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Ethinyl estradiol / segesterone Side Effects

Medically reviewed by Last updated on Sep 10, 2022.

Applies to ethinyl estradiol / segesterone: vaginal insert extended release.


Vaginal route (Insert, Extended Release)

Warning: Cigarette Smoking and Serious Cardiovascular EventsFemales over 35 years old who smoke should not use segesterone acetate/ethinyl estradiol vaginal system. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use.

Serious side effects

Along with its needed effects, ethinyl estradiol/segesterone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ethinyl estradiol / segesterone:

More common

  • Bladder pain
  • bloody or cloudy urine
  • chills
  • difficult, burning, or painful urination
  • fever
  • frequent or painful urination
  • headache, severe and throbbing
  • itching of the vagina or outside the genitals
  • lower back or side pain
  • pain during sexual intercourse
  • stomach pain
  • thick, white curd-like vaginal discharge without odor or with mild odor
  • upper or lower abdominal pain

Less common

  • Anxiety
  • back pain
  • chest pain
  • confusion
  • cough
  • dizziness or lightheadedness
  • expulsion of tissue with clots from your vagina
  • fainting
  • fast heartbeat
  • hives, itching, skin rash
  • hoarseness
  • irritation
  • joint pain, stiffness or swelling
  • mental depression
  • mood or other mental changes
  • numbness of the hands
  • pain, redness, or swelling in the arm or leg
  • redness of the skin
  • severe stomach pain
  • swelling of the eyelids, face, lips, hands, or feet
  • tightness in the chest
  • troubled breathing or swallowing

Other side effects

Some side effects of ethinyl estradiol / segesterone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  • Cramps
  • diarrhea
  • heavy bleeding
  • nausea
  • normal menstrual bleeding occurring earlier, possibly lasting longer than expected
  • vomiting

For Healthcare Professionals

Applies to ethinyl estradiol / segesterone: vaginal ring.


The more commonly reported adverse reactions have included headache/migraine, nausea/vomiting, vulvovaginal mycotic infection/candidiasis, upper and lower abdominal pain, dysmenorrhea, and vaginal discharge; 25% of women reported at least 1 complete expulsion of vaginal system during use.[Ref]


Combination Hormonal Contraceptives (CHC):

Uncommon (0.1% to 1%): Venous thrombotic event (VTE) rate

Frequency not reported: Increased blood pressure

Segesterone and Ethinyl Estradiol Vaginal System:

Frequency not reported: Venous thrombotic events (VTEs)

Serious adverse reactions occurred in 2% or more of subjects in clinical trials and included VTEs (deep vein thrombosis, cerebral vein thrombosis, and pulmonary embolism). At about 50% enrollment, females with BMI greater than 29 kg/m2 were excluded from participation due to the occurrence of 2 VTEs in this subgroup.

The rate of VTE in females using CHC has been estimated at 3 to 12 cases per 10,000 women. The risk of VTE for females who are not pregnant and do not use CHC is estimated to be between 1 and 5 for 10,000 women. For pregnant women, the risk is estimated to be 5 to 20 per 10,000 women and for those through 12 weeks postpartum, 40 to 65 per 10,000 women.


One complete vaginal system expulsion was experienced by 25% of women during clinical trials; 1.4% of patients discontinued use due to vaginal system expulsions.

Very common (10% or more): Vaginal system expulsion


Frequency not reported: Hypersensitivity reactions

Serious adverse reactions occurred in 2% or more of subjects in clinical trials and included drug hypersensitivity. Hypersensitivity reactions included throat constriction, facial edema, urticaria, hives, and wheezing.

Nervous system

Very common (10% or more): Headache, including migraine (38.6%)


An estimate of the attributable risk of hepatic adenomas associated with CHC use is 3.3 cases per 100,000 CHC users.

Combination Hormonal Contraceptives (CHC):

Very rare (less than 0.01%): Hepatic adenomas

Segesterone and Ethinyl Estradiol Vaginal System:

Frequency not reported: Liver enzyme elevations (with concomitant hepatitis C treatment)


Combination Hormonal Contraceptives (CHC)

Frequency not reported: Gallbladder disease (new onset or worsening)

Segesterone and Ethinyl Estradiol Vaginal System:

Very common (10% or more): Nausea/vomiting (25%), Abdominal pain/lower/upper (13.3%)

Common (1% to 10%): Diarrhea


Very common (10% or more): Vulvovaginal mycotic infection/vaginal candidiasis (14.5%), dysmenorrhea (12.5%), vaginal discharge (11.8%)

Common (1% to 10%): Unscheduled (breakthrough) bleeding, amenorrhea, UTI/cystitis/pyelonephritis/genitourinary tract infection, metorrhagia/menstrual disorder, genital pruritus

Frequency not reported: Metrorrhagia, menorrhagia, abnormal withdrawal bleeding


Common (1% to 10%): Breast pain/discomfort

Frequency not reported: Spontaneous abortions

Serious adverse reactions occurred in 2% or more of subjects in clinical trials and included spontaneous abortions.


Serious adverse reactions occurred in 2% or more of subjects in clinical trials and included psychiatric events. These events were not further defined.

Frequency not reported: Psychiatric events


Combination Hormonal Contraceptives (CHC)

Very rare (less than 0.01%): Hepatocellular carcinoma

The risk of long-term CHC users developing hepatocellular carcinomas is less than 1 case per million users. Long-term use is greater than 8 years.

Frequently asked questions


1. "Product Information. Annovera (ethinyl estradiol-segesterone)." Population Council (2018):

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.