas of your body or to another person, allow the treated area to dry for 15 minutes after you apply Picato(R) gel.How should store Picato(R) gelStore Picato(R) gel in refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.Picato(R) gel has an expiration date (exp) marked on the end of the tube. Do not use the gel after this date.Safely throw away used Picato(R) gel tubes in household trash.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: LEO Laboratories Ltd. (LEO Pharma)285 Cashel RoadDublin 12, IrelandDistributed by: LEO Pharma Inc.Seven Giralda FarmsMadison, NJ 07940, USAFor more information call: 1-877-494-4536.Revised: 06/2017. Always use Picato(R) gel exactly as your healthcare provider tells you. Check with your healthcare provider or pharmacist if you are not sure.. Only use Picato(R) gel, 0.015% to treat actinic keratosis on your face or scalp.. Apply Picato(R) gel, 0.015% to the skin area to be treated time each day for days in row. Use new tube for each day of treatment.. Avoid touching the treatment area or doing activities that cause lot of sweating for hours after applying Picato(R) gel. After hours you may wash the treatment area with mild soap and water.. apply right after taking shower or less than hours before bedtime.. get Picato(R) gel in, around, or near your eyes. Do not touch your eyes while you are applying Picato(R) gel. Wash your hands well with soap and water after applying it. After applying Picato(R) gel, be careful to keep Picato(R) gel on the treated area from coming into contact with your eyes. Irritation may happen if you get Picato(R) gel in your eyes.If you accidentally get Picato(R) gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see the section of Patient Information leaflet section called What are the possible side effects of Picato(R) gel.. Wash your hands well with soap and water after applying it. After applying Picato(R) gel, be careful to keep Picato(R) gel on the treated area from coming into contact with your eyes. Irritation may happen if you get Picato(R) gel in your eyes.. If you accidentally get Picato(R) gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see the section of Patient Information leaflet section called What are the possible side effects of Picato(R) gel.. get Picato(R) gel in, around, or near your lips and mouth.. Store Picato(R) gel in refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.. Picato(R) gel has an expiration date (exp) marked on the end of the tube. Do not use the gel after this date.. Safely throw away used Picato(R) gel tubes in household trash.. Figure A. Figure B. Figure C. Figure D.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism of action by which Picato gel induces cell death in treating AK lesions is unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption The systemic exposure to Picato gel, 0.05% was assessed in two studies in total of 16 subjects with AK, following application of approximately g of Picato gel, 0.05% to an area of 100 cm2 of the dorsal forearm once daily for two consecutive days. In these studies, the blood levels of ingenol mebutate and two of its metabolites (acyl isomers of ingenol mebutate) were measured. Blood levels of ingenol mebutate and the two metabolites were below the lower limit of quantification (0.1 ng/mL) in all the blood samples of the subjects evaluated.Drug InteractionsIn vitro studies demonstrated that [3H]-ingenol mebutate undergoes extensive metabolism in human hepatocytes.In vitro studies to assess the potential of ingenol mebutate to inhibit or induce human cytochrome P450 (CYP) enzymes demonstrated that ingenol mebutate does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 2C9, and 3A4. The estimated expected systemic exposure (< 0.1 ng/mL) following topical application of Picato(R) gel, 0.05% to AK subjects in the pharmacokinetic studies described above is negligible compared to the concentrations of ingenol mebutate evaluated in the in vitro studies.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on Picato gel use in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Systemic concentrations following topical administration of Picato gel were below the limit of quantification of 0.1 ng/ml, and maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3)].In animal reproduction studies, ingenol mebutate did not cause malformations in pregnant rats and rabbits when given by the intravenous route of administration during the period of organogenesis (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposure of ingenol mebutate observed in the animal studies to the systemic exposure that would be expected in humans after topical use of Picato(R) gel.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data. Animal DataIntravenous doses of 1.5, 3, and ug/kg/day (9, 18, and 30 ug/m2/day, respectively) ingenol mebutate were administered during the period of organogenesis (gestational days - 16) to pregnant female rats. No treatment-related effects on embryofetal development or malformations were noted at doses up to ug/kg/day (30 ug/m2/day).Intravenous doses of 1, 2, and ug/kg/day (12, 24, and 48 ug/m2/day, respectively) ingenol mebutate were administered during the period of organogenesis (gestational days - 18) to pregnant female rabbits. Maternal toxicity (increased breathing rate) was observed at doses >= ug/kg/day (12 ug/m2/day). An increase in embryo-fetal mortality was noted at ug/kg/day (48 ug/m2/day). An increased incidence of fetal visceral and skeletal variations was noted in all three ingenol mebutate dose groups.