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.

SEASONALE (NDA-021544)

(ETHINYL ESTRADIOL; LEVONORGESTREL)

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

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01/27/2023 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

SEASONALE is contraindicated in females who are known to have or develop the following conditions:

A high risk of arterial or venous thrombotic diseases. Examples include females who are known to:

Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)].
Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions (5.1)].
Have cerebrovascular disease [see Warnings and Precautions (5.1)].
Have coronary artery disease [see Warnings and Precautions (5.1)].
Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)].
Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)].
Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.4)].
Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration [see Warnings and Precautions (5.7)].

Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.8)].

Current diagnosis of, or history of breast cancer, which may be hormone sensitive [see Warnings and Precautions (5.11)].
Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)].
Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.3)].

5 Warnings and Precautions

5.1 Thromboembolic Disorders and Other Vascular Conditions

Extensive changes; please refer to label

5.2 Liver Disease

Additions and/or revisions underlined:

Elevated Liver Enzymes

SEASONALE is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute liver test abnormalities may necessitate the discontinuation of SEASONALE until the liver tests return to normal and SEASONALE causation has been excluded.

Discontinue SEASONALE if jaundice develops.

Liver Tumors

SEASONALE is contraindicated in females with benign and malignant liver tumors [see Contraindications (4)]. COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users.

5.4 Hypertension

Subsection title revised; Additions and/or revisions underlined:

SEASONALE is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop SEASONALE if blood pressure rises significantly.

An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC.

5.5 Age-related Considerations

Newly added subsection:

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating SEASONALE for women over 35 years, such as:

Hypertension

Diabetes

Dyslipidemia

Obesity

5.6 Gallbladder Disease

Additions and/or revisions underlined:

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including SEASONALE, may worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

5.7 Adverse Carbohydrate and Lipid Metabolic Effects

Subsection title revised; Additions and/or revisions underlined:

Hyperglycemia

SEASONALE is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease or females with diabetes of >20 years of duration [see Contraindications (4)]. SEASONALE may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using SEASONALE.

Dyslipidemia

Consider alternative contraception for females with uncontrolled dyslipidemia. SEASONALE may cause adverse lipid changes.

Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using SEASONALE, which may increase the risk of pancreatitis.

5.8 Headache

Additions and/or revisions underlined:

SEASONALE is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura [see Contraindications (4)].

If a female taking SEASONALE develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue SEASONALE if indicated. Consider discontinuation of SEASONALE if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].

5.9 Bleeding Irregularities and Amenorrhea

Additions and/or revisions underlined:

…

Females using SEASONALE may experience unscheduled (breakthrough or intracyclic) bleeding and spotting especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.

Before prescribing SEASONALE, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting.

…

Females who use SEASONALE may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of SEASONALE, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4.

Because females using SEASONALE will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

After discontinuation of SEASONALE, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

5.10 Depression

Additions and/or revisions underlined:

Carefully observe females with a history of depression and discontinue SEASONALE if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited.

5.13 Hereditary Angioedema

Additions and/or revisions underlined:

In females with hereditary angioedema, exogenous estrogens, including SEASONALE, may induce or exacerbate symptoms of hereditary angioedema.

5.14 Chloasma

Additions and/or revisions underlined:

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

6 Adverse Reactions

6.2 Postmarketing Experience

Figure numbers have been revised; please refer to label

7 Drug Interactions

Additions and/or revisions underlined:

The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested.

Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations.

No drug-drug interaction studies were conducted with SEASONALE.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Extensive changes; please refer to label

7.2 Effects of Combined Oral Contraceptives on Other Drugs

Extensive changes; please refer to label

7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation

Subsection title revised; Additions and/or revisions underlined:

Co-administration of SEASONALE with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warning and Precautions (5.3)]. Co-administration of SEASONALE and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

7.4 Effect on Laboratory Tests

Subsection title revised; Additions and/or revisions underlined:

The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

There is no use for contraception in pregnancy; therefore, SEASONALE should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy.

