Drospirenone and estetrol

Drospirenone and estetrol
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]

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Black Box Warning

CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete Boxed Warning. Condition Name: (Females over 35 years old who smoke should not use NEXTSTELLIS (4) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) )

Overview

Drospirenone and estetrol is a combination of drospirenone, a progestin, and estetrol, an estrogen, that is FDA approved for the treatment of reproductive potential to prevent pregnancy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased ..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Dosage and Administration

Start NEXTSTELLIS using a Day 1 start. Take one tablet by mouth at the same time every day with or without food.

Additional Administration Information

To achieve maximum contraceptive effectiveness, take one tablet every day at about the same time each day. The recommended dosage of NEXTSTELLIS is one tablet daily for 28 consecutive days: one pink active tablet daily during the first 24 days followed by one white inactive tablet daily during the 4 following days (see TABLE 1).

NEXTSTELLIS Administration Instructions

NEXTSTELLIS Administration Instructions

Missed Doses

Instructions for Missed NEXTSTELLLIS Tablets in a Monthly Dosing Regimen

Administration Recommendations after Vomiting or Acute Diarrhea

• If vomiting or acute diarrhea occurs within 3 to 4 hours after taking an active tablet, take the new active tablet (scheduled for the next day) as soon as possible. Take the new tablet within 12 hours of the usual time of tablet-taking if possible. If more than two tablets are missed, follow the advice concerning missed tablets, including using backup non-hormonal contraception. For additional recommendations, refer to the table above.

3 DOSAGE FORMS AND STRENGTHS

• NEXTSTELLIS (drospirenone and estetrol tablets) is available in a blister card, with 28 6-mm round, bi-convex film-coated tablets in the following order:
  • 24 pink active tablets containing 3 mg drospirenone and 14.2 mg estetrol embossed with a drop-shaped logo on one side.
  • 4 white inert tablets embossed with a drop-shaped logo on one side.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Drospirenone and estetrol in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Drospirenone and estetrol in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Drospirenone and estetrol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Drospirenone and estetrol in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Drospirenone and estetrol in pediatric patients.

Contraindications

• NEXTSTELLIS is contraindicated in females who are known to have or develop the following conditions:
  • A history of, increased risk for, or current arterial or venous thrombotic/thromboembolic diseases. Examples include females who are known to:

- Smoke, if 35 years of age and older. - Have current or history of deep vein thrombosis or pulmonary embolism. - Have cerebrovascular disease.

- Have coronary artery disease.

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

- Have inherited or acquired hypercoagulopathies .

- Have uncontrolled hypertension or hypertension with vascular disease .

- Have diabetes mellitus with hypertension or end-organ damage; or diabetes mellitus of > 20 years duration.

- Have migraine headaches with aura.

• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive .

• Hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or severe (decompensated) cirrhosis.

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

• Abnormal uterine bleeding that has an undiagnosed etiology.

• Renal Impairment.

• Adrenal insufficiency.

Warnings

CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete Boxed Warning. Condition Name: (Females over 35 years old who smoke should not use NEXTSTELLIS (4) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) )

Thromboembolic Disorders and Other Vascular Problems

• Stop NEXTSTELLIS if an arterial or venous thrombotic/thromboembolic event occurs. • Stop NEXTSTELLIS if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. • Discontinue NEXTSTELLIS during prolonged immobilization. • Start NEXTSTELLIS no earlier than four weeks after delivery in females who are not breast feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

• Before starting NEXTSTELLIS, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. NEXTSTELLIS is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases.

Cardiovascular and Cerebrovascular Events

• Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among females over age 40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. The risk increases with age, particularly in females 35 years of age and older, and with the number of cigarettes smoked. In addition to cigarettes, use of other nicotine-containing products – including cigars, smokeless tobacco, hookah tobacco, e-cigarettes, and nicotine replacement therapy – may also increase the risk of serious cardiovascular events from CHC use.

Venous Thromboembolism

• Use of CHCs also increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years and should be considered in the context of other female of reproductive potential subpopulations who are not taking CHCs.
• Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs.
• The presence of multiple risk factors for VTE may increase the risk synergistically. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of four weeks or longer. The risk of VTE returns to baseline approximately 3 months after CHC use is discontinued.

Postpartum Venous Thromboembolism

• The risk of VTE is increased during the first six weeks postpartum compared to the risk in non-pregnant, non-postpartum females. The risk is highest in the first three weeks postpartum, but remains higher than baseline until at least six weeks postpartum. The presence of multiple risk factors for VTE may further increase the risk. Obstetric complications may extend the elevated risk up to 12 weeks postpartum.

• Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use COCs, for females who use COCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: if 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Figure 1 Likelihood of Developing a VTE

• Two prospective studies of NEXTSTELLIS have been conducted, one in Europe/Russia (NCT02817828; C301) and one in North America (NCT02817841; C302) (N=3,632), for the prevention of pregnancy in females 16-50 years of age. There was one reported VTE in the Europe/Russia study.

