segesterone/ethinyl estradiol (Rx)

>10%

>10% Headache, including migraine (38.6%)

Nausea/vomiting (25.0%)

Vulvovaginal mycotic infection/vaginal candidiasis (14.5%)

Abdominal pain/lower/upper (13.3%)

Dysmenorrhea (12.5%)

Vaginal Discharge (11.8%)

1-10%

Metrorrhagia/menorrhagia (1.7%)

Headache, including migraine (1.3%)

Vaginal discharge/vulvovaginal mycotic infections (1.3%)

Nausea/vomiting (1.2%)

Contraindications

A high risk of arterial or venous thrombotic diseases, including females who are known to smoke, if >35 years, current or history of deep vein thrombosis or pulmonary embolism, cerebrovascular disease, coronary artery disease, thrombogenic valvular or thrombogenic rhythm diseases of the heart, inherited or acquired hypercoagulopathies, uncontrolled hypertension or hypertension with vascular disease, diabetes mellitus and are >35 years, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years' duration, have headaches with focal neurological symptoms, or are >35 years with any migraine headaches

Current or history of breast cancer or other estrogen- or progestin-sensitive cancer

Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis

Undiagnosed abnormal uterine bleeding Hypersensitivity to drug or excipients

Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir

Cautions

Acute liver test abnormalities may necessitate discontinuation of use until liver tests return to normal and causation from the vaginal system has been excluded

Discontinue the vaginal system prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; the vaginal system can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen

For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop the vaginal system if blood pressure rises significantly; increase in blood pressure is more likely in older females and with extended duration of use; effect of CHCs on blood pressure may vary according to progestin in the CHC

Consider the presence of underlying risk factors that may increase risk of cardiovascular disease or venous thromboembolism (VTE), particularly before initiating the vaginal system for women >35 years, including hypertension, diabetes, dyslipidemia, or obesity

Studies suggest a small increased relative 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

Carefully monitor prediabetic and diabetic females who are using the vaginal system

Consider alternative contraception for females with uncontrolled dyslipidemia; the vaginal system may cause adverse lipid changes; females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using the vaginal system

If a female using the vaginal system develops new headaches that are recurrent, persistent, or severe, evaluate cause and discontinue use if indicated; consider discontinuation in the case of increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event)

Carefully observe females with a history of depression and discontinue use if depression recurs to a serious degree; data on depression are limited

Some studies suggest that CHCs are associated with increase in risk of cervical cancer or intraepithelial neoplasia; however, the extent to which these findings are due to differences in sexual behavior and other factors is controversial

Estrogen component of the vaginal system may raise serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin; dose of replacement thyroid hormone or cortisol therapy may need to be increased

In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema

Chloasma may occur with use, especially in females with a history of chloasma gravidarum; advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while using the vaginal system

Cases of toxic shock syndrome (TSS) reported by vaginal ring users; TSS has been associated with tampons and certain barrier contraceptives, and in some TSS cases ring users were also using tampons; the causal relationship between use of vaginal ring and TSS not established; no cases of TSS occurred in clinical trials with the vaginal system; if a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis, remove the vaginal system, and initiate appropriate medical evaluation and treatment

Breast cancer

• Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk; studies do not show an association between ever (current or past) use of COCs and risk of breast cancer
• Some studies report a small increase in risk of breast cancer among current or recent users(<6 months since last use) and current users with longer duration of COC use
• A woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early-onset menstruation before age 12, late-onset menopause, after age 55, first child after age 30, nulliparity

Bleeding irregularities and amenorrhea

• Bleeding and/or spotting occurring at any time while the vaginal system is inserted is considered “unscheduled” bleeding/spotting; bleeding/spotting occurring during dose-free week when the vaginal system is out is considered “scheduled” bleeding
• Females using the vaginal system may experience unscheduled (breakthrough) bleeding and spotting, especially during first month of use; if unscheduled bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy; if pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different CHC
• Females who are not pregnant and use the vaginal system may experience amenorrhea; if scheduled bleeding does not occur, consider the possibility of pregnancy; if the patient has not adhered to the prescribed dosing schedule (removed vaginal system for >2 hours during first 21 days, or does not replace after 7 days of vaginal system-free period), consider the possibility of pregnancy at the time of the first missed period and perform a pregnancy test; if the patient has adhered to the prescribed dosing schedule and misses 2 consecutive periods, perform a pregnancy test to rule out pregnancy
• Some females may experience amenorrhea or oligomenorrhea after stopping the vaginal system, especially when such a condition was preexistent