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

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well- established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [see Dosage and Administration (2.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SEASONALE and any potential adverse effects on the breastfed child from SEASONALE or the underlying maternal condition.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

The pharmacokinetics of SEASONALE have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. SEASONALE is contraindicated in females with acute hepatitis or severe decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.2)].

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).

Cigarette Smoking

Cigarette smoking increases the risk of serious cardiovascular events from COC use. Women who are over 35 years old and smoke should not use SEASONALE [see Boxed Warning and Warnings and Precautions (5.1)].

Venous Thromboembolism

The increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see Warnings and Precautions (5.1)].

Use During Pregnancy

Instruct females to stop further intake of SEASONALE if pregnancy is confirmed during treatment.

Sexually Transmitted Infections

SEASONALE does not protect against HIV-infection (AIDS) and other sexually transmitted infections.

Dosing and Missed Pill Instructions

Patients should take one tablet daily by mouth at the same time every day [see Dosage and Administration (2.1)].

Instruct patients what to do in the event tablets are missed. See “What should I do if I miss any SEASONALE pills” section in FDA-approved Instructions for Use [see Dosage and Administration (2.3)].

Need for Additional Contraception

Postpartum females who start SEASONALE who have not yet had a period when they start SEASONALE need to use an additional method of contraception until they have taken a pink tablet for 7 consecutive days [see Dosage and Administration (2.1)].

There is a need for a back-up or alternative method of contraception when enzyme inducers are used with SEASONALE [see Drug Interactions (7.1)].

Lactation

SEASONALE may reduce breast milk production. This is less likely to occur if breastfeeding is well established. When possible, nursing women should use other methods of contraception until they have discontinued breastfeeding [see Use in Specific Populations (8.2)].

Amenorrhea and Possible Symptoms of Pregnancy

Amenorrhea may occur. Because women using SEASONALE will likely have scheduled bleeding only 4 times per year, advise women to contact their health care provider in the event of amenorrhea with symptoms of pregnancy such as morning sickness or unusual breast tenderness [see Warnings and Precautions (5.9)].

Depression

Depressed mood and depression may occur. Women should contact their healthcare provider if mood changes and depressive symptoms occur, including shortly after initiating the treatment [see Warnings and Precautions (5.10)].

PATIENT INFORMATION

Extensive changes; please refer to label

01/27/2023 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

SEASONALE is contraindicated in females who are known to have or develop the following conditions:

A high risk of arterial or venous thrombotic diseases. Examples include females who are known to:

Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)].
Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions (5.1)].
Have cerebrovascular disease [see Warnings and Precautions (5.1)].
Have coronary artery disease [see Warnings and Precautions (5.1)].
Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)].
Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)].
Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.4)].
Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration [see Warnings and Precautions (5.7)].

Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.8)].

Current diagnosis of, or history of breast cancer, which may be hormone sensitive [see Warnings and Precautions (5.11)].
Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)].
Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.3)].

5 Warnings and Precautions

5.1 Thromboembolic Disorders and Other Vascular Conditions

Extensive changes; please refer to label

5.2 Liver Disease

Additions and/or revisions underlined:

Elevated Liver Enzymes

Discontinue SEASONALE if jaundice develops.

Liver Tumors

5.4 Hypertension

Subsection title revised; Additions and/or revisions underlined:

5.5 Age-related Considerations

Newly added subsection:

Hypertension

Diabetes

Dyslipidemia

Obesity

5.6 Gallbladder Disease

Additions and/or revisions underlined:

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including SEASONALE, may worsen existing gallbladder disease.

5.7 Adverse Carbohydrate and Lipid Metabolic Effects

Subsection title revised; Additions and/or revisions underlined:

Hyperglycemia

Dyslipidemia

Consider alternative contraception for females with uncontrolled dyslipidemia. SEASONALE may cause adverse lipid changes.

Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using SEASONALE, which may increase the risk of pancreatitis.

