Picato gel: Indications, Dosage, Precautions, Adverse Effects
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Picato gel - Product Information

Manufacture: LEO Pharma
Country: Canada
Condition: Actinic Keratosis, Keratosis
Class: Topical antineoplastics
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: ingenol mebutate, isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified water

Summary product information

Route of AdministrationDosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients
TopicalGel
0.015% strength contains 70 mcg ingenol mebutate per unit dose tube
0.05% strength contains 235 mcg ingenol mebutate per unit dose tube
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and clinical use

PICATO (ingenol mebutate) is indicated for:

  • topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) in adults.

Geriatrics (≥ 65 years)

No overall differences in safety or efficacy were observed between patients aged 65 years and over compared with younger patients (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations).

Pediatrics (< 18 years)

The safety and efficacy of PICATO in patients less than 18 years of age have not been established.

Contraindications

  • Hypersensitivity to the ingenol mebutate or to any of the excipients. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

Warnings and precautions

General

The efficacy of PICATO (ingenol mebutate) in the prevention of squamous cell carcinoma (SCC) associated with actinic keratosis (AK) has not been studied. The rate of SCC reported in the treatment area was comparable in patients treated with PICATO (0.3%) and in vehicle treated patients (0.3%) in the AK clinical studies. SCC in the treatment area was reported in no patients previously treated with PICATO in three prospective, observational long term 1 year follow-up studies.

Clinical data on re-treatment and treatment of more than one area with PICATO is not available (see DOSAGE AND ADMINISTRATION, Dosing Considerations).

Clinical data on treatment in immunocompromised patients is not available, but systemic risks are not expected since systemic exposure of ingenol mebutate was not detected following topical treatment with PICATO.

PICATO should not be used near the eyes, on the inside of the nostrils, on the inside of the ears, or on the lips.

Ophthalmologic

Severe eye disorders occurred more frequently in patients treated with PICATO than vehicle, including periorbital edema, eyelid edema, eye edema, eye pain, and eyelid ptosis in the AK clinical studies. These eye disorders may result from spreading of application site edema. All eye disorders resolved without sequelae.

Ingenol mebutate is a known ocular irritant. Precautions should be taken to avoid accidental exposure. If accidental exposure occurs, the eyes should be flushed immediately with large amounts of water, and the patient should seek medical care as soon as possible.

Gastrointestinal

PICATO (ingenol mebutate) must not be ingested. If accidental ingestion occurs the patient should drink plenty of water.

Skin

Severe local skin responses (LSRs) such as erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration can occur after topical application of PICATO. LSRs are common and the majority are mild to moderate. A treatment effect may not be adequately assessed until resolution of local skin responses.

Administration of PICATO is not recommended until the skin is healed from treatment with any previous medicinal product or surgical treatment.

Due to the irritant properties of ingenol mebutate, contact with skin outside the treatment area should be avoided. If there is inadvertent contact with skin not in the treatment area, the area must be washed with mild soap and water.

Carcinogenesis and Mutagenesis

Long-term animal carcinogenicity studies with ingenol mebutate have not been conducted. Ingenol mebutate was not genotoxic or clastogenic in a bacterial mutation (Ames) assay, mouse lymphoma cell assay, or rat in vivo micronucleus assay. Ingenol mebutate was positive in the Syrian hamster embryo (SHE) cell transformation test, which detects both genotoxic and epigenetic carcinogens.

Carcinogenic and mutagenic risks to humans receiving treatment with PICATO are considered unlikely since systemic exposure of ingenol mebutate was not detected following topical treatment.

Special Populations

Pregnant Women

There are no data from the use of PICATO in pregnant women. Embryo- fetal development studies in rabbits with intravenous ingenol mebutate demonstrated an increase in embryo-fetal mortality and an increased incidence of fetal visceral and skeletal variations (see TOXICOLOGY, Reproduction). Risks to humans receiving treatment with PICATO are considered unlikely since systemic exposure of ingenol mebutate was not detected following topical treatment. However, as a precautionary measure, it is preferable to avoid the use of PICATO during pregnancy.

