BRIEF SUMMARY

DROSPERENONE AND ESTEROL TABLETS- (Apr 2021)

Indn-    To prevent pregnancy

Comp-   consists of 28 tablets in the following order                                                           • 24 pink active tablets each containing drospirenone 3 mg and estetrol 14.2                       mg                                                                                                                                       • 4 white inert tablets 

ADR- Most common adverse reactions bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased 

CI- • A high risk of arterial or venous thrombotic diseases                                                       • Current or history of a hormonally-sensitive malignancy (e.g., breast cancer)                   • Hepatic adenoma, hepatocellular carcinoma, acute hepatitis or decompensated                 cirrhosis                                                                                                                           WARNINGS--

Thromboembolic Disorders and Other Vascular Problems: Stop  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.

Pat Inform-

Sexually Transmitted Infections-                                                                                    Advise females that  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

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 16

Name of the Drug-    NEXTELLIS

Active Ingredient -   Drospirenone and Esterol Tablets

Pharmacological Classification-   To prevent pregnancy                                                                                                                                                                                                                                                     

Date of Approval-          4/15/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

WARNINGS AND PRECAUTIONS

­ These highlights do not include all the information needed to use NEXTSTELLIS safely and effectively. See full prescribing information for NEXTSTELLIS.

NEXTSTELLIS (drospirenone and estetrol tablets), for oral use

Initial U.S. Approval: 2021

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

See full prescribing information for complete boxed warning.

• Females over 35 years old who smoke should not use NEXTSTELLIS

 • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.

INDICATIONS AND USAGE

­ NEXTSTELLIS is a combination of drospirenone, a progestin, and estetrol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. 

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 (14).

ADVERSE REACTIONS

­ Most common adverse reactions (=2%): bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased 

CONTRAINDICATIONS

­ • A high risk of arterial or venous thrombotic diseases                                                       • Current or history of a hormonally-sensitive malignancy (e.g., breast cancer)                 • Hepatic adenoma, hepatocellular carcinoma, acute hepatitis or decompensated                 cirrhosis                                                                                                                               • Co-administration with hepatitis C drug combinations containing                                      ombitasvir/paritaprevir/ritonavir, with or without dasabuvir                                                • Abnormal uterine bleeding that has an undiagnosed etiology                                              • Renal impairment                                                                                                              • Adrenal insufficiency 

 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.

 • 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.

 • Hypertension: Monitor blood pressure periodically and stop use if blood pressure rises significantly.

 • Migraine: Discontinue if new, recurrent, persistent, or severe migraines occur.

 • Hormonally-Sensitive Malignancy: Discontinue NEXTSTELLIS if a hormonally-sensitive malignancy is diagnosed.

 • Liver Disease: Withhold or permanently discontinue for persistent or significant elevation of liver enzymes

 • Glucose Tolerance and Hypertriglyceridemia: Monitor glucose in females with prediabetes or diabetes. Consider an alternate contraceptive method for females with hypertriglyceridemia.

 • Gallbladder Disease and Cholestasis: Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder or cholestatic disease.

 • Bleeding Irregularities and Amenorrhea: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist.

DOSAGE AND ADMINISTRATION

­ • Take one tablet by mouth at the same time every day.                                                    • Take tablets in the order directed on the blister pack.

DOSAGE FORMS AND STRENGTHS

­ NEXTSTELLIS consists of 28 tablets in the following order                                                     • 24 pink active tablets each containing drospirenone 3 mg and estetrol 14.2 mg                  • 4 white inert tablets 

 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 [see Warnings and Precautions 

• 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

Manufactured for: Mayne Pharma LLC 1240 Sugg Parkway Greenville, NC 27834 Manufactured in Germany Date: 04/2021

 CLINICAL PHARMACOLOGY

1. Mechanism of Action CHCs prevent pregnancy primarily by suppressing ovulation.

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-a (ER-a) and ER-ß. Effect of NEXTSTELLIS on ovarian function

Cardiac Electrophysiology- At a dose 5 times the maximum recommended dose (i.e., supra-therapeutic dose of 15 mg DRSP /71 mg E4), NEXTSTELLIS does not prolong the QT interval to any clinically relevant extent.

Drugs- That Have the Potential to Increase Serum Potassium Concentration There is a potential for an increase in serum potassium concentration in females taking NEXTSTELLIS with other drugs that may increase serum potassium concentration

Specific Populations No clinically significant differences in the pharmacokinetics of E4 or DRSP in females were observed based on race/ethnicity (Japanese and Caucasian).

Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of E4 is unknown.

The mean exposure to DRSP is approximately three times higher in females with moderate liver impairment than the exposure in females with normal liver function. The effect of severe hepatic impairment on the pharmacokinetics of DRSP is unknown.

Patients with Renal Impairment -                                                                                   The effect of renal impairment on the pharmacokinetics of E4 is unknown. The mean serum DRSP concentrations increased by 37% in subjects with CLcr of 30 to 49 mL/min on a low potassium diet using potassium-sparing drugs.

No clinically significant differences in the pharmacokinetics of DRSP were observed based on CLcr of 50 to 79 mL/min. DRSP treatment did not show any clinically significant effect on serum potassium concentration.

Drug Interaction Studies

Clinical Studies Strong CYP3A4 Inhibitor: Concomitant use of a COC containing DRSP 3 mg/EE 20 µg with ketoconazole (strong CYP3A4 inhibitor) increased the AUC0-24h and Cmax of DRSP by 2.68-fold (90% CI: 2.44, 2.95) and 1.97-fold (90% CI: 1.79, 2.17), respectively.

CYP3A4 Inducer: Concomitant use of a COC containing DRSP 3 mg/EE 20 µg with high dose (strong CYP3A induction) and low dose of rifampin (weakCYP3A4 induction) decreased the AUC0-24h of DRSP by 86% (90% CI: 85%, 87%) and 30% (90% CI: 25%, 34%), respectively.

UGT2B7 Inhibitor: No clinically significant differences in the pharmacokinetics of NEXTSTELLIS were observed when used concomitantly with valproic acid (UGT2B7 inhibitor).

CYP3A Substrate: Pharmacokinetics of CYP3A substrates midazolam and simvastatin were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day.

CYP2C19 Substrate: Daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of the CYP2C19 substrate omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                           Discontinue NEXTSTELLIS if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy 

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.

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 

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.

3. 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.

4. Geriatric Use -                                                                                                        NEXTSTELLIS has not been studied in postmenopausal females and is not indicated in this population

5. Hepatic Impairment-                                                                                       NEXTSTELLIS is contraindicated in females with hepatic impairment [see Contraindications 

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 

6. Renal Impairment-                                                                                                NEXTSTELLIS is contraindicated in females with renal impairment [see Contraindications

 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.