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.

DIVIGEL (NDA-022038)

(ESTRADIOL)

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

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02/15/2024 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Malignant Neoplasms

Additions and/or revisions underlined:

Breast Cancer

…

Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy.

05/23/2023 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Visual Abnormalities

Additions and/or revisions underlined:

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue Divigel pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Divigel, if examination reveals papilledema or retinal vascular lesions.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

Additions and/or revisions underlined:

…

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Divigel and any potential adverse effects on the breastfed child from Divigel or from the underlying maternal condition.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Unintentional Secondary Exposure to Divigel

Inform women about the possibility of secondary exposure to Divigel:

Apply Divigel as directed and keep children from contacting exposed application site(s). If direct contact with the application site occurs, wash the contact area thoroughly with soap and water.
Look for signs of unexpected sexual development, such as breast mass or increased breast size in prepubertal children.
If signs of unintentional secondary exposure are noticed:
- Have the child(ren) evaluated by a healthcare provider.
- Have women contact their healthcare provider to discuss the appropriate use and handling of Divigel when around children.
Pets may also be unintentionally exposed to Divigel if above precautions are not followed.
…
PATIENT INFORMATION
Additions and/or revisions underlined:
…
Who should not use Divigel?
Do not start using Divigel if you:

have any unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

have been diagnosed with a bleeding disorder

…

What should I do if someone else is exposed to Divigel?

To reduce the chance of transfer to another person (or pet) let the Divigel dry completely. Wash your hands with soap and water after application. If someone else is exposed to Divigel by direct contact with the wet gel, have that person wash the area of contact with soap and water right away. This is especially important for men and children. The longer the gel is in contact with the skin before washing, the greater the chance that the other person (or pet) will absorb some of the estrogen hormone. This may harm them. In case of any signs or symptoms of estrogen exposure in the other person (or pet), contact your healthcare provider (or veterinarian, if appropriate).

…

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

…

swelling of face, lips, and tongue with or without red, itchy bumps

…

You may report side effects to FDA at 1-800-FDA-1088 or Vertical Pharmaceuticals, LLC at 1-800-444-5164.

…

12/12/2019 (SUPPL-5)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

…

Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.

...

Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestin therapy, taking into account her individual risk profile.

…

4 Contraindications

(addition underlined)

…

Known anaphylactic reaction, angioedema, or hypersensitivity to Divigel

…

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

… Animal studies to evaluate embryo/fetal toxicity were not conducted with Divigel.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting.

PATIENT INFORMATION

(additions and/or revisions underlined)

…

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Divigel (AN ESTROGEN HORMONE)?

…

Only one estrogen-alone product and dose has been shown to increase your chances of getting strokes, blood clots, and dementia. Only one estrogen with progestin product and dose has been shown to increase your chances of getting heart attacks, strokes, breast cancer, blood clots, and dementia.

Because other products and doses have not been studied in the same way, it is not known how the use of Divigel will affect your chances of these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with Divigel.

…

08/17/2018 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(addition underlined)

…

Divigel was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse events that occurred at a rate greater than 5 percent and greater than placebo in any of the treatment groups are summarized in Table 1.

(please refer to label to view Table 1)

…

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Divigel is not indicated for use in pregnancy. There are no data with the use of Divigel in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy.

8.2 Lactation

(PLLR conversion)

Risk Summary

Divigel is not indicated for use in females of reproductive potential. Estrogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well- established.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Possible Less Serious but More Common Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory infection.

…

PATIENT INFORMATION

(additions underlined)

…

What are the possible side effects of Divigel?

Side effects are grouped by how serious they are and how often they happen when you are treated. Serious, but less common side effects include:

…

Low blood calcium (hypocalcemia)
Fluid retention
…
Low thyroid levels in your blood
…
High triglyceride (fat) levels in your blood
High blood calcium (hypercalcemia)
Worsening of angioedema (swelling of face and tongue)
Changes in certain laboratory test results
…
The most common side effects of Divigel include:
- Irregular vaginal bleeding or spotting
- Breast tenderness
- Vaginal yeast infection
- Cold
- Upper respiratory tract (nose, sinuses, pharynx or larynx) infection
  
  …

11/01/2017 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Malignant Neoplasms

Ovarian Cancer

Additions and/or revisions underlined:

… A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

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

PATIENT INFORMATION

What are the possible side effects of Divigel?

Additions and/or revisions underlined:

These are not all the possible side effects of Divigel. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Vertical Pharmaceuticals, LLC at 1-877-95-VERTI (1-877-958-3784) or to FDA at 1-800-FDA-1088.

Keep Divigel out of the reach of children.

… You can get more information by calling the toll free number Customer Service: 1-866-600-4799.