5.8 Headache

Additions and/or revisions underlined:

5.9 Bleeding Irregularities and Amenorrhea

Additions and/or revisions underlined:

…

Because females using SEASONALE will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

After discontinuation of SEASONALE, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

5.10 Depression

Additions and/or revisions underlined:

5.13 Hereditary Angioedema

Additions and/or revisions underlined:

In females with hereditary angioedema, exogenous estrogens, including SEASONALE, may induce or exacerbate symptoms of hereditary angioedema.

5.14 Chloasma

Additions and/or revisions underlined:

6 Adverse Reactions

6.2 Postmarketing Experience

Figure numbers have been revised; please refer to label

7 Drug Interactions

Additions and/or revisions underlined:

No drug-drug interaction studies were conducted with SEASONALE.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Extensive changes; please refer to label

7.2 Effects of Combined Oral Contraceptives on Other Drugs

Extensive changes; please refer to label

7.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy – Liver Enzyme Elevation

Subsection title revised; Additions and/or revisions underlined:

7.4 Effect on Laboratory Tests

Subsection title revised; Additions and/or revisions underlined:

The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

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

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

8.6 Hepatic Impairment

Additions and/or revisions underlined:

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).

Cigarette Smoking

Venous Thromboembolism

Use During Pregnancy

Instruct females to stop further intake of SEASONALE if pregnancy is confirmed during treatment.

Sexually Transmitted Infections

SEASONALE does not protect against HIV-infection (AIDS) and other sexually transmitted infections.

Dosing and Missed Pill Instructions

Patients should take one tablet daily by mouth at the same time every day [see Dosage and Administration (2.1)].

Instruct patients what to do in the event tablets are missed. See “What should I do if I miss any SEASONALE pills” section in FDA-approved Instructions for Use [see Dosage and Administration (2.3)].

Need for Additional Contraception

Postpartum females who start SEASONALE who have not yet had a period when they start SEASONALE need to use an additional method of contraception until they have taken a pink tablet for 7 consecutive days [see Dosage and Administration (2.1)].

There is a need for a back-up or alternative method of contraception when enzyme inducers are used with SEASONALE [see Drug Interactions (7.1)].

Lactation

Amenorrhea and Possible Symptoms of Pregnancy

Depression

PATIENT INFORMATION

Extensive changes; please refer to label

04/29/2022 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

Additions underlined

SEASONALE is contraindicated in females who are known to have or develop the following conditions:

…

Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.11)].

…

5 Warnings and Precautions

5.11 Malignant Neoplasms

Additions underlined

Breast Cancer

SEASONALE is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

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 Postmarketing Experience (6.2)].

…

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

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 C).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure C). 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.

Figure C: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

Please refer to label to view Figure C.

…

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

PATIENT INFORMATION

Additions underlined

…

Do birth control pills cause 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.

…

08/09/2017 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

Do not prescribe SEASONALE to women who are known to have the following conditions:

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

5 Warnings and Precautions

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

(Newly added subsection)

During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/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 SEASONALE prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. SEASONALE can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

7 Drug Interactions

7.3 Concomitant Use with Hepatitis C Vaccine (HCV) Combination Therapy – Liver Enzyme Elevation

(Newly added subsection)

Do not co-administer SEASONALE with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

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

Patient Information

(Additions and/or revisions are underlined)

Who should not take SEASONALE?

Do not take SEASONALE 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.

03/31/2017 (SUPPL-10)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion; revised as below:

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination 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 are contraindicated in women who are over 35 years of age and smoke.

