Limitations of Use

NEXTSTELLIS may be less effective in females with a BMI ≥ 30 kg/m2. In females with BMI ≥ 30 kg/m2, decreasing effectiveness may be associated with increasing BMI [see Clinical Studies (14)].

2.1 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.

2.2 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).

2.3 Missed Doses

2.4 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 [see Dosage and Administration (2.3)].

5.1 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 [see Contraindications (4)].

5.2 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). [see Drug interactions (7)]. 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.

5.3 Hypertension

NEXTSTELLIS is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. 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.

5.4 Migraine

NEXTSTELLIS is contraindicated in females who have migraines with aura [see Contraindications (4)]. 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.

5.5 Malignant Neoplasms

5.6 Liver Disease

5.7 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) [see Contraindications (4)]. 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.

5.8 Glucose Tolerance and Hypertriglyceridemia

5.9 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.

5.10 Effect on Binding Globulins

Increase the dosage of thyroid hormone replacement therapy as needed in females taking NEXTSTELLIS [see Clinical Pharmacology (12.2)]. The estrogen component of NEXTSTELLIS may increase the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.

5.11 Bleeding Irregularities and Amenorrhea

5.12 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.

5.13 Hereditary Angioedema

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

5.14 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.

6.1 Clinical Trials Experience

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.

6.2 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

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.

7.1 Effects of Other Drugs on Hormonal Contraceptives

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

7.2 Effects of NEXTSTELLIS on Other Drugs

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and efficacy of NEXTSTELLIS have been established in females of reproductive potential. The study population of C302 [see Clinical Studies (14)] was in females of reproduction age 16-50 years of age. Use of NEXTSTELLIS before menarche is not indicated.

8.5 Geriatric Use

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

8.6 Hepatic Impairment

NEXTSTELLIS is contraindicated in females with hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1, 5.3)]. 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 [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

NEXTSTELLIS is contraindicated in females with renal impairment [see Contraindications (4), Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

8.8 Race/Ethnicity

No clinically significant difference was observed between the pharmacokinetics of E4 or DRSP depending on race [see Clinical Pharmacology (12.3)].

8.9 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.

Overdosage Management Recommendations

Consider short-term prophylactic anticoagulation therapy for patients with high risk of VTE. Monitor serum potassium and sodium levels, and for evidence of metabolic acidosis.

12.1 Mechanism of Action

CHCs prevent pregnancy primarily by suppressing ovulation.

12.2 Pharmacodynamics

Drospirenone is a spironolactone analogue with anti-mineralocorticoid and antiandrogenic activity. The estrogen in NEXTSTELLIS is estetrol, a synthetic analogue of a native estrogen present during pregnancy, that is selective for nuclear estrogen receptor-α (ER-α) and ER-β.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month oral carcinogenicity study in mice with doses up to 10 mg/kg/day DRSP, equating to 2 times the maximum clinical exposure (based on AUC), there was an increase in carcinomas of the harderian gland in the high dose DRSP group. In a similar study in rats given doses up to 10 mg/kg/day DRSP, 10 times the maximum clinical exposure (based on AUC), there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the high dose DRSP group.

Mutagenesis studies for DRSP were conducted in vivo and in vitro and no evidence of mutagenic activity was observed. E4 is not considered to be genotoxic based on weight of evidence from in vivo and in vitro mutagenesis 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.

16.1 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.

16.2 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].

16.3 Disposal

Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do NOT flush down the toilet.

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 [see Dosage and Administration (2.3)].

• 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 [see Dosage and Administration (2.1)]
• 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 [see Dosage and Administration (2.3, 2.4)]

Thromboembolic Disorders and Other Vascular Problems [see Warnings and Precautions (5.1)].

• 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 [see Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.5)].

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 [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2)].

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 [see Warnings and Precautions (5.8)].

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 [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

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 [see Warnings and Precautions (5.14)].

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 [see Use in Specific Populations (8.2)].

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 [see Drug Interactions (7.1, 7.2)].