Drospirenone and estetrol
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
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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) )
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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).
Missed Doses
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
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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) )
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There is limited information regarding Drospirenone and estetrol Warnings' in the drug label.
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 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
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.
Effects of NEXTSTELLIS on Other Drugs
Table 6 includes clinically significant drug interactions with NEXTSTELLIS that affect other drugs.
Use in Specific Populations
Pregnancy
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.
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.