Nextstellis
drospirenone and estetrol · Kit
Uses
1 INDICATIONS AND USAGE NEXTSTELLIS is indicated for use by females of reproductive potential to prevent pregnancy. NEXTSTELLIS is a combination of drospirenone, a progestin, and estetrol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use NEXTSTELLIS may be less effective in females with a BMI ≥ 30 kg/m 2 . In females with BMI ≥ 30 kg/m 2 , decreasing effectiveness may be associated with increasing BMI ( 14 ). Limitations of Use NEXTSTELLIS may be less effective in females with a BMI ≥ 30 kg/m 2 . In females with BMI ≥ 30 kg/m 2 , decreasing effectiveness may be associated with increasing BMI [see Clinical Studies (14) ].
Dosage and administration
Take one tablet by mouth at the same time every day. ( 2.1 ) Take tablets in the order directed on the blister pack. ( 2.1 ) 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 ). Table 1 NEXTSTELLIS Administration Instructions Starting NEXTSTELLIS in females with no current use of hormonal contraception Important: In females with irregular menstrual cycles, pregnancy testing may be necessary prior to initiation of this product. Day 1 Start : Take the first pink active tablet on the first day of menses. Take subsequent pink active tablets once daily at the same time each day for a total of 24 days. Take one white inert tablet daily for 4 days and at the same time of day that active tablets were taken. Begin each subsequent 28-day pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) If not starting on the first day of menses, use a non-hormonal contraceptive (e.g. condoms and/or spermicide) as back-up until one active tablet has been taken daily for 7 days in a row. Switching to NEXTSTELLIS from another contraceptive method Start NEXTSTELLIS on the day: Combined Oral Contraceptive (COC) When the new pack of the previous COC would have started. Transdermal System When the next application would have been scheduled. Vaginal Insert When the next insertion would have been scheduled. Injection When the next injection would have been scheduled. Intrauterine System (IUS) After removal. Implant After removal. Progestin-only pill After the last tablet was taken. Starting NEXTSTELLIS after delivery (>20 weeks gestation) Must not start earlier than 4 weeks after delivery (due to the increased risk of thromboembolism [see Contraindications (4) and Warnings and Precautions (5.1) ] If menstrual cycles have returned, follow instructions for "Starting NEXTSTELLIS in females with no current use of hormonal contraception". If menstrual cycles have not resumed, consider the possibility of ovulation and pregnancy. If not pregnant, use additional nonhormonal contraception for the first 7 days of NEXTSTELLIS use. Starting NEXTSTELLIS after Abortion or Miscarriage ≤14 weeks gestation Within the first 7 days of complete first trimester abortion or miscarriage, use additional nonhormonal contraception for the next 7 days. After the first 7 days, follow instructions for "Starting NEXTSTELLIS in females with no current use of hormonal contraception". > 14 weeks but ≤ 20 weeks gestation After 4 weeks following second trimester abortion or miscarriage. Consider duration of pregnancy and increased risk of thromboembolism [see Warnings and Precautions (5.1) ] If menstrual cycles have returned, follow instructions for "Starting NEXTSTELLIS in females with no current use of hormonal contraception." If menstrual cycles have not resumed, consider the possibility of ovulation and pregnancy. If not pregnant, use additional nonhormonal contraception for the first 7 days of NEXTSTELLIS use. 2.3 Missed Doses Table 2 Instructions for Missed NEXTSTELLLIS Tablets in a Monthly Dosing Regimen If one pink active tablet is missed Take the missed tablet as soon as possible and take the next tablet at the scheduled time, even if two active tablets are taken in one day. Continue taking one tablet a day until the pack is finished. If two or more pink active tablets are missed in Week 1 or Week 2 Take one missed tablet as soon as possible and take the tablet for the current day (that means taking two tablets in one day) and discard the other missed tablets. Continue taking one tablet a day until the pack is finished. Use additional non-hormonal contraception as back-up until pink tablets have been taken for 7 consecutive days. If two pink active tablets are missed in Week 3 Take one missed tablet as soon as possible and take the tablet for the current day (that means taking two tablets in one day) and discard the other missed tablets. Finish the active tablets and discard the inactive tablets in the pack. Start a new pack of tablets the next day. Use additional non-hormonal contraception as back-up until pink tablets have been taken for 7 consecutive days. If one or more white inert tablets are missed Skip the missed pill days and continue taking one tablet a day until the pack is finished. 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) ].
