PICATO- ingenol mebutate gel
For Healthcare Providers >

1. Patient Information
2. Who Should Not Use Picato Gel?
3. Gel, Tell Your Healthcare Provider About All Of Your Medical Conditions, Including If You:

Patient Information ⮝

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Ophthalmic Adverse Reactions

Inform patients that severe eye injury can occur with Picatogel. Advise patients that Picatogel 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

• Picato gel, 0.015%is a prescription medicine used on the skin to treat actinic keratosis on theface or scalp.

• Picato gel, 0.05%is a prescription medicine used on the skin to treat actinic keratosis on thebody 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 Gel? ⮝

Do not use Picato gelif you are allergic to ingenol mebutate or any of the ingredients in Picato gel.

Before 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.

Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins and herbal supplements.

How should I use Picatogel?

• Use Picato gel exactly as your healthcare provider tells you.Picatogel is for skin useonly.
• 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 a severe skin reaction or other side effects.
• Do not get Picatogel 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 Picatogel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also

    
    Picato gel may cause serious or severe side effects including:

    • Eye problems can happen if Picatogel 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 Picatogel 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 a hospital.
      • Store Picato gel in a refrigerator at 36 F to 46 F (2 C to 8 C). 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 Picatogel and all medicines out of the reach of children.

      General information about the safe and effective use of Picatogel.

      Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Picato gel for a 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 Picatogel?

      Active ingredient: ingenol mebutate

      Inactive ingredients: isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified water

      Manufactured 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.

      Copyright LEO Laboratories Ltd., 09-2016

      This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2017

1. Highlights Of Prescribing Information
2. Indications And Usage
3. Dosage And Administration
4. Dosage Forms And Strengths
5. Contraindications
6. Warnings And Precautions
7. Adverse Reactions
8. 1 Indications And Usage
9. 2 Dosage And Administration
10. 3 Dosage Forms And Strengths
11. 4 Contraindications
12. 5 Warnings And Precautions
13. 6 Adverse Reactions
14. 8 Use In Specific Populations
15. 10 Overdosage
16. 11 Description
17. 12 Clinical Pharmacology
18. 13 Nonclinical Toxicology
19. 14 Clinical Studies
20. 16 How Supplied/storage And Handling
21. Instructions For Use
22. Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.05%
23. Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.015%
24. Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.015% Physician Sample
25. Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.05% Physician Sample

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use
PICATO gel safely and effectively. See full prescribing information for
PICATO gel.

PICATO (ingenol mebutate) gel, 0.015% for topical use
PICATO (ingenol mebutate) gel, 0.05% for topical use
Initial U.S. Approval: 2012

Indications And Usage ⮝

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

Dosage And Administration ⮝

• For topical use only; not for oral, ophthalmic, or intravaginal use. (2)
• Avoid transfer of Picato gel to periocular area. (2)
• Avoid application near and around the mouth and lips. (2)
• For application of up to one contiguous skin area of approximately 25 cm2 (5 cm x 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 3 consecutive days. (2)
• Actinic keratosis on the trunk or extremities: Apply Picato gel, 0.05% to the affected area once daily for 2 consecutive days. (2)

Dosage Forms And Strengths ⮝

Gel containing ingenol mebutate, 0.015% or 0.05% (3)

Contraindications ⮝

Known hypersensitivity to ingenol mebutate or any component of the formulation. (4)

Warnings And Precautions ⮝

Avoid treatment in the periocular area. 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)

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. (5.3)

Adverse Reactions ⮝

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.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 6/2017

1 Indications And Usage ⮝

Picato gel is indicated for the topical treatment of actinic keratosis.

2 Dosage And Administration ⮝

For topical use only; Picato gel is not for oral, ophthalmic, or intravaginal use.

Avoid transfer of Picato gel to periocular area [see Warnings and Precautions (5.1)].

Avoid application near and around the mouth and lips.

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 3 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 2 consecutive days.

Picato gel may be applied to the affected area, up to one contiguous skin area of approximately 25 cm2 (e.g., 5 cm x 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 a period of 6 hours after application of Picato gel. Following this time, patients may wash the area with a mild soap.

3 Dosage Forms And Strengths ⮝

Gel, 0.015% or 0.05%, in a clear colorless gel base.

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 Adverse Reactions (6.2)].