Hyperkalemia

• NEXTSTELLIS is contraindicated in females with conditions that predispose to hyperkalemia (e.g., renal impairment, hepatic impairment, and adrenal insufficiency). Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Monitor serum potassium concentration in females at increased risk for hyperkalemia (i.e., those females who take a strong CYP3A4 inhibitor long-term and concomitantly with NEXTSTELLIS).
• Monitor females taking NEXTSTELLIS who later develop medical conditions and/or begin medication that put them at an increased risk for hyperkalemia.
• NEXTSTELLIS contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk females, comparable to a 25 mg dose of spironolactone. In two Phase 3 trials of NEXTSTELLIS (N = 3,632) for the prevention of pregnancy in females 16-50 years of age, seven subjects were noted to have hyperkalemia and one subject discontinued due to elevated potassium levels. Most females who developed hyperkalemia in the clinical development studies of NEXTSTELLIS had only mild potassium elevations and/or isolated increases that returned to normal while still on study medication.

Hypertension

• NEXTSTELLIS is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease .
• For all females, including those with well-controlled hypertension, monitor blood pressure periodically and stop NEXTSTELLIS if blood pressure rises significantly.

An increase in blood pressure has been reported in females using COCs. This increase is more likely in older females with extended duration of use.

Migraine

• NEXTSTELLIS is contraindicated in females who have migraines with aura. Discontinue NEXTSTELLIS in females using NEXTSTELLIS who develop new migraines that are recurrent, persistent, or severe. Discontinue NEXTSTELLIS if there is an increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event).
• Migraines with aura increase the risk for stroke. This stroke risk is further increased in females who have migraines with aura with use of CHCs.

Malignant Neoplasms

• Breast Cancer.
  • NEXTSTELLIS is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive.

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.

• Cervical Cancer.
  • A causal relationship between the use of CHCs and the development of cervical cancer and intraepithelial neoplasia has not been clearly established. In observational studies, the use of oral hormonal contraceptives in females for five years or more, compared to females who did not use oral hormonal contraceptives, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. In these studies, the use of oral hormonal contraceptives in females for 10 years or more, compared to females who received oral hormonal contraceptives for 5-9 years, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. Limitations in these epidemiologic studies include potential recall bias, differences in sexual behavior, and other factors such as establishing whether there were data on persistent high-risk Human Papilloma Virus (HPV) infection.

Liver Disease

• Elevated Liver Enzymes.
  • NEXTSTELLIS is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis .
  • Withhold or permanently discontinue NEXTSTELLIS for persistent or significant elevation of liver enzymes. NEXTSTELLIS can cause elevated liver enzymes.
• Liver Tumors>
  • NEXTSTELLIS is contraindicated in females with hepatic adenomas and malignant liver tumors.CHCs increase the risk of hepatic tumors, particularly hepatic adenomas. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

• CHCs, such as NEXTSTELLIS, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir).
• Discontinue NEXTSTELLIS prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). NEXTSTELLIS can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen.
• During clinical trials with the above-mentioned Hepatitis C combination drug regimen, 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 females using ethinyl estradiol (EE)-containing drugs, such as CHCs. Females using medications containing estrogens other than EE had a rate of *ALT elevation similar to those not receiving any estrogens. NEXTSTELLIS contains E4 rather than EE, but as no data are available for co-administration with this Hepatitis C combination drug regimen, caution is warranted.

Glucose Tolerance and Hypertriglyceridemia

• Glucose Tolerance.
  • Carefully monitor females with prediabetes and diabetes who are using NEXSTELLIS. NEXTSTELLIS may decrease glucose tolerance.

• Hypertriglyceridemia.
  • Consider alternative contraception for females with hypertriglyceridemia. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using NEXSTELLIS, which may increase the risk of pancreatitis.

Gallbladder Disease and Cholestasis

• Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder disease or cholestatic disease. Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
• A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.

Effect on Binding Globulins

• Increase the dosage of thyroid hormone replacement therapy as needed in females taking NEXTSTELLIS .
• The estrogen component of NEXTSTELLIS may increase the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.

Bleeding Irregularities and Amenorrhea

Unscheduled Bleeding and Spotting

• Females using NEXTSTELLIS may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 4 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
• Unscheduled bleeding was defined as bleeding or spotting that occurred on Day 4 through Day 24 of a 28-day cycle. Based on subject diaries from C302 (US/CA), the proportion of subjects reporting unscheduled bleeding or spotting per 28-day cycle decreased over time: 30.3% at Cycle 1 versus 17.4% at Cycle 12. The mean number of unscheduled bleeding/spotting days per cycle also gradually decreased over time, with a mean of 0.4 (± 1.42) bleeding days at Cycle 1, versus a mean of 0.2 (± 0.98) bleeding days at Cycle 12.

Absence of Scheduled Bleeding

• Females who use NEXTSTELLIS may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant . The proportion of subjects reporting absence of scheduled bleeding remained constant overall, with on average 15.5% of subjects reporting absence of scheduled bleeding from Cycles 1 through 12.
• If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than prescribed), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures.
• After discontinuation of NEXTSTELLIS, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

Depression

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

Hereditary Angioedema

• Avoid NEXTSTELLIS in females with hereditary angioedema. Exogenous estrogens may induce or exacerbate symptoms of hereditary angioedema.

Chloasma

• Avoid NEXTSTELLIS in females with a history of chloasma gravidarum or increased sensitivity to sun and/or ultraviolet radiation exposure. Chloasma may occur with NEXTSTELLIS use, especially in females with a history of chloasma gravidarum.

Thromboembolic Disorders and Other Vascular Problems

• Stop NEXTSTELLIS if an arterial or venous thrombotic/thromboembolic event occurs. • Stop NEXTSTELLIS if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. • Discontinue NEXTSTELLIS during prolonged immobilization. • Start NEXTSTELLIS no earlier than four weeks after delivery in females who are not breast feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

• Before starting NEXTSTELLIS, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. NEXTSTELLIS is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases.