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Non-Melanoma Skin Cancer (5.3)03/2021.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION PICATO(R) (Pih-KAY-toe) (ingenol mebutate) gelImportant: For use on the skin only (topical). Do not use Picato gel in, around, or near your eyes, lips, mouth, or vagina.What is Picato gelPicato gel, 0.015% is prescription medicine used on the skin to treat actinic keratosis on the face or scalp. Picato gel, 0.05% is prescription medicine used on the skin to treat actinic keratosis on the body or arms and legs. It is not known if Picato gel is safe and effective for the treatment of actinic keratosis in children less than 18 years of age.Who should not use Picato gelDo not use Picato gel if you are allergic to ingenol mebutate or any of the ingredients in Picato gel. See the end of this leaflet for list of the ingredients in Picato gel.What should tell my healthcare provider before using Picato gelBefore using Picato gel, tell your healthcare provider about all of your medical conditions, including if you:are being treated or have been treated for actinic keratosis with other medicines or surgery. You should not use Picato gel until your skin has healed from other treatments.have other skin problems or sunburn in the treatment area.are pregnant or plan to become pregnant. It is not known if Picato gel can harm your unborn baby.are breastfeeding or plan to breastfeed. If you use Picato gel while breastfeeding, make sure that your treated skin does not come into contact with the infant.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.How should use Picato gelUse Picato gel exactly as your healthcare provider tells you. Picato gel is for skin use only. Your healthcare provider will tell you where to apply Picato gel, and how often, and how long to apply it. Do not apply Picato gel to other areas. Do not use more Picato gel than you need to cover the treatment area. Using too much Picato gel, or using it too often, or for too long can increase your chances for having severe skin reaction or other side effects. Do not get Picato gel in, around, or near your eyes. Do not touch your eyes while you are applying Picato gel.Wash your hands well with soap and water after applying Picato gel. After applying Picato gel, be careful to keep Picato gel on the treated area from coming into contact with your eyes. Irritation may happen if you get Picato gel in your eyes.If you accidentally get Picato gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see What are the possible side effects of Picato gel Do not get Picato gel in, around, or near your mouth or lips.To help prevent accidental transfer of Picato gel to other areas of your body or to another person:allow the treated area to dry for 15 minutes after you apply Picato gel.avoid washing and touching the treated area, or doing activities that cause lot of sweating, for hours after treatment. After hours, you may wash the area with mild soap and water.Only use tube of Picato gel time. Throw away any open tube of Picato gel after use even if there is medicine still left in it.See the Instructions for Use that comes with your Picato gel for information about the right way to apply it.What are the possible side effects of Picato gelPicato gel may cause serious or severe side effects including:Eye problems can happen if Picato gel gets in your eyes. Eye problems may include severe eye pain, swelling or drooping of your eyelids, or swelling around your eyes. If you accidentally get Picato gel in your eyes, flush them with large amounts of water and get medical care as soon as possible.Serious allergic reactions. Serious allergic reactions have happened with Picato gel, and in some cases have required treatment in hospital. See Who should not use Picato gel. Get medical help right away if you get any of the following symptoms of serious allergic reaction:swelling of the lips or tongue chest tightnesstrouble breathing or wheezingdizziness or passing outSkin cancers. Actinic keratosis occurs on sun-damaged skin which is more prone to developing skin cancer. Some people treated with PICATO were diagnosed with certain types of skin cancer within the treatment area after treatment completion. Tell your doctor if you notice any new skin changes in the treated area after completing treatment with PICATO.Local skin reactions. Skin reactions in the treatment area are common with Picato(R) gel. You may get skin reaction such as mild redness, flaking or scaling, crusting, or swelling. You may also see changes in your skin color (pigmentation changes) and scarring where Picato gel is applied. Call your healthcare provider if you get skin redness, flaking or scaling, crusting, or swelling that is more severe, or if you get blisters, pus, ulcers or breakdown of your skin.The most common side effects with Picato gel include:local skin reactions, see Local skin reactions aboveswelling around the eyespain, itching, or skin irritation at the treatment areainfection at the treatment areanose and throat irritationheadacheTell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Picato gel. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to LEO Pharma Inc. at 1-877-494-4536.How should store Picato gelStore Picato gel in refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.Picato gel has an expiration date (exp) marked on the end of the tube. Do not use the gel after this date.Safely throw away used Picato gel tubes in household trash.Keep Picato gel and all medicines out of the reach of children.General information about the safe and effective use of Picato gel.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Picato gel for condition for which it was not prescribed. Do not give Picato gel to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Picato gel that is written for health professionals.What are the ingredients in Picato gelActive ingredient: ingenol mebutateInactive ingredients: isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified waterManufactured by: LEO Laboratories Ltd. (LEO Pharma), 285 Cashel Road, Dublin 12, Ireland Distributed by: LEO Pharma Inc., Seven Giralda Farms, Madison, NJ 07940, USA.For more information call 1-877-494-4536.Picato is registered trademark of LEO Laboratories Ltd.(C) 2020, LEO Pharma Inc. All rights reserved. March 2021This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 03/2021. Picato gel, 0.015% is prescription medicine used on the skin to treat actinic keratosis on the face or scalp. Picato gel, 0.05% is prescription medicine used on the skin to treat actinic keratosis on the body or arms and legs. are being treated or have been treated for actinic keratosis with other medicines or surgery. You should not use Picato gel until your skin has healed from other treatments.. have other skin problems or sunburn in the treatment area.. are pregnant or plan to become pregnant. It is not known if Picato gel can harm your unborn baby.. are breastfeeding or plan to breastfeed. If you use Picato gel while breastfeeding, make sure that your treated skin does not come into contact with the infant.. Use Picato gel exactly as your healthcare provider tells you. Picato gel is for skin use only. Your healthcare provider will tell you where to apply Picato gel, and how often, and how long to apply it. Do not apply Picato gel to other areas. Do not use more Picato gel than you need to cover the treatment area. Using too much Picato gel, or using it too often, or for too long can increase your chances for having severe skin reaction or other side effects. Do not get Picato gel in, around, or near your eyes. Do not touch your eyes while you are applying Picato gel.Wash your hands well with soap and water after applying Picato gel. After applying Picato gel, be careful to keep Picato gel on the treated area from coming into contact with your eyes. Irritation may happen if you get Picato gel in your eyes.If you accidentally get Picato gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see What are the possible side effects of Picato gel Wash your hands well with soap and water after applying Picato gel. After applying Picato gel, be careful to keep Picato gel on the treated area from coming into contact with your eyes. Irritation may happen if you get Picato gel in your eyes.. If you accidentally get Picato gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see What are the possible side effects of Picato gel. Do not get Picato gel in, around, or near your mouth or lips.. To help prevent accidental transfer of Picato gel to other areas of your body or to another person:allow the treated area to dry for 15 minutes after you apply Picato gel.avoid washing and touching the treated area, or doing activities that cause lot of sweating, for hours after treatment. After hours, you may wash the area with mild soap and water.. allow the treated area to dry for 15 minutes after you apply Picato gel.. avoid washing and touching the treated area, or doing activities that cause lot of sweating, for hours after treatment. After hours, you may wash the area with mild soap and water.. Only use tube of Picato gel time. Throw away any open tube of Picato gel after use even if there is medicine still left in it.. See the Instructions for Use that comes with your Picato gel for information about the right way to apply it.. Eye problems can happen if Picato gel gets in your eyes. Eye problems may include severe eye pain, swelling or drooping of your eyelids, or swelling around your eyes. If you accidentally get Picato gel in your eyes, flush them with large amounts of water and get medical care as soon as possible.. Serious allergic reactions. Serious allergic reactions have happened with Picato gel, and in some cases have required treatment in hospital. See Who should not use Picato gel. Get medical help right away if you get any of the following symptoms of serious allergic reaction:swelling of the lips or tongue chest tightnesstrouble