Estradiol and dienogest: Drug information

(For additional information see "Estradiol and dienogest: Patient drug information" and see "Estradiol and dienogest: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

ALERT: US Boxed Warning

Cigarette smoke and serious cardiovascular events:

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives should not be used by women who are over 35 years of age and smoke.

Brand Names: US

Natazia

Pharmacologic Category

Contraceptive;
Estrogen and Progestin Combination

Dosing: Adult

Abnormal uterine bleeding, nonacute, or contraception

Abnormal uterine bleeding, nonacute, or contraception: Note: Not indicated for management of acute abnormal bleeding (ie, excessively heavy or prolonged bleeding that requires urgent evaluation) (Ref).

Oral: One tablet once daily in the order presented in the blister pack.

Patients not currently using a hormonal contraceptive:

Day 1 start: Start on first day of menstrual cycle. Use an additional method of contraception (nonhormonal) until after the first 9 days of consecutive administration.

Patients Switching From Another Contraceptive Method to Estradiol/Dienogest
Current method	Instructions for switching to estradiol/dienogest
Combined oral contraceptive	Take the first dark yellow tablet on the first day of withdrawal bleeding; do not continue taking tablets from previous contraceptive pack. If withdrawal bleeding does not occur, rule-out pregnancy before starting therapy. Use a nonhormonal contraceptive for the first 9 days.
Vaginal ring or patch	Take the first dark yellow tablet on the day the ring or patch is removed. Use a nonhormonal contraceptive for the first 9 days.
Progestin-only contraceptive	Take the first dark yellow tablet on the day of the next progestin-only tablet would have been given, or the day the progestin implant or intrauterine system (IUS) is removed, or on the day the next injection would have been given. Use a nonhormonal contraceptive for the first 9 days.

Use of Estradiol/Dienogest After Childbirth or Abortion
Use after childbirth (not breastfeeding)	Do not initiate estradiol/dienogest <4 weeks after delivery due to the increased risk of venous thromboembolism. If postpartum menstrual cycles have not returned, evaluate for possible pregnancy; use a n additional method of contraception (nonhormonal) for the first 9 days of consecutive administration.
Use after second trimester abortion	Do not initiate estradiol/dienogest <4 weeks after a second trimester abortion due to the increased risk of venous thromboembolism. If menstrual cycles have not returned, evaluate for possible pregnancy; use an additional method of contraception (nonhormonal) for the first 9 days of consecutive administration.

Use of Estradiol/Dienogest After Childbirth or Abortion

Use after childbirth (not breastfeeding)

Do not initiate estradiol/dienogest <4 weeks after delivery due to the increased risk of venous thromboembolism.

If postpartum menstrual cycles have not returned, evaluate for possible pregnancy; use a n additional method of contraception (nonhormonal) for the first 9 days of consecutive administration.

Use after second trimester abortion

Do not initiate estradiol/dienogest <4 weeks after a second trimester abortion due to the increased risk of venous thromboembolism.

If menstrual cycles have not returned, evaluate for possible pregnancy; use an additional method of contraception (nonhormonal) for the first 9 days of consecutive administration.

Missed or Late Doses of Estradiol/Dienogest
If ≤12 hours late, take tablet as soon as remembering and take the next tablet at the usual time. If >12 hours late, instructions vary by day of cycle and number of tablets missed:
If missed ONE dose:	Days 1 to 17: Take missed tablet immediately; take next tablet at usual time (may require 2 tablets that day); use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. Days 18 to 24: Do not continue using current blister pack (throw away); take day 1 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. Days 25 to 28: Take missed tablet immediately; take next tablet at usual time (may require 2 tablets that day); continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.
If missed TWO doses in a row:	Days 1 to 17: Do not take missed tablets; start by taking the tablet for the day it was first noticed that the tablet was missed; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 17 and 18, follow directions for missed tablets on days 17 to 25. Days 17 to 25: Do not continue using current blister pack (throw away); take day 3 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 25 and 26, follow directions for missed tablets on days 25 to 28. Days 25 to 28: Do not continue using current blister pack (throw away); start a new pack on the same day, or start a new pack the day it would normally be started; continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.

Missed or Late Doses of Estradiol/Dienogest

If ≤12 hours late, take tablet as soon as remembering and take the next tablet at the usual time.

If >12 hours late, instructions vary by day of cycle and number of tablets missed:

If missed ONE dose:

Days 1 to 17: Take missed tablet immediately; take next tablet at usual time (may require 2 tablets that day); use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle.