Cardiovascular and Cerebrovascular Events

• Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among females over age 40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. The risk increases with age, particularly in females 35 years of age and older, and with the number of cigarettes smoked. In addition to cigarettes, use of other nicotine-containing products – including cigars, smokeless tobacco, hookah tobacco, e-cigarettes, and nicotine replacement therapy – may also increase the risk of serious cardiovascular events from CHC use.

Venous Thromboembolism

• Use of CHCs also increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years and should be considered in the context of other female of reproductive potential subpopulations who are not taking CHCs.
• Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs.
• The presence of multiple risk factors for VTE may increase the risk synergistically. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of four weeks or longer. The risk of VTE returns to baseline approximately 3 months after CHC use is discontinued.

Postpartum Venous Thromboembolism

• The risk of VTE is increased during the first six weeks postpartum compared to the risk in non-pregnant, non-postpartum females. The risk is highest in the first three weeks postpartum, but remains higher than baseline until at least six weeks postpartum. The presence of multiple risk factors for VTE may further increase the risk. Obstetric complications may extend the elevated risk up to 12 weeks postpartum.

• Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use COCs, for females who use COCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: if 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Figure 1 Likelihood of Developing a VTE

• Two prospective studies of NEXTSTELLIS have been conducted, one in Europe/Russia (NCT02817828; C301) and one in North America (NCT02817841; C302) (N=3,632), for the prevention of pregnancy in females 16-50 years of age. There was one reported VTE in the Europe/Russia study.

Hyperkalemia

• NEXTSTELLIS is contraindicated in females with conditions that predispose to hyperkalemia (e.g., renal impairment, hepatic impairment, and adrenal insufficiency). Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Monitor serum potassium concentration in females at increased risk for hyperkalemia (i.e., those females who take a strong CYP3A4 inhibitor long-term and concomitantly with NEXTSTELLIS).
• Monitor females taking NEXTSTELLIS who later develop medical conditions and/or begin medication that put them at an increased risk for hyperkalemia.
• NEXTSTELLIS contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk females, comparable to a 25 mg dose of spironolactone. In two Phase 3 trials of NEXTSTELLIS (N = 3,632) for the prevention of pregnancy in females 16-50 years of age, seven subjects were noted to have hyperkalemia and one subject discontinued due to elevated potassium levels. Most females who developed hyperkalemia in the clinical development studies of NEXTSTELLIS had only mild potassium elevations and/or isolated increases that returned to normal while still on study medication.

Hypertension

• NEXTSTELLIS is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease .
• For all females, including those with well-controlled hypertension, monitor blood pressure periodically and stop NEXTSTELLIS if blood pressure rises significantly.

An increase in blood pressure has been reported in females using COCs. This increase is more likely in older females with extended duration of use.

Migraine

• NEXTSTELLIS is contraindicated in females who have migraines with aura. Discontinue NEXTSTELLIS in females using NEXTSTELLIS who develop new migraines that are recurrent, persistent, or severe. Discontinue NEXTSTELLIS if there is an increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event).
• Migraines with aura increase the risk for stroke. This stroke risk is further increased in females who have migraines with aura with use of CHCs.

Malignant Neoplasms

• Breast Cancer.
  • NEXTSTELLIS is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive.

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.

• Cervical Cancer.
  • A causal relationship between the use of CHCs and the development of cervical cancer and intraepithelial neoplasia has not been clearly established. In observational studies, the use of oral hormonal contraceptives in females for five years or more, compared to females who did not use oral hormonal contraceptives, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. In these studies, the use of oral hormonal contraceptives in females for 10 years or more, compared to females who received oral hormonal contraceptives for 5-9 years, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. Limitations in these epidemiologic studies include potential recall bias, differences in sexual behavior, and other factors such as establishing whether there were data on persistent high-risk Human Papilloma Virus (HPV) infection.

Liver Disease

• Elevated Liver Enzymes.
  • NEXTSTELLIS is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis .
  • Withhold or permanently discontinue NEXTSTELLIS for persistent or significant elevation of liver enzymes. NEXTSTELLIS can cause elevated liver enzymes.
• Liver Tumors>
  • NEXTSTELLIS is contraindicated in females with hepatic adenomas and malignant liver tumors.CHCs increase the risk of hepatic tumors, particularly hepatic adenomas. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

• CHCs, such as NEXTSTELLIS, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir).
• Discontinue NEXTSTELLIS prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). NEXTSTELLIS can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen.
• During clinical trials with the above-mentioned Hepatitis C combination drug regimen, 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 females using ethinyl estradiol (EE)-containing drugs, such as CHCs. Females using medications containing estrogens other than EE had a rate of *ALT elevation similar to those not receiving any estrogens. NEXTSTELLIS contains E4 rather than EE, but as no data are available for co-administration with this Hepatitis C combination drug regimen, caution is warranted.

Glucose Tolerance and Hypertriglyceridemia

• Glucose Tolerance.
  • Carefully monitor females with prediabetes and diabetes who are using NEXSTELLIS. NEXTSTELLIS may decrease glucose tolerance.

• Hypertriglyceridemia.
  • Consider alternative contraception for females with hypertriglyceridemia. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using NEXSTELLIS, which may increase the risk of pancreatitis.