breathing or wheezingdizziness or passing out. swelling of the lips or tongue chest tightness. trouble breathing or wheezing. dizziness or passing out. Skin cancers. Actinic keratosis occurs on sun-damaged skin which is more prone to developing skin cancer. Some people treated with PICATO were diagnosed with certain types of skin cancer within the treatment area after treatment completion. Tell your doctor if you notice any new skin changes in the treated area after completing treatment with PICATO.. Local skin reactions. Skin reactions in the treatment area are common with Picato(R) gel. You may get skin reaction such as mild redness, flaking or scaling, crusting, or swelling. You may also see changes in your skin color (pigmentation changes) and scarring where Picato gel is applied. Call your healthcare provider if you get skin redness, flaking or scaling, crusting, or swelling that is more severe, or if you get blisters, pus, ulcers or breakdown of your skin.. local skin reactions, see Local skin reactions above. swelling around the eyes. pain, itching, or skin irritation at the treatment area. infection at the treatment area. nose and throat irritation. headache. Store Picato gel in refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.. Picato gel has an expiration date (exp) marked on the end of the tube. Do not use the gel after this date.. Safely throw away used Picato gel tubes in household trash.

SPL UNCLASSIFIED SECTION.

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 Picato gel. If accidental exposure occurs, the area should be flushed with water and the patient should seek medical care as soon as possible.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on Picato gel use in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Systemic concentrations following topical administration of Picato gel were below the limit of quantification of 0.1 ng/ml, and maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3)].In animal reproduction studies, ingenol mebutate did not cause malformations in pregnant rats and rabbits when given by the intravenous route of administration during the period of organogenesis (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposure of ingenol mebutate observed in the animal studies to the systemic exposure that would be expected in humans after topical use of Picato(R) gel.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data. Animal DataIntravenous doses of 1.5, 3, and ug/kg/day (9, 18, and 30 ug/m2/day, respectively) ingenol mebutate were administered during the period of organogenesis (gestational days - 16) to pregnant female rats. No treatment-related effects on embryofetal development or malformations were noted at doses up to ug/kg/day (30 ug/m2/day).Intravenous doses of 1, 2, and ug/kg/day (12, 24, and 48 ug/m2/day, respectively) ingenol mebutate were administered during the period of organogenesis (gestational days - 18) to pregnant female rabbits. Maternal toxicity (increased breathing rate) was observed at doses >= ug/kg/day (12 ug/m2/day). An increase in embryo-fetal mortality was noted at ug/kg/day (48 ug/m2/day). An increased incidence of fetal visceral and skeletal variations was noted in all three ingenol mebutate dose groups.. 8.2 Lactation. Risk SummaryThere are no data on the presence of ingenol mebutate in human or animal milk, the effects on the breastfed infant or the effects on milk production. Systemic concentrations following topical administration of Picato(R) gel were below the limit of quantification of 0.1 ng/mL, and breastfeeding is not expected to result in exposure of the child to Picato gel [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Picato gel and any potential adverse effects on the breastfed infant from Picato gel or from the underlying maternal condition.. Clinical ConsiderationsAdvise breastfeeding women to avoid accidental transfer of Picato gel to the nipple and areola area to prevent direct infant exposure.. 8.4 Pediatric Use. Actinic keratosis is not condition generally seen within the pediatric population. The safety and effectiveness of Picato gel for actinic keratosis in patients less than 18 years of age have not been established. 8.5 Geriatric Use. Of the 1165 subjects treated with Picato gel in the clinical trials, 56% were 65 years and older and, 21% were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

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 Picato. 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 Picato 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 Picato 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 Picato gel immediately and institute appropriate medical therapy.. 5.3 Non-Melanoma Skin Cancer. Non-melanoma skin cancers have been reported in patients treated with Picato. Cases of rapidly growing squamous cell carcinoma have been reported in the treatment area within 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/pustulation, and erosion/ulceration, can occur after topical application of Picato(R) gel [see Adverse Reactions (6 )]. Administration of Picato gel is not recommended until the skin is healed from any previous drug or surgical treatment.