Days 18 to 24: Do not continue using current blister pack (throw away); take day 1 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle.

Days 25 to 28: Take missed tablet immediately; take next tablet at usual time (may require 2 tablets that day); continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.

If missed TWO doses in a row:

Days 1 to 17: Do not take missed tablets; start by taking the tablet for the day it was first noticed that the tablet was missed; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 17 and 18, follow directions for missed tablets on days 17 to 25.

Days 17 to 25: Do not continue using current blister pack (throw away); take day 3 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 25 and 26, follow directions for missed tablets on days 25 to 28.

Days 25 to 28: Do not continue using current blister pack (throw away); start a new pack on the same day, or start a new pack the day it would normally be started; continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Safety and efficacy have not been evaluated; dose adjustment not expected to be required.

Dosing: Hepatic Impairment: Adult

Use is contraindicated with hepatic disease. Discontinue if hepatic dysfunction occurs.

Dosing: Pediatric

(For additional information see "Estradiol and dienogest: Pediatric drug information")

Contraception or heavy menstrual bleeding

Contraception or heavy menstrual bleeding: Postmenarche patients: Oral: 1 tablet once daily in the order presented in the blister pack. Patients not currently using a hormonal contraceptive should start on day 1 of menstrual period (first day of bleeding). A nonhormonal contraceptive should be used for the first 9 consecutive days.

**Patients Switching From Another Contraceptive Method to Estradiol/Dienogest**
Current method	Instructions for switching to estradiol/dienogest
Combined oral contraceptive	Take the first dark yellow tablet on the first day of withdrawal bleeding; do not continue taking tablets from previous contraceptive pack. If withdrawal bleeding does not occur, rule out pregnancy before starting therapy. A nonhormonal contraceptive should be used for the first 9 days.
Vaginal ring or patch	Take the first dark yellow tablet on the day the ring or patch is removed. A nonhormonal contraceptive should be used for the first 9 days.
Progestin-only contraceptive	Take the first dark yellow tablet on the day the next progestin-only tablet would have been given, or the day the progestin implant or intrauterine system (IUS) is removed, or on the day the next injection would have been given. A nonhormonal contraceptive should be used for the first 9 days.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; use with caution (has not been studied); however, an effect which would require a dosage adjustment is unlikely.

Dosing: Hepatic Impairment: Pediatric

Use is contraindicated with hepatic disease. Discontinue if hepatic dysfunction occurs.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%: Central nervous system: Headache (13%, including migraine)

1% to 10%:

Central nervous system: Mood changes (3%, including depression)

Dermatologic: Acne vulgaris (4%)

Endocrine & metabolic: Menstrual disease (≤7% to 8%), breast changes (discomfort: ≤7%), weight gain (3%)

Gastrointestinal: Nausea (≤7%), vomiting (≤7%)

Genitourinary: Uterine hemorrhage (≤7% to 8%), breast tenderness (≤7%), mastalgia (≤7%)

Contraindications

Breast cancer (current or a history of; may be hormonal-sensitive), hepatic tumors (benign or malignant) or hepatic disease, pregnancy, undiagnosed abnormal uterine bleeding.

Use is also contraindicated in patients at high risk of arterial or venous thrombotic diseases, for example, patients with: Cerebrovascular disease, coronary artery disease, diabetes mellitus with vascular disease, DVT or PE (current or history of), hypercoagulopathies (inherited or acquired), headaches with focal neurological symptoms or migraine headaches with or without aura if >35 years of age, hypertension (uncontrolled), thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease or atrial fibrillation), patients >35 years of age who smoke.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding irregularities: Amenorrhea, spotting, and unscheduled bleeding may occur, primarily during the first 3 months of therapy. Evaluate unscheduled or breakthrough bleeding that persists more than a few cycles to rule out malignancy or pregnancy. Amenorrhea or oligomenorrhea may occur after discontinuing combination hormonal contraceptives, especially when such a condition was preexistent.

• Cervical cancer: The use of combination hormonal contraceptives has been associated with a slight increased risk of cervical cancer; however, studies are not consistent, and the risk may be related to the specific histologic type of cervical cancer, duration of contraceptive use, and other factors (Asthana 2020; Gadducci 2020). Theoretically, use may affect prognosis of existing disease. Patients awaiting treatment for cervical cancer may use combination hormonal contraceptives (CDC [Curtis 2016b]).

