Drug Safety-related Labeling Changes (SrLC)

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SEASONALE (NDA-021544)

(ETHINYL ESTRADIOL; LEVONORGESTREL)

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

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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:

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.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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