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Picato

Generic Name: Ingenol Mebutate
Class: Skin and Mucous Membrane Agents, Miscellaneous
VA Class: IM900
Chemical Name: (2Z) - (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 - 2 - methyl - 2 - butenoic acid ester
Molecular Formula: C25H34O6
CAS Number: 75567-37-2

Warning(s)

Special Alerts:

[Posted 08/21/2015]

AUDIENCE: Dermatology, Pharmacy, Patient

ISSUE: FDA is warning about reports of severe allergic reactions and herpes zoster (shingles) associated with the use of ingenol mebutate (Picato) gel. FDA received reports of cases involving severe eye injuries and skin reactions associated with the application of ingenol mebutate gel. Some cases were associated with ingenol mebutate gel not being used according to the instructions for use on the label. As a result, FDA is requiring changes to the label to warn about these new safety risks and to provide additional instructions on the safe and appropriate application of the product. See the FDA Drug Safety Communication for additional information and recommendations.

Patients should use ingenol mebutate gel as prescribed by their health care professionals, and should not use it on an area of skin larger or for a longer period than instructed in the drug label. Also patients should avoid applying the gel in, near, and around the mouth, lips and eye area. Accidental transfer of ingenol mebutate gel from the hands even after washing has occurred, including through application of make-up and insertion of contact lenses. Applying ingenol mebutate gel in a manner other than recommended in the product label has been associated with severe skin reactions and eye injuries.

The allergic reaction may include throat tightness, difficulty breathing, feeling faint, or swelling of the lips or tongue.

BACKGROUND: Ingenol mebutate is used to treat actinic keratosis, a scaly, crusty lesion on the skin that may be red or yellow in color.

RECOMMENDATION: Patients who experience a severe allergic reaction should stop using ingenol mebutate gel and seek immediate medical attention. The allergic reaction may include throat tightness, difficulty breathing, feeling faint, or swelling of the lips or tongue. Patients should also stop using the product and contact their health care professionals if they develop hives, itching, or severe skin rash. If accidental eye exposure occurs, flush the eyes thoroughly with water and seek medical care.

For more information visit the FDA website at: and .

Introduction

Macrocyclic diterpene ester; inducer of cell death.1 3 4

Uses for Picato

Actinic Keratosis

Treatment of actinic keratosis lesions on the face and scalp (0.015% gel) or on the trunk and extremities (0.05% gel).1 3

Appears to have similar efficacy as other topical treatments (e.g., fluorouracil, imiquimod, diclofenac) with a shorter duration of treatment (2–3 days versus 4–16 weeks); however, clinical studies that directly compare the safety and efficacy of these drugs are needed.3 5 7 8

When selecting a regimen for treatment of actinic keratoses (e.g., topical drug therapy, photodynamic therapy, cryotherapy), consider the number of lesions, the individual patient's desired outcome (e.g., cosmetic effects, relief of associated symptoms, prevention of skin cancer), and adverse effects associated with the regimen.7

Picato Dosage and Administration

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Topical Administration

Apply topically as a 0.015 or 0.05% gel.1

For external use only.1 Do not administer orally, vaginally, or topically to the eyes.1

Apply evenly to affected area, up to one contiguous area of skin approximately 25 cm2.1 Wash hands immediately after applying ingenol mebutate gel.1 Allow gel to dry for 15 minutes; avoid washing or touching the treated area for 6 hours after application.1 After 6 hours, may wash area with a mild soap.1

Dosage

Adults

Actinic Keratosis
Actinic Keratosis of the Face and Scalp
Topical

0.015% Gel: Apply evenly to affected area once daily for 3 consecutive days.1

Actinic Keratosis of the Trunk and Extremities
Topical

0.05% Gel: Apply evenly to affected area once daily for 2 consecutive days.1

Prescribing Limits

Adults

Actinic Keratosis
Topical

Use only enough gel to cover the treatment area (≤1 single-use tube per application); do not use more often or for longer than instructed.1