5 Warnings And Precautions ⮝

5.1 Ophthalmic Adverse Reactions

Avoid treatment in the periocular area. 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 [see Adverse Reactions (6.2)]. If anaphylactic or other clinically significant hypersensitivity reactions occur, discontinue Picato gel immediately and institute appropriate medical therapy.

5.3 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 gel [see Adverse Reactions (6)]. Administration of Picato 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)]

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 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 a concentration of 0.015% once daily for 3 consecutive days, and 225 subjects exposed to Picato gel field treatment (skin area of 25 cm2 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) Picato gel, 0.015% once daily for 3 days
Skin reactions	Any Gradea > Baseline	Grade 4
	Picato gel (n=274)	Vehicle (n=271)	Picato 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%)

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 gel, 0.05% once daily for 2 days
Skin reactions	Any Gradea > Baseline	Grade 4
	Picato gel (n=225)	Vehicle (n=232)	Picato 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%)

aMild (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 Picato 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 Picato gel and at higher frequency than vehicle (face/scalp trials)

	Face/Scalp
Adverse Reactions	Picato 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 Picato gel and at higher frequency than vehicle (trunk/extremities trials)

	Trunk/Extremities
Adverse Reactions	Picato 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 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%: hypersensitivity, allergic contact dermatitis, application site pigmentation changes, application site scarring, herpes zoster, chemical conjunctivitis, and corneal burn.

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.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Picato gel in pregnant women. Picato gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Systemic embryofetal development studies were conducted with ingenol mebutate in rats and rabbits. Intravenous doses of 1.5, 3, and 5 g/kg/day (9, 18, and 30 g/m2/day) ingenol mebutate were administered during the period of organogenesis (gestational days 6 16) to pregnant female rats. No treatment related effects on embryofetal toxicity or teratogenicity were noted at doses up to 5 g/kg/day (30 g/m2/day). Intravenous doses of 1, 2, and 4 g/kg/day (12, 24, and 48 g/m2/day) ingenol mebutate were administered during the period of organogenesis (gestational days 6 18) to pregnant female rabbits. An increase in embryo-fetal mortality was noted at 4 g/kg/day (48 g/m2/day). An increased incidence of fetal visceral and skeletal variations was noted in all three ingenol mebutate dose groups. The clinical relevance of these findings is unclear since systemic exposure of ingenol mebutate was not detected in subjects with actinic keratosis treated with Picato gel, 0.05% applied to a 100 cm2 treatment area [see Clinical Pharmacology (12.3)].

8.4 Pediatric Use

Actinic keratosis is not a 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.

10 Overdosage ⮝

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

11 Description ⮝

Picato (ingenol mebutate) gel, 0.015% or 0.05% is a 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 a white to pale yellow crystalline powder.

Picato gel, 0.015% and 0.05% contains 150 mcg and 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 a clear colorless gel and supplied in unit dose laminate tubes, for single use, containing a nominal fill weight of 0.47 g, with a deliverable weight of 0.25 g. The tubes should be discarded after single use.

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 a total of 16 subjects with AK, following application of approximately 1 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 Interactions

In 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 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.

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 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.

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 3 consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete AK lesions within a 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. A total of 536 subjects (98%) completed these studies. 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 5 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 1	Study 2
	Picato gel, 0.015% (N=135)	Vehicle (N=134)	Picato gel, 0.015% (N=142)	Vehicle (N=136)
Complete Clearance Rate	50 (37%)	3 (2%)	67 (47%)	7 (5%)
Partial Clearance Rate ( 75%)	81 (60%)	9 (7%)	96 (68%)	11 (8%)

Table 6 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 Trial
	Study 1	Study 2
	Picato gel, 0.015% (N=135)	Vehicle (N=134)	Picato gel, 0.015% (N=142)	Vehicle (N=136)
Scalp	4/26 (15%)	0/25 (0%)	9/31 (29%)	1/25 (4%)
Face	46/109 (42%)	3/109 (2%)	58/111 (52%)	6/111 (5%)

Subjects who achieved complete clearance at Day 57 in Study 1 and Study 2 entered a 12-month follow-up period. Based on 108 Picato gel-treated subjects who achieved complete clearance in Study 1 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 gel, 0.05% or vehicle gel for 2 consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete AK lesions within a 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. A total of 447 subjects (98%) completed these studies. 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 7 presents the efficacy results for each study.