Nursing Women

No effects on breastfed newborns/infants are anticipated since systemic exposure of ingenol mebutate was not detected following topical treatment with PICATO. The nursing mother should be instructed that physical contact between her newborn/infant and the treated area should be avoided for a period of 6 hours after application of PICATO.

Pediatrics (< 18 years)

The safety and efficacy of PICATO in patients less than 18 years of age have not been established.

Adverse reactions

Adverse Drug Reaction Overview

The most frequently reported adverse drug reactions associated with PICATO (ingenol mebutate) treatment were general disorders and administration site disorders, including application site pain and application site pruritus.

Local Skin Responses (LSRs) were assessed independently in an effort to provide a better profile of the specific types of visible local skin reactions. LSRs included erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. LSRs are transient and typically occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion of treatment. These effects typically resolve within 2 weeks for areas treated on the face and scalp and within 4 weeks for areas treated on the trunk and extremities.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The adverse drug reaction profile described below reflects exposure to PICATO on a skin area of 25 cm2 in 499 patients with actinic keratosis, including 274 patients exposed to PICATO at a concentration of 0.015% once daily for 3 consecutive days on the face or scalp, and 225 subjects exposed to PICATO at a concentration of 0.05% once daily for two consecutive days on the trunk and extremities.

Adverse Drug Reactions that occurred in ≥1% of patients treated with PICATO are presented in

Table 1 and Table 2. Adverse drug reactions were generally mild to moderate in severity.

Table 1. Adverse Drug Reactions Occurring in ≥ 1 % of Patients Treated with PICATO Gel or Vehicle in Controlled Phase 3 Face/Scalp Studies
MedDRA SOC (Preferred term)PICATO gel,
0.015%
n=274 (%)
Vehicle
n=271 (%)
General disorders and administration site disorders
Application site pain13.9 %0.4 %
Application site pruritus8.0 %1.1 %
Application site irritation1.8 %0.0 %
Infections and infestations
Application site infection2.6 %0.0 %
Skin and subcutaneous tissue disorders
Periorbital edema2.6 %0.0 %
Nervous system disorders
Headache2.2 %1.1 %
Eye Disorders
Eyelid edema1.1 %0.0 %

Table 2. Adverse Drug Reactions Occurring in ≥ 1 % of Patients Treated with
PICATO Gel or Vehicle in Controlled Phase 3 Trunk/Extremities Studies
MedDRA SOC (Preferred term)PICATO gel,
0.05%
n=225 (%)
Vehicle
n=232 (%)
General disorders and administration site disorders
Application site pruritus8.4 %0.0 %
Application site irritation3.6 %0.4 %
Application site pain2.2 %0.0 %

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Other less common adverse drug reactions (less than 1% but more than 0.5%) were for scalp/face: eye pain, application site discharge, and application site parasthesia; for trunk/extremities: application site parasthesia and application site warmth.

Local Skin Responses

LSRs were evaluated within the selected treatment area and graded by the investigator on a scale of 0 to 4 (see Table 3 and Table 4).

Table 3. Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area during the 57 Days Post Treatment Period (face/scalp studies)
Face and Scalp
(n=545)
0.015% PICATO gel, once daily for 3 days
Skin reactions
Any Grade* >Baseline
MildModerateSevere
Grade 1Grade 2Grade 3Grade 4
PICATO
gel (n=274)
Vehicle

(n=271)
PICATO
gel (n=274)
PICATO
gel (n=274)
PICATO
gel (n=274)
PICATO
gel (n=274)
Erythema258 (94%)69 (25%)25 (9%)56 (20%)125 (46%)66 (24%)
Flaking / Scaling233 (85%)67 (25%)52 (19%)91 (33%)98 (36%)25 (9%)
Crusting220 (80%)46 (17%)85 (31%)64 (23%)64 (23%)16 (6%)
Swelling217 (79%)11 (4%)88 (32%)67 (24%)48 (18%)14 (5%)
Vesiculation /
Pustulation
154 (56%)1 (0%)36 (13%)53 (19%)50 (18%)15 (5%)
Erosion / Ulceration87 (32%)3 (1%)55 (20%)26 (9%)5 (2%)1 (0%)

*A grade of 0 represented no reaction present in the treated area, and a grade of 4 indicated a marked and discernable skin reaction that extended beyond the area treated.