4 Contraindications

PLR conversion; revised as below:

Do not prescribe SEASONALE to women who are known to have the following conditions:

· A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:

o Smoke, if over age 35

o Have deep vein thrombosis or pulmonary embolism, now or in the past

o Have inherited or acquired hypercoagulopathies

o Have cerebrovascular disease

o Have coronary artery disease

o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)

o Have uncontrolled hypertension

o Have diabetes mellitus with vascular disease

o Have headaches with focal neurological symptoms or migraine headaches with aura

· Women over age 35 with any migraine headaches

· Liver tumors, benign or malignant, or liver disease

Undiagnosed abnormal uterine bleeding
Pregnancy, because there is no reason to use COCs during pregnancy
Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past

5 Warnings and Precautions

PLR conversion; revised as below:

5.1 Thrombotic Disorders and Other Vascular Problems

Stop SEASONALE if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
Stop SEASONALE if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
If feasible, stop SEASONALE at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization.
Start SEASONALE no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk
of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman- years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
Use of SEASONALE provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used SEASONALE.
Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. Stroke has been reported in women associated with the use of SEASONALE. COCs have been shown to increase both the relative and attributable risks
of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
Use COCs with caution in women with cardiovascular disease risk factors.
5.2 Liver Disease
Impaired Liver Function
Do not use SEASONALE in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver.. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue SEASONALE if jaundice develops.
Liver Tumors
SEASONALE is contraindicated in women with benign and malignant liver tumor. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users …
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (greater than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.
5.3 High Blood Pressure
SEASONALE is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease. For women with well-controlled hypertension, monitor blood pressure and stop SEASONALE if blood pressure rises significantly.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.
5.4 Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease.
A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.
5.5 Carbohydrate and Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are taking SEASONALE. COCs may decrease glucose tolerance.
Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
5.6 Headache
If a woman taking SEASONALE develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue SEASONALE if indicated.
Consider discontinuation of SEASONALE in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).
5.7 Bleeding Irregularities and Amenorrhea
Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white inert tablets is considered “scheduled” bleeding.
Unscheduled and Scheduled Bleeding and Spotting
Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on SEASONALE, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.
Before prescribing SEASONALE, advise the woman to weigh the convenience of fewer scheduled menses (4 per year instead of 13 per year) against the inconvenience of increased unscheduled bleeding and/or spotting.
The clinical trial of the efficacy of SEASONALE (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting greater than or equal to 10 consecutive days on oral contraceptives were excluded from the study. More SEASONALE subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [SEASONALE] vs. 1.8% [28-day cycle regimen]). Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.
Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle
Newly added table; please refer to label.
Table 4 shows the percentages of women with greater than or equal to 7 days and less than or equal to 20 days of unscheduled spotting and/or bleeding in the SEASONALE and the 28-day cycle treatment groups.
Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting (renamed table)
Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for SEASONALE subjects and subjects on the 28-day cycle regimen.
Amenorrhea and Oligomenorrhea
Women who are not pregnant and use SEASONALE may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 0.8% of women during Cycle 1, 1.2% of women during Cycle 2, 3.7% of women during Cycle 3, and 3.4% of women during Cycle 4. Because women using SEASONALE will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.
Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.
5.8 COC Use Before or During Early Pregnancy
… Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue SEASONALE use if pregnancy is confirmed. Administration of oral contraceptives …
5.9 Depression
Depression associated with the use of SEASONALE has been reported. Carefully observe women with a history of depression and discontinue SEASONALE if severe depression recurs.
5.10 Carcinoma of the Breast and Cervix

SEASONALE is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive.
There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
5.11 Effect on Binding Globulins
The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.
5.12 Monitoring
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
5.13 Hereditary Angioedema
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
5.14 Chloasma
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to develop chloasma should avoid prolonged exposure to the sun or ultraviolet radiation while taking SEASONALE.