Gallbladder Disease and Cholestasis

• Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder disease or cholestatic disease. Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
• A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.

Effect on Binding Globulins

• Increase the dosage of thyroid hormone replacement therapy as needed in females taking NEXTSTELLIS .
• The estrogen component of NEXTSTELLIS may increase the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.

Bleeding Irregularities and Amenorrhea

Unscheduled Bleeding and Spotting

• Females using NEXTSTELLIS may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 4 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
• Unscheduled bleeding was defined as bleeding or spotting that occurred on Day 4 through Day 24 of a 28-day cycle. Based on subject diaries from C302 (US/CA), the proportion of subjects reporting unscheduled bleeding or spotting per 28-day cycle decreased over time: 30.3% at Cycle 1 versus 17.4% at Cycle 12. The mean number of unscheduled bleeding/spotting days per cycle also gradually decreased over time, with a mean of 0.4 (± 1.42) bleeding days at Cycle 1, versus a mean of 0.2 (± 0.98) bleeding days at Cycle 12.

Absence of Scheduled Bleeding

• Females who use NEXTSTELLIS may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant . The proportion of subjects reporting absence of scheduled bleeding remained constant overall, with on average 15.5% of subjects reporting absence of scheduled bleeding from Cycles 1 through 12.
• If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than prescribed), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures.
• After discontinuation of NEXTSTELLIS, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

Depression

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

Hereditary Angioedema

• Avoid NEXTSTELLIS in females with hereditary angioedema. Exogenous estrogens may induce or exacerbate symptoms of hereditary angioedema.

Chloasma

• Avoid NEXTSTELLIS in females with a history of chloasma gravidarum or increased sensitivity to sun and/or ultraviolet radiation exposure. Chloasma may occur with NEXTSTELLIS use, especially in females with a history of chloasma gravidarum.

Thromboembolic Disorders and Other Vascular Problems

• Stop NEXTSTELLIS if an arterial or venous thrombotic/thromboembolic event occurs. • Stop NEXTSTELLIS if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. • Discontinue NEXTSTELLIS during prolonged immobilization. • Start NEXTSTELLIS no earlier than four weeks after delivery in females who are not breast feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

• Before starting NEXTSTELLIS, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. NEXTSTELLIS is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases.

Cardiovascular and Cerebrovascular Events

• Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among females over age 40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. The risk increases with age, particularly in females 35 years of age and older, and with the number of cigarettes smoked. In addition to cigarettes, use of other nicotine-containing products – including cigars, smokeless tobacco, hookah tobacco, e-cigarettes, and nicotine replacement therapy – may also increase the risk of serious cardiovascular events from CHC use.

Venous Thromboembolism

• Use of CHCs also increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years and should be considered in the context of other female of reproductive potential subpopulations who are not taking CHCs.
• Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs.
• The presence of multiple risk factors for VTE may increase the risk synergistically. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of four weeks or longer. The risk of VTE returns to baseline approximately 3 months after CHC use is discontinued.

Postpartum Venous Thromboembolism

• The risk of VTE is increased during the first six weeks postpartum compared to the risk in non-pregnant, non-postpartum females. The risk is highest in the first three weeks postpartum, but remains higher than baseline until at least six weeks postpartum. The presence of multiple risk factors for VTE may further increase the risk. Obstetric complications may extend the elevated risk up to 12 weeks postpartum.

• Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use COCs, for females who use COCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: if 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Figure 1 Likelihood of Developing a VTE

• Two prospective studies of NEXTSTELLIS have been conducted, one in Europe/Russia (NCT02817828; C301) and one in North America (NCT02817841; C302) (N=3,632), for the prevention of pregnancy in females 16-50 years of age. There was one reported VTE in the Europe/Russia study.

Hyperkalemia

• NEXTSTELLIS is contraindicated in females with conditions that predispose to hyperkalemia (e.g., renal impairment, hepatic impairment, and adrenal insufficiency). Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Monitor serum potassium concentration in females at increased risk for hyperkalemia (i.e., those females who take a strong CYP3A4 inhibitor long-term and concomitantly with NEXTSTELLIS).
• Monitor females taking NEXTSTELLIS who later develop medical conditions and/or begin medication that put them at an increased risk for hyperkalemia.
• NEXTSTELLIS contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk females, comparable to a 25 mg dose of spironolactone. In two Phase 3 trials of NEXTSTELLIS (N = 3,632) for the prevention of pregnancy in females 16-50 years of age, seven subjects were noted to have hyperkalemia and one subject discontinued due to elevated potassium levels. Most females who developed hyperkalemia in the clinical development studies of NEXTSTELLIS had only mild potassium elevations and/or isolated increases that returned to normal while still on study medication.

Hypertension

• NEXTSTELLIS is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease .
• For all females, including those with well-controlled hypertension, monitor blood pressure periodically and stop NEXTSTELLIS if blood pressure rises significantly.

An increase in blood pressure has been reported in females using COCs. This increase is more likely in older females with extended duration of use.

Migraine

• NEXTSTELLIS is contraindicated in females who have migraines with aura. Discontinue NEXTSTELLIS in females using NEXTSTELLIS who develop new migraines that are recurrent, persistent, or severe. Discontinue NEXTSTELLIS if there is an increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event).
• Migraines with aura increase the risk for stroke. This stroke risk is further increased in females who have migraines with aura with use of CHCs.

Malignant Neoplasms

• Breast Cancer.
  • NEXTSTELLIS is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive.