Cautions for Picato

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • No known contraindications.1

Warnings/Precautions

Local Effects

Severe skin reactions (e.g., erythema, crusting, swelling, vesiculation/pustulation, erosion/ulceration) reported.1 3 Local skin reactions typically occur ≤1 day following treatment initiation, peak in intensity ≤1 week following completion of treatment, and resolve ≤2 weeks following treatment of the face or scalp and ≤4 weeks following treatment of the trunk or extremities.1

Do not apply until skin has healed from any previous drug or surgical treatment.1

Ocular Effects

Ocular exposure may result in adverse effects (e.g., severe eye pain, eyelid edema, ptosis, periorbital edema).1 3 (See Advice to Patients.)

Specific Populations

Pregnancy

Category C.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

No overall differences in safety and efficacy reported in patients ≥65 years of age relative to younger adults.1

Common Adverse Effects

Local skin reactions: Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration.1

Application site reactions: Pain, pruritus.1

Interactions for Picato

Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 2C9, and 3A4.1

No formal drug interaction studies to date; clinically important interactions following topical application considered unlikely.6

Picato Pharmacokinetics

Absorption

Bioavailability

Minimally absorbed following application; plasma concentrations of ingenol mebutate and metabolites were below lower limit of quantification (0.1 ng/mL).1

Stability

Storage

Topical

Gel

2–8°C (may be exposed to 0–15°C).1 Avoid freezing.1

Actions

  • Macrocyclic diterpene ester extracted from the sap of the plant Euphorbia peplus.1 3 4

  • Induces rapid and direct cell death and causes an immune response mediated by specific activation of protein kinase C delta, including neutrophil-mediated oxidative burst and clearance of tumors.3 4

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of providing patient a copy of manufacturer's patient information.1

  • Importance of advising patients that ingenol mebutate gel is for external use only and should not be used in the eyes, mouth, or vagina.1

  • Importance of advising patients to wash their hands thoroughly with soap and water following application and to avoid inadvertent transfer of gel to other areas or to another person.1

  • Importance of avoiding contact with eyes.1 Risk of ocular problems (e.g., severe eye pain, eyelid edema, ptosis, periorbital edema).1 In case of accidental ocular exposure, importance of flushing the eyes with large amounts of water and seeking medical care as soon as possible.1

  • Importance of instructing patients to allow the treated area to dry for 15 minutes following application.1 Advise patients to avoid washing or touching the treated area or participating in activities that cause excessive sweating for 6 hours after treatment.1

  • Importance of advising patients to keep ingenol mebutate gel out of the reach of children.1

  • Risk of local skin reactions; importance of informing clinician if severe local skin reactions occur.1

  • Importance of women informing clinicians if they are or plan to become pregnant.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ingenol Mebutate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Gel

0.015%

Picato

LEO Pharma

0.05%

Picato

LEO Pharma

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date modified: February 08, 2016
Last reviewed: August 28, 2015
Date published: January 01, 2013

References

1. LEO Pharma Inc. Picato (ingenol mebutate) gel prescribing information. Parsippany, NJ; 2012 Jan. Available at . Accessed 2012 Apr 3.

3. Lebwohl M, Swanson N, Anderson LL et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012; 366:1010-9. [PubMed 22417254]

4. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune reponse. J Am Acad Dermatol. 2012; 66:486-93. [PubMed 22055282]

5. Anderson L, Schmieder GJ, Werschler WP et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009; 60:934-43. [PubMed 19467365]

6. Office of Clinical Pharmacology, Food and Drug Administration. Picato (ingenol mebutate) Gel. Clinical pharmacology and biopharmaceutics review, FDA approval package. NDA number: 202833. From the FDA website. 2013 Mar 4.

7. Gupta AK, Paquet M, Villanueva E et al. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012; 12:CD004415. [PubMed 23235610]

8. Anon. Ingenol mebutate (Picato) for actinic keratosis. Med Lett Drugs Ther. 2012; 54:35-6. [PubMed 22538622]

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