Table 7 Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial
	Study 3	Study 4
	Picato gel, 0.05% (N=126)	Vehicle (N=129)	Picato gel, 0.05% (N=100)	Vehicle (N=103)
Complete Clearance Rate	35 (28%)	6 (5%)	42 (42%)	5 (5%)
Partial Clearance Rate ( 75%)	56 (44%)	9 (7%)	55 (55%)	7 (7%)

Table 8 presents the response rates by anatomical location for each study.

Table 8 Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by Trial
	Study 3	Study 4
	Picato gel, 0.05% (N=126)	Vehicle (N=129)	Picato gel, 0.05% (N=100)	Vehicle (N=103 )
Arm	22/84 (26%)	4/82 (5%)	27/59(46%)	3/67(5%)
Back of Hand	4/25 (16%)	0/29 (0%)	6/28 (21%)	0/27(0%)
Chest	8/9 (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 4 entered a 12-month follow-up period. Based on 38 Picato 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 a 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 a second treatment course of Picato or its vehicle gel. Some subjects had a treatment benefit with the second treatment course of Picato gel when evaluated 8 weeks after the retreatment.

16 How Supplied/storage And Handling ⮝

Picato gel is a clear colorless gel and is supplied in unit dose laminate tubes containing a nominal fill weight of 0.47 g, with a deliverable weight of 0.25 g. The tubes should be discarded after single use.

Picato gel is available in 2 dosage strengths: 0.015% and 0.05%.

Dosage Strength	Number of unit dose tubes per carton	NDC#
0.015 %	3	50222-502-47
0.05 %	2	50222-503-47

Store Picato gel in a refrigerator at 36 F 46 F (2 C 8 C); excursions permitted between 32 F 59 F (0 C 15 C) (see USP for controlled cold temperature). Protect from freezing.

Instructions For Use ⮝

Instructions for Use: PICATO (Pih-KAY-toe) (ingenol mebutate) gel, 0.05%

Be sure that you read, understand, and follow these Instructions for Use before you use Picato gel for the first time. Also read the Patient Information leaflet that comes with Picato gel.

Important:

• Always use Picato gel exactly as your healthcare provider tells you. Check with your healthcare provider or pharmacist if you are not sure.

• Only use Picato gel, 0.05% to treat actinic keratosis on your body, arms, hands or legs.

• Apply Picato gel, 0.05% to the skin area to be treated 1 time each day for 2 days in a row. Use a new tube for each day of treatment.

• Avoid touching the treatment area or doing activities that cause a lot of sweating for 6 hours after applying Picato gel. After 6 hours you may wash the treatment area with a mild soap and water.

Do not:

• apply right after taking a shower or less than 2 hours before bedtime.
• 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 it. After applying Picato gel, be careful to keep Picato gel on 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 the section of Patient Information leaflet section called What are the possible side effects of Picato gel? .

• get Picato gel in, around, or near your lips and mouth.

Applying Picato gel.

Step 1. Open a new tube each time you use Picato gel.

Step 2. Remove cap from tube just before use. (See Figure A.)

Figure A

Step 3. Squeeze the gel from the tube onto a 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 a skin area of about 2 inches by 2 inches.

Figure B

Step 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 C

Step 5. Wash your hands right away after applying Picato gel. (See Figure D.) If you are treating your hands you should only wash the fingertip which you used for applying the gel.

Figure D

Step 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 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.

How should I store Picato gel?

• Store Picato gel in a refrigerator at 36 F to 46 F (2 C to 8 C). 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.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured 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.

Revised: 06/2017

Instructions for Use: PICATO (Pih-KAY-toe) (ingenol mebutate) gel, 0.015%

Be sure that you read, understand, and follow these Instructions for Use before you use Picato gel for the first time. Also read the Patient Information leaflet that comes with Picato gel.

Important:

• Always use Picato gel exactly as your healthcare provider tells you. Check with your healthcare provider or pharmacist if you are not sure.

• Only use Picato gel, 0.015% to treat actinic keratosis on your face or scalp.

• Apply Picato gel, 0.015% to the skin area to be treated 1 time each day for 3 days in a row. Use a new tube for each day of treatment.

• Avoid touching the treatment area or doing activities that cause a lot of sweating for 6 hours after applying Picato gel. After 6 hours you may wash the treatment area with a mild soap and water.

Do not:

• apply right after taking a shower or less than 2 hours before bedtime.
• 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 it. 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 the section of Patient Information leaflet section called What are the possible side effects of Picato gel? .

• get Picato gel in, around, or near your lips and mouth.

Applying Picato gel.