Dosage forms and strengths
(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. NEXTSTELLIS consists of 28 tablets in the following order ( 3 ): 24 pink active tablets each containing drospirenone 3 mg and estetrol 14.2 mg 4 white inert tablets
Contraindications
4 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 [see Boxed Warning and Warnings and Precautions (5.1) ] - Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions (5.1) ] - Have cerebrovascular disease [see Warnings and Precautions (5.1) ] - Have coronary artery disease [see Warnings and Precautions (5.1) ] - Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1) ] - Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1) ] - Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.1) ] - Have diabetes mellitus with hypertension or end-organ damage; or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.9) ] - Have migraine headaches with aura [see Warnings and Precautions (5.4) ] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.5) ] Hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.6) ] Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.7) ] Abnormal uterine bleeding that has an undiagnosed etiology [see Warnings and Precautions (5.5) ] Renal Impairment [see Warnings and Precautions (5.2) ] Adrenal insufficiency [see Warnings and Precautions (5.2) ] A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer or history of breast cancer ( 4 ) Hepatic adenoma, hepatocellular carcinoma, acute hepatitis or decompensated cirrhosis ( 4 ) Co-administration with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 , 7.1 ) Abnormal uterine bleeding that has an undiagnosed etiology ( 4 ) Renal impairment ( 4 ) Adrenal insufficiency ( 4 )
Warnings and precautions
Thromboembolic Disorders and Other Vascular Problems : Stop NEXTSTELLIS if a thrombotic or thromboembolic event occurs. Start no earlier than 4 weeks after delivery. Consider all cardiovascular risk factors before initiating in any female, particularly in the presence of multiple risk factors. ( 5.1 ) Hyperkalemia : Check serum potassium concentration during the first NEXTSTELLIS treatment cycle in females on long-term treatment with medications that may increase serum potassium concentration. ( 5.2 , 7.2 ) Hypertension : Monitor blood pressure periodically and stop use if blood pressure rises significantly. ( 5.3 ) Migraine : Discontinue if new, recurrent, persistent, or severe migraines occur. ( 5.4 ) Hormonally-Sensitive Malignancy: Discontinue NEXTSTELLIS if a hormonally-sensitive malignancy is diagnosed. ( 5.5 ) Liver Disease : Withhold or permanently discontinue for persistent or significant elevation of liver enzymes. ( 5.6 ) Glucose Tolerance and Hypertriglyceridemia : Monitor glucose in females with prediabetes or diabetes. Consider an alternate contraceptive method for females with hypertriglyceridemia. ( 5.8 ) Gallbladder Disease and Cholestasis : Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder or cholestatic disease. ( 5.9 ) Bleeding Irregularities and Amenorrhea : May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.11 ) 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) ] . 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 [see Adverse Reactions (6.1) ]. Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs [see Contraindications (4) ] . 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 [see Adverse Reactions (6.1) ]. Figure 1 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.
Side effects
The following clinically significant adverse reactions with the use of COCs are discussed elsewhere in labeling: Serious cardiovascular events including venous and arterial thromboembolism [see Boxed Warning and Warnings and Precautions (5.1) ] Hyperkalemia [see Warnings and Precautions (5.2) ] Liver disease [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥2%): bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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/m 2 . The racial distribution was 83% White; 11% Black; 3% Asian; and 3% Other. Table 4 Adverse Reactions Occurring in ≥ 2% of Females Receiving NEXTSTELLIS in Studies C301 and C302 Preferred Term (PT) Participants with Adverse Reaction – US/Canada Phase 3 trial (n [%]) (N = 2073) Represents the safety population of C302 only (US/Canada). Participants with Adverse Reaction – Two Phase 3 trials (n [%]) (N=3632) Represents the safety population of C301/C302 for DRSP/E4. Any adverse reaction Any adverse reaction equals any adverse event ≥ 2%. 1205 (58.1) 2126 (58.5) Mood disturbance Includes PTs: adjustment disorder, affective disorder, agitation, anger, anxiety, depressed mood, depression, depressive symptom, disorientation, emotional disorder, emotional distress, euphoric mood, generalized anxiety disorder, insomnia, irritability, mood altered, mood swings, nervousness, panic attack, panic disorder, performance fear, restlessness, sleep disorder, stress, suicidal ideation, tearfulness. 226 (10.9) 329 (9.1) Bleeding irregularities Includes PTs: abnormal withdrawal bleeding, amenorrhea, cervix hemorrhage uterine, coital bleeding, dysfunctional uterine bleeding, menometrorrhagia, menorrhagia, menstrual disorder, menstruation irregular, metrorrhagia, oligomenorrhea, polymenorrhea, uterine hemorrhage, vaginal hemorrhage. 