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.

• Cervical Cancer.
  • A causal relationship between the use of CHCs and the development of cervical cancer and intraepithelial neoplasia has not been clearly established. In observational studies, the use of oral hormonal contraceptives in females for five years or more, compared to females who did not use oral hormonal contraceptives, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. In these studies, the use of oral hormonal contraceptives in females for 10 years or more, compared to females who received oral hormonal contraceptives for 5-9 years, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. Limitations in these epidemiologic studies include potential recall bias, differences in sexual behavior, and other factors such as establishing whether there were data on persistent high-risk Human Papilloma Virus (HPV) infection.

Liver Disease

• Elevated Liver Enzymes.
  • NEXTSTELLIS is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis .
  • Withhold or permanently discontinue NEXTSTELLIS for persistent or significant elevation of liver enzymes. NEXTSTELLIS can cause elevated liver enzymes.
• Liver Tumors>
  • NEXTSTELLIS is contraindicated in females with hepatic adenomas and malignant liver tumors.CHCs increase the risk of hepatic tumors, particularly hepatic adenomas. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

• CHCs, such as NEXTSTELLIS, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir).
• Discontinue NEXTSTELLIS prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). NEXTSTELLIS can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen.
• During clinical trials with the above-mentioned Hepatitis C combination drug regimen, 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 females using ethinyl estradiol (EE)-containing drugs, such as CHCs. Females using medications containing estrogens other than EE had a rate of *ALT elevation similar to those not receiving any estrogens. NEXTSTELLIS contains E4 rather than EE, but as no data are available for co-administration with this Hepatitis C combination drug regimen, caution is warranted.

Glucose Tolerance and Hypertriglyceridemia

• Glucose Tolerance.
  • Carefully monitor females with prediabetes and diabetes who are using NEXSTELLIS. NEXTSTELLIS may decrease glucose tolerance.

• Hypertriglyceridemia.
  • Consider alternative contraception for females with hypertriglyceridemia. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using NEXSTELLIS, which may increase the risk of pancreatitis.

Gallbladder Disease and Cholestasis

• Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder disease or cholestatic disease. Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
• A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.

Effect on Binding Globulins

• Increase the dosage of thyroid hormone replacement therapy as needed in females taking NEXTSTELLIS .
• The estrogen component of NEXTSTELLIS may increase the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.

Bleeding Irregularities and Amenorrhea

Unscheduled Bleeding and Spotting

• Females using NEXTSTELLIS may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 4 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
• Unscheduled bleeding was defined as bleeding or spotting that occurred on Day 4 through Day 24 of a 28-day cycle. Based on subject diaries from C302 (US/CA), the proportion of subjects reporting unscheduled bleeding or spotting per 28-day cycle decreased over time: 30.3% at Cycle 1 versus 17.4% at Cycle 12. The mean number of unscheduled bleeding/spotting days per cycle also gradually decreased over time, with a mean of 0.4 (± 1.42) bleeding days at Cycle 1, versus a mean of 0.2 (± 0.98) bleeding days at Cycle 12.

Absence of Scheduled Bleeding

• Females who use NEXTSTELLIS may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant . The proportion of subjects reporting absence of scheduled bleeding remained constant overall, with on average 15.5% of subjects reporting absence of scheduled bleeding from Cycles 1 through 12.
• If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than prescribed), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures.
• After discontinuation of NEXTSTELLIS, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

Depression

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

Hereditary Angioedema

• Avoid NEXTSTELLIS in females with hereditary angioedema. Exogenous estrogens may induce or exacerbate symptoms of hereditary angioedema.

Chloasma

• Avoid NEXTSTELLIS in females with a history of chloasma gravidarum or increased sensitivity to sun and/or ultraviolet radiation exposure. Chloasma may occur with NEXTSTELLIS use, especially in females with a history of chloasma gravidarum.

Thromboembolic Disorders and Other Vascular Problems

• Stop NEXTSTELLIS if an arterial or venous thrombotic/thromboembolic event occurs. • Stop NEXTSTELLIS if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. • Discontinue NEXTSTELLIS during prolonged immobilization. • Start NEXTSTELLIS no earlier than four weeks after delivery in females who are not breast feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

• Before starting NEXTSTELLIS, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. NEXTSTELLIS is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases.

Cardiovascular and Cerebrovascular Events

• Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among females over age 40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. The risk increases with age, particularly in females 35 years of age and older, and with the number of cigarettes smoked. In addition to cigarettes, use of other nicotine-containing products – including cigars, smokeless tobacco, hookah tobacco, e-cigarettes, and nicotine replacement therapy – may also increase the risk of serious cardiovascular events from CHC use.

Venous Thromboembolism

• Use of CHCs also increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years and should be considered in the context of other female of reproductive potential subpopulations who are not taking CHCs.
• Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs.
• The presence of multiple risk factors for VTE may increase the risk synergistically. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of four weeks or longer. The risk of VTE returns to baseline approximately 3 months after CHC use is discontinued.

Postpartum Venous Thromboembolism

• The risk of VTE is increased during the first six weeks postpartum compared to the risk in non-pregnant, non-postpartum females. The risk is highest in the first three weeks postpartum, but remains higher than baseline until at least six weeks postpartum. The presence of multiple risk factors for VTE may further increase the risk. Obstetric complications may extend the elevated risk up to 12 weeks postpartum.

• Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use COCs, for females who use COCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: if 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Figure 1 Likelihood of Developing a VTE

• Two prospective studies of NEXTSTELLIS have been conducted, one in Europe/Russia (NCT02817828; C301) and one in North America (NCT02817841; C302) (N=3,632), for the prevention of pregnancy in females 16-50 years of age. There was one reported VTE in the Europe/Russia study.

Hyperkalemia

• NEXTSTELLIS is contraindicated in females with conditions that predispose to hyperkalemia (e.g., renal impairment, hepatic impairment, and adrenal insufficiency). Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Monitor serum potassium concentration in females at increased risk for hyperkalemia (i.e., those females who take a strong CYP3A4 inhibitor long-term and concomitantly with NEXTSTELLIS).
• Monitor females taking NEXTSTELLIS who later develop medical conditions and/or begin medication that put them at an increased risk for hyperkalemia.
• NEXTSTELLIS contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk females, comparable to a 25 mg dose of spironolactone. In two Phase 3 trials of NEXTSTELLIS (N = 3,632) for the prevention of pregnancy in females 16-50 years of age, seven subjects were noted to have hyperkalemia and one subject discontinued due to elevated potassium levels. Most females who developed hyperkalemia in the clinical development studies of NEXTSTELLIS had only mild potassium elevations and/or isolated increases that returned to normal while still on study medication.

Hypertension

• NEXTSTELLIS is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease .
• For all females, including those with well-controlled hypertension, monitor blood pressure periodically and stop NEXTSTELLIS if blood pressure rises significantly.

An increase in blood pressure has been reported in females using COCs. This increase is more likely in older females with extended duration of use.

Migraine

• NEXTSTELLIS is contraindicated in females who have migraines with aura. Discontinue NEXTSTELLIS in females using NEXTSTELLIS who develop new migraines that are recurrent, persistent, or severe. Discontinue NEXTSTELLIS if there is an increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event).
• Migraines with aura increase the risk for stroke. This stroke risk is further increased in females who have migraines with aura with use of CHCs.

Malignant Neoplasms

• Breast Cancer.
  • NEXTSTELLIS is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive.

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.

• Cervical Cancer.
  • A causal relationship between the use of CHCs and the development of cervical cancer and intraepithelial neoplasia has not been clearly established. In observational studies, the use of oral hormonal contraceptives in females for five years or more, compared to females who did not use oral hormonal contraceptives, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. In these studies, the use of oral hormonal contraceptives in females for 10 years or more, compared to females who received oral hormonal contraceptives for 5-9 years, was associated with an increased risk of cervical cancer and intraepithelial neoplasia. Limitations in these epidemiologic studies include potential recall bias, differences in sexual behavior, and other factors such as establishing whether there were data on persistent high-risk Human Papilloma Virus (HPV) infection.

Liver Disease

• Elevated Liver Enzymes.
  • NEXTSTELLIS is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis .
  • Withhold or permanently discontinue NEXTSTELLIS for persistent or significant elevation of liver enzymes. NEXTSTELLIS can cause elevated liver enzymes.
• Liver Tumors>
  • NEXTSTELLIS is contraindicated in females with hepatic adenomas and malignant liver tumors.CHCs increase the risk of hepatic tumors, particularly hepatic adenomas. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

• CHCs, such as NEXTSTELLIS, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir).
• Discontinue NEXTSTELLIS prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). NEXTSTELLIS can be restarted approximately 2 weeks following completion of treatment with this hepatitis C combination drug regimen.
• During clinical trials with the above-mentioned Hepatitis C combination drug regimen, 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 females using ethinyl estradiol (EE)-containing drugs, such as CHCs. Females using medications containing estrogens other than EE had a rate of *ALT elevation similar to those not receiving any estrogens. NEXTSTELLIS contains E4 rather than EE, but as no data are available for co-administration with this Hepatitis C combination drug regimen, caution is warranted.

Glucose Tolerance and Hypertriglyceridemia

• Glucose Tolerance.
  • Carefully monitor females with prediabetes and diabetes who are using NEXSTELLIS. NEXTSTELLIS may decrease glucose tolerance.

• Hypertriglyceridemia.
  • Consider alternative contraception for females with hypertriglyceridemia. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using NEXSTELLIS, which may increase the risk of pancreatitis.

Gallbladder Disease and Cholestasis

• Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder disease or cholestatic disease. Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
• A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.

Effect on Binding Globulins

• Increase the dosage of thyroid hormone replacement therapy as needed in females taking NEXTSTELLIS .
• The estrogen component of NEXTSTELLIS may increase the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.

Bleeding Irregularities and Amenorrhea

Unscheduled Bleeding and Spotting

• Females using NEXTSTELLIS may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 4 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
• Unscheduled bleeding was defined as bleeding or spotting that occurred on Day 4 through Day 24 of a 28-day cycle. Based on subject diaries from C302 (US/CA), the proportion of subjects reporting unscheduled bleeding or spotting per 28-day cycle decreased over time: 30.3% at Cycle 1 versus 17.4% at Cycle 12. The mean number of unscheduled bleeding/spotting days per cycle also gradually decreased over time, with a mean of 0.4 (± 1.42) bleeding days at Cycle 1, versus a mean of 0.2 (± 0.98) bleeding days at Cycle 12.