PICATO
gel (n=225)
Table 4. Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area during the 57 Days Post Treatment Period (trunk/extremities studies)
Trunk and Extremities
(n=457)
0.05% PICATO gel , once daily for 2 days
Skin reactionsAny Grade* >BaselineMildModerateSevere
Grade 1Grade 2Grade 3Grade 4
Vehicle

(n=232)
PICATO
gel (n=225)
PICATO
gel (n=225)
PICATO
gel (n=225)
PICATO
gel (n=225)
Erythema207 (92%)43 (19%)31 (14%)94 (42%)61 (27%)34 (15%)
Flaking / Scaling203 (90%)44 (19%)52 (23%)86 (38%)66 (29%)18 (8%)
Crusting167 (74%)23 (10%)105 (47%)39 (17%)23 (10%)8 (4%)
Swelling143 (64%)13 (6%)65 (29%)51 (23%)20 (9%)7 (3%)
Vesiculation /
Pustulation
98 (44%)2 (1%)46 (20%)30 (13%)19 (8%)3 (1%)
Erosion / Ulceration58 (26%)6 (3%)37 (16%)15 (7%)4 (2%)2 (1%)

*A grade of 0 represented no reaction present in the treated area, and a grade of 4 indicated a marked and discernable skin reaction that extended beyond the area treated.

For patients treated on the face or scalp for 3 consecutive days, the majority of patients treated with PICATO gel, 0.015% had a maximum LSR score on Day 4, which returned to baseline or below by Day 15.

For patients treated on the trunk or extremities for 2 consecutive days, the majority of patients treated with PICATO gel 0.05% had a maximum LSR score on Days 3 or 8, which returned to baseline or below by Day 29.

Long-term Safety Follow-up

A total of 108 patients treated with PICATO on the face/scalp and 76 patients treated on the trunk/extremities were enrolled in three prospective, observational long-term follow-up studies. There were no adverse drug reactions reported in these studies (see CLINICAL TRIALS).

Drug interactions

No interaction studies have been performed. Interactions with systemically absorbed medicinal products are considered unlikely since systemic exposure of ingenol mebutate was not detected following topical treatment with PICATO (see ACTION AND CLINICAL PHARMACOLOGY).

Dosage and administration

Dosing Considerations

For topical use only.


PICATO (ingenol mebutate) gel is not for oral, ophthalmic or intravaginal use.


Clinical data on treatment for more than one treatment course of 2 or 3 consecutive days is not available. Clinical data on treatment of more than one area is not available.


The treated area should not be covered with occlusive bandages after PICATO is applied.

Recommended Dose and Dosage Adjustment

Actinic keratosis on the face and scalp:

PICATO 0.015% gel should be applied to the treatment field area (25 cm2) once daily for 3 consecutive days.

Actinic keratosis on the trunk and extremities:

PICATO 0.05% gel should be applied to the treatment field area (25 cm2) once daily for 2 consecutive days.

Geriatrics (≥ 65 years)

No dose adjustment is required (see ACTION & CLINICAL PHARMACOLOGY, Special Populations).

Administration

PICATO should be applied to the treatment field area as defined by the treating physician. Each tube contains enough gel to cover an area of approximately 25 cm2 (e.g., 5 cm x 5 cm).

The gel from the unit dose tube should be squeezed onto the fingertip and spread evenly over the entire treatment area, allowing it to dry for 15 minutes. One unit dose tube should be used for the field treatment area.

Patients should be instructed to wash their hands immediately after applying PICATO. If treating the hands, only the fingertip which is used for applying the gel should be washed. Washing and touching the treated area should be avoided for a period of 6 hours after the application of PICATO.

PICATO should not be applied immediately after taking a shower or less than 2 hours before bedtime

Overdosage

There has been no experience of overdose in clinical studies with PICATO (ingenol mebutate).

