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
RECENT MAJOR CHANGES
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Dosage and Administration (2) ...............................................................10/2015
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Contraindications (4)............................................................................ 10/2015
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Warnings and Precautions, Ophthalmic Adverse Reactions (5.1)................. 10/2015
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Warnings and Precautions, Hypersensitivity Reactions (5.2)...................... 10/2015
INDICATIONS AND USAGE
Picato ® gel is an inducer of cell death indicated for the topical treatment of actinic keratosis. (1)
DOSAGE AND ADMINISTRATION
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For topical use only; not for oral, ophthalmic, or intravaginal use. (2)
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Avoid transfer of Picato® to periocular area. (2)
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Avoid application near and around the mouth and lips. (2)
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For application of up to one contiguous skin area of approximately 25 cm2 (5 cm x 5 cm) using one unit dose tube. (2)
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Actinic keratosis on the face or scalp: Apply Picato® gel, 0.015% to the affected area once daily for 3 consecutive days. (2)
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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: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATION 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 post-marketing [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/postulation, 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:
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Ophthalmic Adverse Reaction [see Warnings and Precautions (5.1)]
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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)
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)
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)
Table 4 Adverse reactions occurring in ≥ 2% of subjects treated with Picato® gel and at higher frequency than vehicle (trunk/extremities trials)
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, 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 µg/kg/day (9, 18, and 30 μg/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 µg/kg/day (30 μg/m2/day). Intravenous doses of 1, 2, and 4 µg/kg/day (12, 24, and 48 μg/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 µg/kg/day (48 μg/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 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 eva luated.
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 eva luated in the in vitro studies.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to eva luate the carcinogenic potential of Picato® gel or ingenol mebutate. The effects of ingenol mebutate on fertility have not been eva luated.
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.
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