Thromboembolic disorders and other vascular conditions

• Stop the vaginal system if an arterial or deep venous thrombotic event occurs ir if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions (evaluate for retinal vein thrombosis immediately)
• Discontinue use during prolonged immobilization; if feasible, stop use at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE.
• Start the vaginal system no earlier than 4 weeks after delivery in females who are not breastfeeding; risk of postpartum VTE decreases after the third postpartum week, whereas risk of ovulation increases after the third postpartum week
• Before starting the vaginal system, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether history suggests an inherited or acquired hypercoagulopathy; the vaginal system is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases
• Risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception following a break of 4 weeks or longer; risk of VTE due to CHCs gradually disappears after use discontinued

Vaginal use

• Some females are aware of the vaginal system on occasion during 21 days of use or during coitus, and partners may feel the vaginal system during coitus
• There is no information on concomitant use of the vaginal system with diaphragms, cervical caps, or female condoms
• The vaginal system may not be suitable for females with conditions that make the vagina more susceptible to vaginal irritation or ulceration; vaginal and cervical erosion and/or ulceration have been reported in females using other contraceptive vaginal devices; in some cases, the ring has adhered to vaginal tissue, which necessitates removal by a healthcare provider

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 CHCs before conception or during early pregnancy; discontinue the vaginal system if pregnancy occurs; there is no reason to use CHCs during pregnancy

Lactation

Contraceptive hormones and/or metabolites are present in human milk; CHCs can reduce milk production in breastfeeding females; reduction can occur at any time but is less likely to occur once breastfeeding is well established; advise a nursing female to use another method of contraception until she discontinues breastfeeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation

Ethinyl estradiol (EE): Reduces LHRH release from hypothalamus, reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues

Segesterone acetate (SA): Progestin; inhibits gonadotropin secretion from pituitary; prevents follicular maturation and ovulation, and stimulates growth of mammary tissues

Absorption

Median Tmax SA and EE absorption in cycles 1, 3, and 13: 2 hr

Average serum concentration of SA over first 48 hr of dosing: 191 pg/mL (cycle 1), 131 pg/mL (cycle 3), 94 pg/mL (cycle 13)

Average serum concentration of EE over first 48 hr of dosing: 44 pg/mL (cycle 1), 29 pg/mL (cycle 3), 19 pg/mL cycle 13)

Distribution

Vd (SA): 19.6 L/kg

Protein-bound SA: 95% to human serum proteins and negligible binding for sex hormone-binding globulin (SHBG); EE is highly protein bound (98.5%) but not specifically to serum albumin; induces an increase in SHBG serum concentration

Metabolism

SA and EE are metabolized by cytochrome P450 3A4 isoenzyme; EE is primarily metabolized by aromatic hydroxylation; a wide variety of hydroxylated and methylated metabolites are formed with weak estrogenic activity

Elimination

Half-life: 4.5 hr (SA); 15.1 hr (EE)

Intravaginal Administration

After placing the vaginal system for 21 days, in the vagina, it should be removed and cleaned with mild soap and warm water, patted dry with a clean cloth towel or paper towel, and placed in its case during the 1-week dose-free interval; at the end of the dose-free interval, clean the vaginal system and place back in the vagina for another 21 days (3 complete weeks) Removing the vaginal system

Removing the vaginal system

• The vaginal system can be removed by hooking an index finger into the vaginal system inside the vagina and gently pulling the vaginal system

No hormonal contraceptive use in preceding cycle and after IUD removal

• Insert the vaginal system between days 2 and 5 of the regular menstrual bleeding; backup contraception is not necessary; if menstrual cycles are irregular or if start is more than 5 days from menstrual bleeding, use an additional barrier method during coitus, including male condom or spermicide for first 7 days of use