201 (9.7) 393 (10.8) Breast symptoms Includes PTs: anisomastia, breast cyst, breast discoloration, breast discomfort, breast disorder, breast engorgement, breast enlargement, breast mass, breast edema, breast pain, breast swelling, breast tenderness, fibrocystic breast disease, galactorrhea, gynecomastia, mastoptosis, nipple disorder, nipple pain. 110 (5.3) 197 (5.4) Headache Includes PTs: headache, premenstrual headache, and tension headache. 100 (4.8) 227 (6.3) Dysmenorrhea Includes PTs: adnexa uteri pain, dysmenorrhea, premenstrual cramps, pelvic discomfort, pelvic pain, uterine spasm. 84 (4.1) 133 (3.7) Weight increased Includes PTs: weight increased, weight fluctuation, body mass index increased, weight loss poor, and obesity. 68 (3.3) 108 (3.0) Acne Includes PTs: acne and cystic acne. 66 (3.2) 136 (3.7) Libido decreased/lost Includes PTs: libido decreased and loss of libido. 27 (1.3) 72 (2.0) 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/m 2 . 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. 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. Figure 2
Drug interactions
7 DRUG INTERACTIONS CYP3A Inducers: May lead to contraceptive failure and/or increase breakthrough bleeding. Avoid concomitant use. If concomitant use is unavoidable, use an alternative or back-up contraceptive method during co-administration and up to 28 days after discontinuation of the CYP3A inducer. ( 7.1 ) See Full Prescribing Information for additional clinically significant drug interactions ( 7 ). 7.1 Effects of Other Drugs on Hormonal Contraceptives Clinically significant drug interactions with other drugs that affect NEXTSTELLIS are presented in Table 5. Table 5. Clinically Significant Drug Interactions With Other Drugs that Affect NEXTSTELLIS CYP3A Inducers Clinical Effect DRSP is a CYP3A4 substrate. Concomitant use with strong CYP3A inducers or certain moderate or weak CYP3A inducers may decrease DRSP exposure [see Clinical Pharmacology (12.3) ] , which may lead to contraceptive failure. Prevention or Management Strong CYP3A Inducers Avoid concomitant use. If concomitant use is unavoidable, use an alternative contraceptive method (e.g., intrauterine system) or backup non-hormonal contraceptive method during coadministration and up to 28 days after discontinuation of the strong CYP3A inducer. Moderate and Weak CYP3A Inducers Use an alternative or backup contraceptive method during coadministration and up to 28 days after discontinuation of the CYP3A inducer, unless the Prescribing Information of the specific moderate or weak CYP3A inducer indicates there is no clinically significant interaction with NEXTSTELLIS. Strong CYP3A Inhibitors Clinical Effect DRSP is a CYP3A4 substrate. Concomitant use with a strong CYP3A inhibitor may increase DRSP exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions of NEXTSTELLIS, including hyperkalemia [see Warnings and Precautions (5.2) ] . Prevention or Management Consider monitoring serum potassium concentration in patients who take a strong CYP3A4 inhibitor long-term and concomitantly with NEXTSTELLIS. Drugs that May Reduce the Absorption of NEXTSTELLIS Clinical Effect Concomitant use with drugs such as bile acid sequestrants may decrease the E4 and DRSP exposure, which may lead to contraceptive failure and/or an increase in breakthrough bleeding. Prevention or Management Separate time of administration of NEXTSTELLIS and the concomitant drug. Refer to the concomitant drug's Prescribing Information for additional information. 7.2 Effects of NEXTSTELLIS on Other Drugs Table 6 includes clinically significant drug interactions with NEXTSTELLIS that affect other drugs. Table 6. Clinically Significant Drug Interactions of NEXTSTELLIS on Other Drugs Anti-Diabetic Drugs Clinical Effect Concomitant use of NEXTSTELLIS may reduce the blood glucose lowering effect of anti-diabetic drugs [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.2) . Prevention or Management Increase frequency of glucose monitoring and increase anti-diabetic drug dosage, as needed, based on glucose levels. Drugs that may increase serum potassium concentration Clinical Effect There is a potential for an increase in serum potassium concentration in females taking NEXTSTELLIS with other drugs that may increase serum potassium concentration [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ]. Prevention or Management Monitor serum potassium concentration in females at increased risk for hyperkalemia. Lamotrigine Clinical Effect Concomitant use of NEXTSTELLIS may decrease lamotrigine exposure [see Clinical Pharmacology (12.3) ] , which may reduce efficacy of lamotrigine. Prevention or Management Adjust lamotrigine dosage as recommended in its Prescribing Information based on NEXTSTELLIS initiation or discontinuation. Systemic Corticosteroids Clinical Effect Concomitant use of NEXTSTELLIS may increase the exposure of certain systemic corticosteroids, which may increase the risk of corticosteroid-related adverse reactions [ see Clinical Pharmacology (12.2) . Prevention or Management Follow the recommendation for the corticosteroid in accordance with its Prescribing Information. Consider more frequent monitoring for corticosteroid adverse reactions when used concomitantly with NEXTSTELLIS. Thyroid Hormone Replacement Therapy Clinical Effect Concomitant use of NEXTSTELLIS may increase thyroid-binding globulin concentration [see Warnings and Precautions (5.10) and Clinical Pharmacology (12.2) ]. Prevention or Management Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement in accordance with its Prescribing Information.