6 Adverse Reactions

PLR conversion; revised as below:

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

Serious cardiovascular events and stroke
Vascular events
Liver disease
Adverse reactions commonly reported by COC users are:
Irregular uterine bleeding
Nausea
Breast tenderness
Headache
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The clinical trial that evaluated the safety and efficacy of SEASONALE was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 456 took at least one dose of SEASONALE (345.14 woman-years of exposure).
Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (greater than or equal to 1% of women) leading to discontinuation in the SEASONALE group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%).
Common Adverse Reactions (? 2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%).
Serious Adverse Reactions: pulmonary embolus, cholecystitis.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SEASONALE. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: abdominal distension, vomiting
General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorder: hypersensitivity reactions, including itching, rash, and angioedema Investigations: blood pressure increased
Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity
Nervous system disorders: dizziness, loss of consciousness
Psychiatric disorders: insomnia
Reproductive and breast disorders: dysmenorrhea
Skin and subcutaneous tissue disorders: alopecia
Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis

7 Drug Interactions

PLR conversion; revised as below:

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Substances increasing the plasma concentrations of COCs:

Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

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/or progestin have been noted in some cases of co-administration with HIV 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., nevirapine] or increase [e.g., etravirine]).

7.2 Effects of Combined Oral Contraceptives on Other Drugs

COCs containing EE 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 increases with use of COCs.

7.3 Interactions with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 Use in Specific Populations

PLR conversion; revised as below:

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers

Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use

Safety and efficacy of SEASONALE have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of SEASONALE before menarche is not indicated.

8.5 Geriatric Use

SEASONALE has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment

The pharmacokinetics of SEASONALE have not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

8.7 Renal Impairment

The pharmacokinetics of SEASONALE have not been studied in women with renal impairment.

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

PATIENT COUNSELING INFORMATION

PLR conversion; revised as below:

See FDA-approved patient labeling (Patient Information and Instructions for Use). Counsel patients on the following information:

Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.
Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC.
SEASONALE does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
SEASONALE is not to be used during pregnancy; if pregnancy occurs during use of SEASONALE, instruct the patient to stop further use.
Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed.
Use a back-up or alternative method of contraception when enzyme inducers are used with SEASONALE.
COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established.
Women who start on COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a pink tablet for 7 consecutive days.
Amenorrhea may occur. Because women using SEASONALE will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

PATIENT INFORMATION

PLR conversion; reformatted and revised; please refer to label.

03/31/2017 (SUPPL-9)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion; revised as below:

4 Contraindications

PLR conversion; revised as below:

Do not prescribe SEASONALE to women who are known to have the following conditions:

· A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:

o Smoke, if over age 35

o Have deep vein thrombosis or pulmonary embolism, now or in the past

o Have inherited or acquired hypercoagulopathies

o Have cerebrovascular disease

o Have coronary artery disease

o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)

o Have uncontrolled hypertension

o Have diabetes mellitus with vascular disease

o Have headaches with focal neurological symptoms or migraine headaches with aura

· Women over age 35 with any migraine headaches

· Liver tumors, benign or malignant, or liver disease

Undiagnosed abnormal uterine bleeding
Pregnancy, because there is no reason to use COCs during pregnancy
Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past

5 Warnings and Precautions

PLR conversion; revised as below:

5.1 Thrombotic Disorders and Other Vascular Problems

Stop SEASONALE if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
Stop SEASONALE if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
If feasible, stop SEASONALE at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization.
Start SEASONALE no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk
of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman- years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
Use of SEASONALE provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used SEASONALE.
Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. Stroke has been reported in women associated with the use of SEASONALE. COCs have been shown to increase both the relative and attributable risks
of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
Use COCs with caution in women with cardiovascular disease risk factors.
5.2 Liver Disease
Impaired Liver Function
Do not use SEASONALE in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver.. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue SEASONALE if jaundice develops.
Liver Tumors
SEASONALE is contraindicated in women with benign and malignant liver tumor. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users …
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (greater than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.
5.3 High Blood Pressure
SEASONALE is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease. For women with well-controlled hypertension, monitor blood pressure and stop SEASONALE if blood pressure rises significantly.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.
5.4 Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease.
A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.
5.5 Carbohydrate and Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are taking SEASONALE. COCs may decrease glucose tolerance.
Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
5.6 Headache
If a woman taking SEASONALE develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue SEASONALE if indicated.
Consider discontinuation of SEASONALE in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).
5.7 Bleeding Irregularities and Amenorrhea
Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white inert tablets is considered “scheduled” bleeding.
Unscheduled and Scheduled Bleeding and Spotting
Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on SEASONALE, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.
Before prescribing SEASONALE, advise the woman to weigh the convenience of fewer scheduled menses (4 per year instead of 13 per year) against the inconvenience of increased unscheduled bleeding and/or spotting.
The clinical trial of the efficacy of SEASONALE (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting greater than or equal to 10 consecutive days on oral contraceptives were excluded from the study. More SEASONALE subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [SEASONALE] vs. 1.8% [28-day cycle regimen]). Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.
Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle
Newly added table; please refer to label.
Table 4 shows the percentages of women with greater than or equal to 7 days and less than or equal to 20 days of unscheduled spotting and/or bleeding in the SEASONALE and the 28-day cycle treatment groups.
Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting (renamed table)
Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for SEASONALE subjects and subjects on the 28-day cycle regimen.
Amenorrhea and Oligomenorrhea
Women who are not pregnant and use SEASONALE may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 0.8% of women during Cycle 1, 1.2% of women during Cycle 2, 3.7% of women during Cycle 3, and 3.4% of women during Cycle 4. Because women using SEASONALE will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.
Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.
5.8 COC Use Before or During Early Pregnancy
… Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue SEASONALE use if pregnancy is confirmed. Administration of oral contraceptives …
5.9 Depression
Depression associated with the use of SEASONALE has been reported. Carefully observe women with a history of depression and discontinue SEASONALE if severe depression recurs.
5.10 Carcinoma of the Breast and Cervix

SEASONALE is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive.
There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
5.11 Effect on Binding Globulins
The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.
5.12 Monitoring
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
5.13 Hereditary Angioedema
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
5.14 Chloasma
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to develop chloasma should avoid prolonged exposure to the sun or ultraviolet radiation while taking SEASONALE.

6 Adverse Reactions

PLR conversion; revised as below:

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

Serious cardiovascular events and stroke
Vascular events
Liver disease
Adverse reactions commonly reported by COC users are:
Irregular uterine bleeding
Nausea
Breast tenderness
Headache
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The clinical trial that evaluated the safety and efficacy of SEASONALE was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 456 took at least one dose of SEASONALE (345.14 woman-years of exposure).
Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (greater than or equal to 1% of women) leading to discontinuation in the SEASONALE group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%).
Common Adverse Reactions (? 2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%).
Serious Adverse Reactions: pulmonary embolus, cholecystitis.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SEASONALE. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: abdominal distension, vomiting
General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorder: hypersensitivity reactions, including itching, rash, and angioedema Investigations: blood pressure increased
Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity
Nervous system disorders: dizziness, loss of consciousness
Psychiatric disorders: insomnia
Reproductive and breast disorders: dysmenorrhea
Skin and subcutaneous tissue disorders: alopecia
Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis

7 Drug Interactions

PLR conversion; revised as below:

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Substances increasing the plasma concentrations of COCs:

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

7.2 Effects of Combined Oral Contraceptives on Other Drugs

COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.

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

7.3 Interactions with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 Use in Specific Populations

PLR conversion; revised as below:

8.1 Pregnancy

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

SEASONALE has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment

8.7 Renal Impairment

The pharmacokinetics of SEASONALE have not been studied in women with renal impairment.

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

PATIENT COUNSELING INFORMATION

PLR conversion; revised as below:

See FDA-approved patient labeling (Patient Information and Instructions for Use). Counsel patients on the following information:

Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.
Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC.
SEASONALE does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
SEASONALE is not to be used during pregnancy; if pregnancy occurs during use of SEASONALE, instruct the patient to stop further use.
Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed.
Use a back-up or alternative method of contraception when enzyme inducers are used with SEASONALE.
COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established.
Women who start on COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a pink tablet for 7 consecutive days.
Amenorrhea may occur. Because women using SEASONALE will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

PATIENT INFORMATION

PLR conversion; reformatted and revised; please refer to label.