Switching from a combination hormonal contraceptive (CHC)

• A woman who has been using her CHC method consistently and correctly and who is reasonably certain is not already pregnant may switch from her previous CHC to the vaginal system on any day of the CHC cycle (Day 1-28), without the need for back-up contraception, but no more than 7 hormone-free days should occur before starting the vaginal system Switching from a progestin-only method [progestin-only pills (POP), progestin Injection, progestin implant, progestin intrauterine system (IUS)]

Switching from a progestin-only method (progestin-only pills [POP], progestin Injection, progestin implant, progestin intrauterine system [(IUS)]

• If a woman has no contraindications to the use of EE, she may elect to switch from a POPs to the vaginal system; if switching from progestin-only pills, she should begin use at the time she would have taken her next POP pill; if switching from an injection, she should begin at the time of her next scheduled injection; if switching from an implant or an IUS, she should begin at the time of implant or IUS removal; in all of these cases, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of use

Use after abortion or miscarriage

• If a woman has no contraindications to the use of EE, the vaginal system may be initiated for contraception within 5 days following a complete first trimester abortion or miscarriage without additional back-up contraception; if more than 5 days have elapsed from the first trimester abortion or miscarriage, follow the instructions for “No Hormonal Contraceptive Use in the Preceding Cycle” and use a barrier method from the time of the first trimester abortion or miscarriage to the initiation of the vaginal system
• The vaginal system should not be started earlier than 4 weeks after a second trimester abortion or miscarriage owing to increased risk of thromboembolism

Following childbirth

• The vaginal system should not be started sooner than 4 weeks postpartum and only in females who choose not to breastfeed; prior to 4 weeks postpartum, there is an increased risk of thromboembolism
• The initiation of the vaginal system 4 weeks or more postpartum should be accompanied by an additional method of contraception during coitus, such as male condoms or spermicide, for the first 7 days if the woman has not yet had a period; consider the possibility of ovulation and conception occurring prior to initiating the vaginal system
• Females who are breastfeeding should not use the vaginal system until after weaning

Deviations from regimen

• Contraceptive efficacy may be reduced if a woman deviates from recommended use; the vaginal system should remain in the vagina for a continuous period of 21 days (3 weeks), then taken out of the vagina for 7 days; in a 28-day cycle, a deviation that involves the vaginal system being out of the vagina for less than 7 days will not increase pregnancy risk; in a 28-day cycle, a deviation that involves the vaginal system being out of the vagina for more than 7 days will increase pregnancy risk; back-up contraception recommended in these instances; deviations from recommended regimen may result in a new vaginal system change day

• Inadvertent removal or expulsion

  • The vaginal system can be accidently expelled; accidental expulsion could occur while removing a tampon, during coitus, or with straining during a bowel movement; if the vaginal system is accidentally expelled once during the 21 days of intravaginal use and is replaced within 2 hours, contraceptive efficacy should not be reduced and no back-up contraception is needed; if the vaginal system is accidently expelled, wash it with mild soap and warm water, rinse and pat dry with a clean cloth towel or paper towel, and replace it as soon as possible
  • During the 21 days of continuous use, if the vaginal system is out of the vagina for more than 2 continuous hours or more than 2 cumulative hours (multiple inadvertent removals or expulsions adding up to 2 hours), back-up contraception, such as male condoms or spermicide, should be used until the vaginal system has been in the vagina for 7 consecutive days; the use of CHC (those containing an estrogen) for emergency contraception during use of the vaginal system is not recommended

• Prolonged vaginal system-free interval

  • If the vaginal system-free Interval is prolonged, consider the possibility of pregnancy and have the woman use back-up contraception, such as male condoms or spermicide, during coitus until the vaginal system has been in the vagina for 7 consecutive days; the use of CHC (those containing an estrogen) for emergency contraception during use of the vaginal system is not recommended
  • If the vaginal system is left in the vagina for more than 21 days, it should be removed for 7 days and then reinserted for 21 days to resume a 21/7 schedule