ingenol mebutate topical (Rx)

>10%

Face/scalp application

• Erythema (94%)
• Flaking/scaling (85%)
• Crusting (80%)
• Swelling (79%)
• Vesiculation/pustulation (56%)
• Erosion/ulceration (32%)
• Application site pain (15%)

Trunk/extremities application

• Erythema (92%)
• Flaking/scaling (90%)
• Crusting (74%)
• Swelling (64%)
• Vesiculation/pustulation (44%)
• Erosion/ulceration (26%)

1-10%

Face/scalp application

• Application site pruritus (8%)
• Application site infection (3%)
• Periorbital edema (3%)
• Headache (2%)

Trunk/extremities application

• Application site pruritus (8%)
• Application site irritation (4%)
• Nasopharyngitis (2%)
• Application site pain (2%)

Frequency Not Defined

Eyelid edema

Eye pain

Chemical conjunctivitis

Postmarketing Reports

Allergic contact dermatitis

Herpes Zoster

Corneal burn

Eye injuries

Application site pigmentation changes

Application site scarring

Stevens-Johnson syndrome

Hypersensitivity

Non-melanoma skin cancer

Contraindications

Known hypersensitivity to drug or component of formulation

Cautions

Avoid treatment of periocular area; eye disorders, including severe eye pain, eyelid edema, eyelid ptosis, periorbital edema can occur after exposure; caution patients to wash hands well after application and avoid transfer of the drug to other areas of the body; if accidental exposure occurs, flush eyes with water and seek medical care

Severe skin reactions in the treated area, including erythema, crusting, swelling, vesiculation/postulation, and erosion/ulceration occurs after topical application

Severe allergic reactions and herpes zoster infection reported; cases describe severe eye injuries and skin reactions, of which some were associated with the gel not being used according to the instructions

Non-melanoma skin cancers reported; cases of rapidly growing squamous cell carcinoma reported in the treatment area within a few weeks after treatment completion; counsel patients on potential risk and monitor closely those patients with risk factors for skin cancer

Not recommended until skin is healed from any previous drug or surgical treatment

Pregnancy

There are no available data on gel use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; systemic concentrations following topical administration gel were below limit of quantification of 0.1 ng/ml, and maternal use is not expected to result in fetal exposure to drug

Animal data

• In animal reproduction studies, drug did not cause malformations in pregnant rats and rabbits when given by intravenous route of administration during period of organogenesis; available data do not allow calculation of relevant comparisons between systemic exposure of ingenol mebutate observed in animal studies to systemic exposure that would be expected in humans after topical use

Lactation

There are no data on presence of drug in human or animal milk, effects on breastfed infant or on milk production; systemic concentrations following topical administration of gel were below limit of quantification of 0.1 ng/mL, and breastfeeding is not expected to result in exposure of child

Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from gel or from underlying maternal condition

Advise breastfeeding women to avoid accidental transfer of gel to nipple and areola area to prevent direct infant exposure

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

The mechanism by which ingenol mebutate induces cell death is unknown

Absorption

Systemic exposure is negligible; blood levels and 2 of its metabolites were below the lower limit of quantification (ie, <0.1 ng/mL)

Metabolism

Ex vivo studies showed extensive metabolism in human hepatocytes

Topical Administration

Only be used on 1 contiguous skin area not exceeding ~25 cm² (5 cm × 5 cm)

Not for spot treatment of actinic keratosis on multiple application sites simultaneously that exceeds 25 cm²

1 unit dose tube covers up to one contiguous skin area of approximately 25 cm² (eg, 5 cm x 5 cm)

Face or scalp: Apply 0.015% gel topically to the treatment area qDay for 3 consecutive days; avoid application in, near, and around the eyes, in the mouth, and on the lips

On the trunk or extremities: Apply 0.05% gel topically to the treatment area qDay for 2 consecutive days

Do not apply gel to more than 1 area simultaneously

After spreading evenly over the treatment area, allow gel to dry for 15 minutes

Patients should wash their hands immediately after application 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 6 hr after; following this time, patients may wash the area with a mild soap