Step 1. Open a new tube each time you use Picato gel.

Step 2. Remove cap from tube just before use. (See Figure A.)

Figure A

Step 3. Squeeze the gel from the tube onto a 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 a skin area of about 2 inches by 2 inches.

Figure B

Step 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 C

Step 5. Wash your hands right away after applying Picato gel. (See Figure D.)

Figure D

Step 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 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.

How should I store Picato gel?

• Store Picato gel in a refrigerator at 36 F to 46 F (2 C to 8 C). 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.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured 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.

Revised: 06/2017

Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.05% ⮝

NDC 50222-503-47

Rx only

Picato

(ingenol mebutate) gel

0.05%

For Topical Use on Trunk or Extremities Only

Not for Oral, Ophthalmic, or Intravaginal Use

2 Unit Dose Tubes

Net Wt. 0.47 g in each tube

Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.015% ⮝

NDC 50222-502-47

Rx only

Picato

(ingenol mebutate) gel

0.015%

For Topical Use on Face or Scalp Only

Not for Oral, Ophthalmic, or Intravaginal Use

3 Unit Dose Tubes

Net Wt. 0.47 g in each tube

Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.015% Physician Sample ⮝

NDC 50222-502-91

Rx only

Picato

(ingenol mebutate) gel

0.015%

For Topical Use on Face or Scalp Only

Not for Oral, Ophthalmic, or Intravaginal Use

3 Unit Dose Tubes

Net Wt. 0.47 g in each tube

Physician's Sample - Not For Sale

Principal Display Panel For Picato [pih-kay-toe] (ingenol Mebutate) Gel 0.05% Physician Sample ⮝

NDC 50222-503-92

Rx only

Picato

(ingenol mebutate) gel

0.05%

For Topical Use on Trunk or Extremities Only

Not for Oral, Ophthalmic, or Intravaginal Use

2 Unit Dose Tubes

Net Wt. 0.47 g in each tube

Physician's Sample - Not For Sale

PICATO ingenol mebutate gel

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50222-502 Route of Administration TOPICAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ingenol mebutate (UNII: 7686S50JAH) (ingenol mebutate - UNII:7686S50JAH) ingenol mebutate 150 ug in 1 g

Inactive Ingredients Ingredient Name Strength isopropyl alcohol (UNII: ND2M416302) citric acid monohydrate (UNII: 2968PHW8QP) SODIUM CITRATE (UNII: 1Q73Q2JULR) benzyl alcohol (UNII: LKG8494WBH) water (UNII: 059QF0KO0R) HYDROXYETHYL CELLULOSE (2000 MPA.S AT 1%) (UNII: S38J6RZN16)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50222-502-91 3 in 1 CARTON 01/23/2012 1 0.47 g in 1 TUBE; Type 0: Not a Combination Product 2 NDC:50222-502-47 3 in 1 CARTON 01/23/2012 2 0.47 g in 1 TUBE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA202833 01/23/2012

PICATO ingenol mebutate gel

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50222-503 Route of Administration TOPICAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ingenol mebutate (UNII: 7686S50JAH) (ingenol mebutate - UNII:7686S50JAH) ingenol mebutate 500 ug in 1 g

Inactive Ingredients Ingredient Name Strength isopropyl alcohol (UNII: ND2M416302) citric acid monohydrate (UNII: 2968PHW8QP) SODIUM CITRATE (UNII: 1Q73Q2JULR) benzyl alcohol (UNII: LKG8494WBH) water (UNII: 059QF0KO0R) HYDROXYETHYL CELLULOSE (2000 MPA.S AT 1%) (UNII: S38J6RZN16)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50222-503-47 2 in 1 CARTON 01/23/2012 1 0.47 g in 1 TUBE; Type 0: Not a Combination Product 2 NDC:50222-503-92 2 in 1 CARTON 01/23/2012 2 0.47 g in 1 TUBE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA202833 01/23/2012

Labeler - LEO Pharma Inc. (832692615)

Establishment
Name	Address	ID/FEI	Business Operations
LEO Laboratories Ltd.		219532322	manufacture(50222-502, 50222-503) , analysis(50222-502, 50222-503)

Revised: 8/2018 Document Id: 085629ff-ba9d-4097-94e1-639018394d0b 34391-3 Set id: 5accc7a5-8209-4680-b0ae-2a6963500419 Version: 10 Effective Time: 20180829 LEO Pharma Inc.