Use in specific populations
Pregnancy : Discontinue if pregnancy occurs. (8.1) Lactation : Advise postpartum females that NEXTSTELLIS can decrease milk production. ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue NEXTSTELLIS if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy [see Contraindications (4) ] . 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. 8.2 Lactation 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 [see also Dosage and Administration (2.1) ] . 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. 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/m 2 have not been adequately evaluated.
Pregnancy
8.1 Pregnancy Risk Summary Discontinue NEXTSTELLIS if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy [see Contraindications (4) ] . 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.
Pediatric use
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.
Geriatric use
8.5 Geriatric Use NEXTSTELLIS has not been studied in postmenopausal females and is not indicated in this population.
Overdosage
Overdosage of CHCs may cause nausea, vomiting, and severe headaches. Individual reports of thromboembolic complications and vaginal bleeding have occurred from overdosage. Pediatric patients with unintended CHC ingestion have reported nausea and vomiting and some developed irritability and drowsiness; rare reports described vaginal bleeding. 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.
Description
11 DESCRIPTION NEXTSTELLIS ® (drospirenone and estetrol tablets) is an oral contraceptive. It is supplied in a transparent PVC/aluminum blister card containing 28 tablets: 24 pink active tablets contain 3 mg drospirenone and 14.2 mg of estetrol on the anhydrous basis. Drospirenone is a synthetic progestin and estetrol is a synthetic estrogen. 4 white inert tablets. The chemical name for estetrol is estra-1,3,5(10)-triene-3,15α,16α,17α-tetrol monohydrate. It has a molecular formula of C 18 H 24 O 4 ∙H 2 O and a molecular weight of 322.4 g/mol, equivalent to 304.4 g/mol (anhydrous). Estetrol has the following chemical structure: Estetrol (monohydrate) is a white to off-white crystalline solid that is poorly soluble in water and aqueous solutions. It is soluble in methanol, ethanol, sparingly soluble in acetone, and slightly soluble in ethyl acetate and acetonitrile. Drospirenone is chemically described as (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3',4',6,6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro10,13-dimethylspiro-[17H-dicyclopropa-[6,7:15,16]cyclopenta[a]phenanthrene-17,2'(5H)-furan]-3,5'(2H)-dione). It has a molecular weight of 366.5 g/mol, a molecular formula of C 24 H 30 O 3 , and the structural formula below: Drospirenone is a white to almost white or slightly yellow crystalline powder. It is a neutral molecule with slight solubility in water. The active tablet is a 6 mm, round pink film-coated tablet which contains 3 mg of drospirenone and 15 mg of estetrol as the monohydrate, equivalent to 14.2 mg of estetrol on the anhydrous basis, and the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and sodium starch glycolate. Each tablet is embossed on one side with a drop-shaped logo. The pink film-coating has the following inactive ingredients: hydrogenated cottonseed oil, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide. The inert tablet is a 6 mm, round white film-coated tablet which contains the inactive ingredients corn starch, lactose monohydrate, and magnesium stearate. Each tablet is embossed on one side with a drop-shaped logo. The film-coating has the following inactive ingredients: hydrogenated cottonseed oil, hydroxypropyl cellulose, hypromellose, talc, and titanium dioxide. Chemical Structure Chemical Structure
Mechanism of action
12.1 Mechanism of Action CHCs prevent pregnancy primarily by suppressing ovulation.
How supplied
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.
Storage
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].
Patient 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 [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) ] .
Label text from the FDA structured product label by Mayne Pharma (revised May 11, 2023). Long sections are shortened; the complete label is on DailyMed.
Nextstellis NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 51862-258 | Kit | Mayne Pharma | NDA |
Frequently asked questions
What is Nextstellis used for?
1 INDICATIONS AND USAGE NEXTSTELLIS is indicated for use by females of reproductive potential to prevent pregnancy. NEXTSTELLIS is a combination of drospirenone, a progestin, and estetrol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use NEXTSTELLIS may be less effective in females with a BMI ≥ 30 kg/m 2 . In females with BMI ≥ 30…
What are the side effects of Nextstellis?
The following clinically significant adverse reactions with the use of COCs are discussed elsewhere in labeling: Serious cardiovascular events including venous and arterial thromboembolism [see Boxed Warning and Warnings and Precautions (5.1) ] Hyperkalemia [see Warnings and Precautions (5.2) ] Liver disease [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥2%): bleeding… See the full label for the complete list.
Who makes Nextstellis?
Nextstellis is listed by 1 labeler in the FDA NDC directory, including Mayne Pharma.