Absence of Scheduled Bleeding

• Females who use NEXTSTELLIS may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant . The proportion of subjects reporting absence of scheduled bleeding remained constant overall, with on average 15.5% of subjects reporting absence of scheduled bleeding from Cycles 1 through 12.
• If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than prescribed), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures.
• After discontinuation of NEXTSTELLIS, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

Depression

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

Hereditary Angioedema

• Avoid NEXTSTELLIS in females with hereditary angioedema. Exogenous estrogens may induce or exacerbate symptoms of hereditary angioedema.

Chloasma

• Avoid NEXTSTELLIS in females with a history of chloasma gravidarum or increased sensitivity to sun and/or ultraviolet radiation exposure. Chloasma may occur with NEXTSTELLIS use, especially in females with a history of chloasma gravidarum.

Adverse Reactions

Clinical Trials Experience

The following clinically significant adverse reactions with the use of COCs are discussed elsewhere in labeling: • Serious cardiovascular events including venous and arterial thromboembolism.

• Hyperkalemia.

• Liver disease.

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• The data provided reflect the experience with the use of NEXTSTELLIS in two large prospective studies, one in Europe/Russia (C301) and one in North America (C302) (N = 3,632) of NEXTSTELLIS for the prevention of pregnancy in females 16-50 years of age. The mean duration of NEXTSTELLIS exposure was 317 and 257 days for the respective studies. The study population was 27 years of age on average, with a mean BMI of 25 kg/m2. The racial distribution was 83% White; 11% Black; 3% Asian; and 3% Other.

Adverse Reactions Occurring in ≥ 2% of Females Receiving NEXTSTELLIS in Studies C301 and C302

Adverse Reactions Leading to Study Discontinuation (> 1%)

• Of 3,632 females in two clinical studies for prevention of pregnancy in females 16-50 years of age, 9.6% discontinued due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was bleeding irregularity (2.8%). Six subjects (0.17%) discontinued study participation due to new onset of migraine with aura; two subjects (0.05%) discontinued due to severe migraine.

Thromboembolic Disorders and Other Vascular Problems

• During studies C301 and C302, one thromboembolic event was reported in a female who had been taking NEXTSTELLIS for 75 days and had normal BMI < 25 kg/m2.

Depression

• In Study C302 (US/CA), 36 (1.7%) subjects reported depression while using NEXTSTELLIS. Nine (0.3%) subjects had drug withdrawn as a result of symptoms of depression.

Postmarketing Experience

• Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2).
• Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 2 Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

File:Nextf2.png

Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females that never used COCs.

Drug Interactions

Effects of Other Drugs on Hormonal Contraceptives

• Clinically significant drug interactions with other drugs that affect NEXTSTELLIS are presented in Table 5.

Clinically Significant Drug Interactions With Other Drugs that Affect NEXTSTELLIS

Effects of NEXTSTELLIS on Other Drugs

Table 6 includes clinically significant drug interactions with NEXTSTELLIS that affect other drugs.

Clinically Significant Drug Interactions of NEXTSTELLIS on Other Drugs

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

• Discontinue NEXTSTELLIS if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy . Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. Reproductive toxicity studies performed with E4 alone have shown expected pharmacologic effects in animals, which are considered consistent with estrogen exposure.

• 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Drospirenone and estetrol in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Drospirenone and estetrol during labor and delivery.

Nursing Mothers

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. When possible, advise the nursing woman to use other methods of contraception until she discontinues breast-feeding.

• The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for NEXTSTELLIS and any potential adverse effects on the breast-fed child from NEXTSTELLIS or from the underlying maternal condition.

• After oral administration of DRSP 3 mg/EE 30 µg, about 0.02% of the DRSP dose was excreted into the breast milk of postpartum females within 24 hours. This results in a potential maximal daily dose of less than 1 µg DRSP in an infant.

Pediatric Use

Safety and efficacy of NEXTSTELLIS have been established in females of reproductive potential. The study population of C302 was in females of reproduction age 16-50 years of age. Use of NEXTSTELLIS before menarche is not indicated.

Geriatic Use

NEXTSTELLIS has not been studied in postmenopausal females and is not indicated in this population.

Gender

There is no FDA guidance on the use of Drospirenone and estetrol with respect to specific gender populations.

Race

No clinically significant difference was observed between the pharmacokinetics of E4 or DRSP depending on race

Renal Impairment

• NEXTSTELLIS is contraindicated in females with renal impairment.

• In subjects with creatinine clearance (CLcr) of 50–79 mL/min, serum DRSP levels were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30–49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs

Hepatic Impairment

NEXTSTELLIS is contraindicated in females with hepatic impairment. The mean exposure to drospirenone (DRSP) in females with moderate liver impairment is approximately three times higher than the exposure in females with normal liver function. NEXTSTELLIS has not been studied in females with severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Drospirenone and estetrol in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Drospirenone and estetrol in patients who are immunocompromised.

Body Mass Index (BMI)/Body Weight

The safety and efficacy of NEXTSTELLIS in females with a BMI ≥ 35 kg/m2 have not been adequately evaluated.

Administration and Monitoring

Administration

There is limited information regarding Drospirenone and estetrol Administration in the drug label.

Monitoring

There is limited information regarding Drospirenone and estetrol Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Drospirenone and estetrol and IV administrations.

Overdosage

There is limited information regarding Drospirenone and estetrol overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Drospirenone and estetrol Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Drospirenone and estetrol Mechanism of Action in the drug label.

Structure

There is limited information regarding Drospirenone and estetrol Structure in the drug label.

