Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

PICATO (NDA-202833)

(INGENOL MEBUTATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/19/2021 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Non-Melanoma Skin Cancer

(Newly added subsection)

Non-melanoma skin cancers have been reported in patients treated with Picato. Cases of rapidly growing squamous cell carcinoma have been reported in the treatment area within a few weeks after treatment completion. Counsel patients on the potential risk and monitor closely those patients with risk factors for skin cancer.

6 Adverse Reactions

(Additions and/or revisions underlined)

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)]
Non-Melanoma Skin Cancer [see Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of Picato (ingenol mebutate) gel, 0.015% and 0.05%. 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.

Eye disorders: chemical conjunctivitis, corneal burn

Immune system disorders: hypersensitivity, Stevens-Johnson syndrome

Infections: herpes zoster

Skin and subcutaneous disorders: non-melanoma skin cancer, allergic contact dermatitis, application site pigmentation changes, application site scarring

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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 Picato gel. Advise patients that Picato gel 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 seek medical care [see Warnings and Precautions (5.1)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions can occur with Picato gel. Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see Warnings and Precautions (5.2)].

Non-Melanoma Skin Cancer

Inform patients that non-melanoma skin cancers have been reported in patients treated with Picato. Instruct patients to notify their physician if any new or changing skin lesions occur in the treatment area after treatment completion [see Warnings and Precautions (5.3)].

Local Skin Reactions

Inform patients that treatment with Picato gel may lead to local skin reactions [see Warnings and Precautions (5.4)].

Important Administration Instructions

Advise patients that Picato® gel is for external use only. Advise patients to avoid application near and around the eyes, mouth and lips.

Patients should avoid inadvertent transfer of Picato gel to other areas, or to another person. Instruct patients to:

allow the treated area to dry for 15 minutes after application.

avoid washing and touching the treated area, or participating in activities that cause excessive sweating, for 6 hours after treatment. Following this time, patients may wash the area with a mild soap and water.

keep out of the reach of children.

Lactation

Advise breastfeeding women to avoid accidental transfer of Picato gel to the nipple and areola area to prevent direct infant exposure [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

…

What are the possible side effects of Picato gel?

Picato gel may cause serious or severe side effects including:

…

Skin cancers.

Actinic keratosis occurs on sun-damaged skin which is more prone to developing skin cancer. Some people treated with PICATO were diagnosed with certain types of skin cancer within the treatment area after treatment completion. Tell your doctor If you notice any new skin changes in the treated area after completing treatment with PICATO.

…

12/17/2020 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of Picato (ingenol mebutate) gel, 0.015% and 0.05%. 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.

Eye disorders: chemical conjunctivitis, corneal burn

Immune system disorders: hypersensitivity, Stevens-Johnson syndrome

Infections: herpes zoster

Skin and Subcutaneous disorders: allergic contact dermatitis, application site pigmentation changes, application site scarring

02/13/2020 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no available data on Picato® 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 of Picato gel were below the limit of quantification of 0.1 ng/ml, and maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3)].

In animal reproduction studies, ingenol mebutate did not cause malformations in pregnant rats and rabbits when given by the intravenous route of administration during the period of organogenesis (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposure of ingenol mebutate observed in the animal studies to the systemic exposure that would be expected in humans after topical use of Picato gel.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Animal Data

Intravenous doses of 1.5, 3, and 5 µg/kg/day (9, 18, and 30 ?g/m2/day, respectively) ingenol mebutate were administered during the period of organogenesis (gestational days 6 – 16) to pregnant female rats. No treatment-related effects on embryofetal development or malformations were noted at doses up to 5 µg/kg/day (30 ?g/m2/day).