For management of a suspected drug overdose or accidental ingestion, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of Action

The mechanism of action of ingenol mebutate in actinic keratosis (AK) is not fully characterized since there is no adequate animal model of AK. In vivo and in vitro models using tumour cell lines, including squamous cell carcinoma, have shown a dual mechanism of action for the effects of ingenol mebutate: 1) direct cytotoxicity and 2) promoting an inflammatory response characterised by release of inflammatory cytokines and infiltration of immunocompetent cells.

Pharmacodynamics

At a high concentration (100 µg/ml) in vitro and in vivo, studies have shown that ingenol mebutate is cytotoxic.

At lower concentrations (10 to 100 ng/ml), ingenol mebutate activates both novel and classical protein kinase C (PKC) and is associated with immunostimulatory effects. Some classes of PKC activators, such as phorbol esters, are known to be tumour promoters. Ingenol mebutate is structurally related to phorbol esters. The clinical significance of potential proliferative effects via activation of PKC by ingenol mebutate is unknown. However, no evidence of neoplasia was noted in 6 and 9-month dermal repeat dose studies in rats and minipigs (cyclic administration). The risk of tumour induction in humans receiving treatment with PICATO is considered very unlikely due to the short duration of treatment (2-3 days).

Exposure of isolated human keratinocytes to lower concentrations of ingenol mebutate (10 to 100 ng/ml) in vitro, was shown to induce release of the cytokines IL-8 and TNF-alpha and neutrophil activation. Both in vitro and in mice, ingenol mebutate induced IL-8 / murine IL-8 homologue MIP-2, TNF-alpha, and IL-1beta, all mediators of neutrophil recruitment and activation.

Topical treatment with ingenol mebutate gel in the squamous cell carcinoma model resulted in a localized and transient application site inflammatory reaction, which peaked after few days, and resolved within 2 weeks followed by scar resolution after 2 to 3 months. After 3 weeks of treatment with ingenol mebutate, treated mouse skin was similar to untreated skin in elasticity

Ultraviolet Light Exposure

Studies have been conducted to assess the effects of UV irradiation on the skin following single and multiple applications of ingenol mebutate, 100 mcg/g. Ingenol mebutate gel did not demonstrate any potential for photo-irritation or photo-allergic effects.

Pharmacokinetics

The systemic pharmacokinetic profile of ingenol mebutate and its metabolites has not been characterised in humans due to an absence of quantifiable whole blood levels following topical administration.

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, or 3A4, or induce CYP 1A2, 2C9, or 3A4.

Absorption

In humans, the highest concentration and treatment area evaluated was 0.05 µg/mm2 of ingenol mebutate gel, 0.05% applied once daily to a 100 cm2 area for two consecutive days. No systemic blood levels of ingenol mebutate or its two isomers PEP015 and PEP025 were quantifiable, i.e. concentrations were below the LLOQ (0.1 ng/mL).

Special Populations and Conditions

Pediatrics (< 18 years)

The safety and efficacy of PICATO (ingenol mebuate) in patients less than 18 years of age have not been established.

Geriatrics (≥ 65 years)

Of the 1,165 patients treated with PICATO in the actinic keratosis clinical studies, 656 patients (56%) were 65 years and older (9), while 241 patients (21%) were 75 years and older. No overall differences in safety or efficacy were observed between younger and older patients.

Storage and stability

PICATO (ingenol mebutate) gel should be stored in a refrigerator (2oC to 8oC).


Keep out of reach of children.

Dosage forms, composition and packaging

PICATO (ingenol mebutate) is a clear colourless gel.

PICATO, 0.015% Gel

Each unit dose tube contains 70 mcg of ingenol mebutate in 0.47 g gel.

Available as: 3 unit dose tubes per carton.

PICATO, 0.05% Gel

Each unit dose tube contains 235 mcg of ingenol mebutate in 0.47 g gel.

Available as: 2 unit dose tubes per carton.


Non-medicinal ingredients: Isopropyl alcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate, purified water.