Pharmacodynamics

There is limited information regarding Drospirenone and estetrol Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Drospirenone and estetrol Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Drospirenone and estetrol Nonclinical Toxicology in the drug label.

Clinical Studies

Pregnancy Prevention

• The efficacy of NEXTSTELLIS was evaluated in a prospective, multicenter, open-label, single-arm study in North America (NCT02817841; C302) of one-year duration that enrolled 1,674 females 16 to 35 years of age. The mean age was 25.8 years and mean BMI was 25.8 kg/m2. Females with a BMI between 30 and 35 kg/m2 accounted for 22.3% of the study population. Females with a BMI greater than 35 kg/m2 were not enrolled in the study. The racial distribution was 70.1% Caucasian, 19.5% Black or African American, 4.8% Asian, 0.9% American Indian or Alaska native, 0.4% Native Hawaiian or other Pacific Islander and 4.2% other.

• A total of 26 on-treatment pregnancies occurred in 1,524 females contributing 12,763 at-risk cycles. The overall Pearl Index was 2.65 (95% CI: 1.73-3.88) per 100 woman-years of use. Table 9 lists the Pearl Index by BMI subgroup. A trend of decreasing effectiveness with increasing BMI was observed in the study.

Pearl Index Based on At-Risk Cycles and Reported Pregnancies in Females ≤ 35 Years of Age in Study C302

How Supplied

• NEXTSTELLIS® (drospirenone and estetrol tablets) is available in a blister card, with 28 6-mm round, bi-convex film-coated tablets in the following order:

• 24 pink active film-coated tablets containing 3 mg drospirenone and 14.2 mg estetrol embossed with a drop-shaped logo on one side.
• 4 white inert film-coated tablets embossed with a drop-shaped logo on one side.

NEXTSTELLIS® is supplied in cartons containing 1 blister card of 28 tablets: NDC 51862-258-01.

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• Advise the patient to read the FDA-Approved patient labeling (Patient Information and Instructions of Use).

Sexually Transmitted Infections

• Advise females that NEXTSTELLIS does not protect against HIV infection or other sexually transmitted infections.

Important Administration Instructions and Instructions for Missed Doses

Instruct females to take one tablet daily by mouth at the same time every day. Advise patients about what to do in the event that pills are missed. • Advise females starting NEXTSTELLIS to use additional nonhormonal contraception for 7 days after the first dose unless NEXTSTELLIS is started on the first day (Day 1) of menses.

• Advise females who miss more than two consecutive days of NEXTSTELLIS or experience vomiting or diarrhea for > 48 hours consecutively to use additional nonhormonal contraception for 7 days.

Thromboembolic Disorders and Other Vascular Problems

• Advise females that there is an increased risk of arterial and/or venous thrombotic/thromboembolic events with NEXTSTELLIS and the risk of arterial and/or venous thrombotic/thromboembolism is greater in smokers and females with preexisting medical conditions including hypertension, dyslipidemia, diabetes, and obesity.

• Advise patients of the pertinent factors that further increase their risk and ways to diminish the risk, e.g., to stop smoking (if applicable).

• Advise patients to contact their healthcare professional for any signs or symptoms of arterial and/or VTE.

• Advise patients to contact their healthcare professional if they will be immobilized for a prolonged period of time.

Hyperkalemia

• Advise females to contact their healthcare professional if signs or symptoms of hyperkalemia develop.

Hypertension

• Advise females that NEXTSTELLIS can cause an increase in blood pressure over time. Instruct patients to contact their healthcare professional if blood pressure increases.

Liver Disease

• Advise females that use of NEXTSTELLIS can cause elevated liver enzymes and can increase the risk of liver tumors. Instruct females to contact their healthcare professional for any signs or symptoms of liver disease.

Glucose Tolerance

• Advise females that NEXTSTELLIS may decrease glucose tolerance. Instruct females with diabetes and prediabetes to contact their healthcare professional for any signs or symptoms of hyperglycemia.

Gallbladder Disease and Cholestasis

• Advise females that use of NEXTSTELLIS is associated with an increased risk of developing and/or worsening gallbladder disease. Instruct patients to contact their healthcare professional for any signs or symptoms of gallbladder disease.

Bleeding Irregularities, Amenorrhea, and Pregnancy

• Advise females that NEXTSTELLIS can cause unscheduled bleeding and spotting, as well as amenorrhea and oligomenorrhea. Advise females to contact their health care professional if amenorrhea occurs in two or more consecutive cycles or symptoms of pregnancy occur, e.g., morning sickness or unusual breast tenderness. Instruct females to stop NEXTSTELLIS if pregnancy is confirmed during use.

Chloasma

• Advise females that NEXTSTELLIS can cause chloasma and the risk is highest in females with a history of chloasma, especially chloasma gravidarum. Instruct females to take precautions to limit UVA and UVB exposure while using NEXTSTELLIS.

Lactation

Advise postpartum females that NEXTSTELLIS may reduce breast milk production. Advise females that this reduction is less likely to occur if breast-feeding is well established.

Drug Interactions

• NEXTSTELLIS may interact with many drugs, foods, and dietary supplements. Therefore, advise females to report to their healthcare professional the use of any other prescription or nonprescription drugs or dietary supplements.

Precautions with Alcohol

Alcohol-Drospirenone and estetrol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

NEXTSTELLIS

Look-Alike Drug Names

There is limited information regarding Drospirenone and estetrol Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.