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.

ESTROSTEP FE (NDA-020130)

(ETHINYL ESTRADIOL; NORETHINDRONE ACETATE)

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

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04/29/2022 (SUPPL-22)

Approved Drug Label (PDF)

4 Contraindications

Additions underlined

Combined oral contraceptives should not be used in women who currently have the following:

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Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive
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5 Warnings and Precautions

WARNINGS

Additions underlined

…

3.Malignant Neoplasms

Breast Cancer

Estrostep Fe is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among

current or recent users (<6 months since last use) and current users with longer duration of COC use [see Adverse Reactions].

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6 Adverse Reactions

Additions underlined

Post Marketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never- users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 4).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 4). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8- 10 years of COC use.

Please refer to label to view Figure 4.

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

PATIENT INFORMATION

Additions underlined

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Do birth control pills cause cancer?

There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more. Some studies have found an increase in the incidence of precancerous lesions of the cervix in women who use combined oral

contraceptives. However, this finding may be related to factors other than the use of combined oral contraceptives.

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DETAILED PATIENT PACKAGE INSERT

Additions underlined

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5.Risk of Cancer

It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.

If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones.

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07/14/2021 (SUPPL-21)

Approved Drug Label (PDF)

Boxed Warning

(Box Warning in supplement 21 has been updated)

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS:

Cigarette smoking increases the risk of serious cardiovascular side effects from combined oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including ESTROSTEP Fe, are contraindicated in women who are over 35 years of age and smoke.

4 Contraindications

(Additions and/or revisions underlined)

Combined oral contraceptives should not be used in women who currently have the following:

A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
- Smoke, if over age 35
- Have cerebrovascular disease
- Have coronary artery disease
- Have current or history of deep vein thrombosis or pulmonary embolism
- Have thrombogenic valvular or thrombogenic rhythm diseases of the heart
- Have inherited or acquired hypercoagulopathies
- Have uncontrolled hypertension or hypertension with vascular disease
- Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches
- Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or end-organ damage, or diabetes mellitus of > 20 years duration
Known or suspected carcinoma of the breast
Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
Undiagnosed abnormal genital bleeding
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Hepatic adenomas or carcinomas
Known or suspected pregnancy
Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

5 Warnings and Precautions

13. Hereditary Angiodema

(Newly added subsection)

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

14. Chloasma

(Newly added subsection)

Chloasma may occur with ESTROSTEP Fe, especially in women with a history of chloasma gravidarum. Advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking ESTROSTEP Fe.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Mood swings

7 Drug Interactions

(Additions and/or revisions underlined)

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Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation: Do not co- administer ESTROSTEP Fe with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.

Effects of Combined Oral Contraceptives on Other Drugs

COCs containing ethinyl estradiol may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increase with use of COCs.

10/10/2017 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

Precautions

(additions underlined)

8. Drug Interactions

...

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation: Do not co- administer ESTROSTEP Fe with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

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08/09/2017 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

Oral contraceptives should not be used in women who currently have the following:

Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations.

5 Warnings and Precautions

WARNINGS

(Additions and/or revisions are underlined)

5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue ESTROSTEP Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. ESTROSTEP Fe can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

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

Patient Information

(Additions and/or revisions are underlined)

BRIEF SUMMARY PATIENT PACKAGE INSERT

ESTROSTEP Fe (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as “birth control pills” or “the pill”, are taken to prevent pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills.

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Do not take the pill if you take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

DETAILED PATIENT PACKAGE INSERT

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Some women should not use the pill. For example, you should not use the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have any of the following:

Are receiving Hepatitis C drug combination containing ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

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Distributed by: Allergan USA, Inc. Irvine, CA 92612

1-800-678-1605

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.