Intravenous doses of 1, 2, and 4 µg/kg/day (12, 24, and 48 ?g/m2/day, respectively) ingenol mebutate were administered during the period of organogenesis (gestational days 6 – 18) to pregnant female rabbits. Maternal toxicity (increased breathing rate) was observed at doses ? 1

µg/kg/day (12 µg/m2/day). An increase in embryo-fetal mortality was noted at 4 µg/kg/day (48 ?g/m2/day). An increased incidence of fetal visceral and skeletal variations was noted in all three ingenol mebutate dose groups.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of ingenol mebutate in human or animal milk, the effects on the breastfed infant or the effects on milk production. Systemic concentrations following topical administration of Picato gel were below the limit of quantification of 0.1 ng/mL, and breastfeeding is not expected to result in exposure of the child to Picato® gel [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Picato gel and any potential adverse effects on the breastfed infant from Picato gel or from the underlying maternal condition.

Clinical Considerations

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Lactation

Advise breastfeeding women to avoid accidental transfer of Picato gel to the nipple and areola area to prevent direct infant exposure [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

What should I tell my healthcare provider before using Picato gel?

Before using Picato gel, tell your healthcare provider about all of your medical conditions, including if you:

Additions and/or revisions underlined:

are breastfeeding or plan to breastfeed. If you use Picato gel while breastfeeding, make sure that your treated skin does not come into contact with the infant.

09/13/2016 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience (updated)

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 (added), application site scarring (added), herpes zoster, chemical conjunctivitis, and corneal burn.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information (section added)

PICATO® (Pih-KAY-toe)

(ingenol mebutate)

gel, 0.015%, 0.05%

Important: For use on the skin only (topical). Do not use Picato gel in, around, or near your eyes, lips, mouth, or vagina.

What is Picato gel?

Picato gel, 0.015% is a prescription medicine used on the skin to treat actinic keratosis on the face or scalp.
Picato gel, 0.05% is a prescription medicine used on the skin to treat actinic keratosis on the body 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 gel if you are allergic to ingenol mebutate or any of the ingredients in Picato gel. See the end of this leaflet for a list of the ingredients in Picato gel.

What should I tell my healthcare provider before using 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 Picato gel?

Use Picato gel exactly as your healthcare provider tells you. Picato gel is for skin use only.
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 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 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 Picato gel in your eyes, flush them with large amounts of water and get medical care as soon as possible. Also see “What are the possible side effects of Picato gel?”
Do not get Picato gel in, around, or near your mouth or lips.
To help prevent accidental 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.
- avoid washing and touching the treated area, or doing activities that cause a lot of sweating, for 6 hours after treatment. After 6 hours, you may wash the area with a mild soap and water.
Only use a tube of Picato gel 1 time. Throw away any open tube of Picato gel after use even if there is medicine still left in it.
See the Instructions for Use that comes with your Picato gel for information about the right way to apply it.

What are the possible side effects of Picato gel?

Picato gel may cause serious or severe side effects including:

Eye problems can happen if Picato® gel 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 Picato® gel 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. See “Who should not use Picato Gel?” Get medical help right away if you get any of the following symptoms of a serious allergic reaction:
- swelling of the lips or tongue
- trouble breathing or wheezing
- chest tightness
- dizziness or passing out

Local skin reactions. Skin reactions in the treatment area are common with Picato gel. You may get a skin reaction such as mild redness, flaking or scaling, crusting, or swelling. You may also see changes in your skin color (pigmentation changes) and scarring where Picato gel is applied. Call your healthcare provider if you get skin redness, flaking or scaling, crusting, or swelling that is more severe, or if you get blisters, pus, ulcers or breakdown of your skin.

The most common side effects with Picato gel include:

local skin reactions, see “Local skin reactions” above
pain, itching, or skin irritation at the treatment area
infection at the treatment area
swelling around the eyes
nose and throat irritation
headache

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Picato gel. Call your doctor for medical advice about side effects. You may report side effects to

FDA at 1-800-FDA-1088. You may also report side effects to LEO Pharma Inc. at 1-877-494-4536.

How should I store Picato gel?

Store Picato gel in a refrigerator at 36ºF to 46ºF (2ºC to 8ºC). 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 Picato gel and all medicines out of the reach of children.

General information about the safe and effective use of Picato gel.

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 Picato gel?

Active ingredient: ingenol mebutate

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

and purified water.