• Chloasma: Combination hormonal contraceptives, as well as sun exposure and pregnancy, are triggers for chloasma. Avoid exposure to sun or UV radiation during therapy in patients with a susceptibility to chloasma or additional risk factors (Handel 2014).

• Cholestasis: Risk of cholestasis may be increased with previous cholestatic jaundice of pregnancy or cholestasis with prior oral contraceptive use.

• Hepatic adenomas or carcinomas: Use of combination hormonal contraceptives is associated with hepatic adenomas (rare); rupture may cause fatal intra-abdominal hemorrhage. Long-term use may be associated with an increased risk of hepatocellular carcinoma (rare).

• Lipid effects: Combination hormonal contraceptives may adversely affect lipid levels, including serum triglycerides. Patients with hypertriglyceridemia or a family history of hypertriglyceridemia may be at increased risk of pancreatitis when using combination hormonal contraceptives. Consider alternative contraception for patients with uncontrolled dyslipidemia.

• Retinal thrombosis: Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occur and immediately evaluate for retinal thrombosis.

• Thromboembolic disorders: Discontinue use of combination hormonal contraceptives if an arterial or venous thrombotic event (VTE) occurs. The increased risk of VTE associated with combination hormonal contraceptives is greatest during first year of use and less than the risk associated with pregnancy; some studies suggest this risk may be higher in preparations with third- or fourth-generation progestins and/or high-dose ethinyl estradiol. Patients with inherited thrombophilias (eg, protein C or S deficiency, factor V Leiden mutation, prothrombin mutation, antithrombin deficiency) may have increased risk of VTE. Age >35 years, hypertension, obesity, and tobacco use also increase the risk of thromboembolic events in patients taking combination hormonal contraceptives (Abou-Ismail 2020; ASRM 2017; CDC [Curtis 2016b]). Combination hormonal contraceptives may also increase the risk of arterial thrombosis (eg, myocardial infarction, stroke); do not use in patients with a history of stroke or ischemic heart disease (CDC [Curtis 2016b]).

Disease-related concerns:

• Bariatric surgery: Fertility is increased following bariatric surgery. All available forms of contraception can be considered following bariatric surgery, considering the patient's body weight and time since surgery. However, long-acting reversible non-oral contraceptives (eg, implants, intrauterine devices) may be preferred. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy both have the potential to expedite transit through the small bowel. RYGB may not significantly alter the absorption of oral estrogen or progestogens (limited evidence following a single dose). However, gastric and small bowel transit is not well studied following chronic oral dosing; therefore, contraceptive efficacy cannot be guaranteed. Oral contraceptives may be used in patients having adjustable gastric banding unless there is diarrhea or vomiting. Reliable contraception using oral contraceptives cannot be guaranteed following jejunoileal bypass, biliopancreatic diversion, single anastomosis duodeno-ilial bypass, or omega-loop gastric bypass. Discontinue estrogen-containing birth control at least 4 weeks prior to bariatric surgery and resume no earlier than 4 weeks after surgery to minimize risk of VTE (Ciangura 2019; Mechanick 2020; Moreira de Brito 2020; Shawe 2019).

• Breast cancer: Available studies have not shown a consistent association with combination hormonal contraceptives and breast cancer risk. Multiple studies have shown no association in current or ever users (current or past); other studies have shown a small increased risk in current users (higher risk in current users with longer durations of use) and recent users (<6 months since last use). In patients at risk for breast cancer due to family history or susceptibility genes (BRCA1, BRCA2), it is unclear if combination hormonal contraceptives increase the risk for breast cancer. However, breast cancer is a hormonal sensitive tumor and the prognosis for patients with a current or recent history of breast cancer may be worse with combination hormonal contraceptive use (CDC [Curtis 2016b]; SGO/ASRM [Chen 2019]).

• Cardiovascular disease: Use with caution in patients with risk factors for cardiovascular disease (eg, hypertension, low HDL, high LDL, high triglycerides, older age, diabetes, or patients who smoke); use of combination hormonal contraceptives may increase the risk of cardiovascular disease (CDC [Curtis 2016b]).

• Depression: Use with caution in patients with depression; discontinue if serious depression recurs.

• Diabetes: May impair glucose tolerance; use caution in patients with diabetes or prediabetes. In general, use of combination oral contraceptives has limited effects on daily insulin needs and no long-term effects on diabetes control in patients with nonvascular disease. However, evaluate use in patients with concomitant nephropathy, neuropathy, retinopathy, other vascular disease, or diabetes >20 years' duration based on the severity of the condition (CDC [Curtis 2016b]).

• Endometrial cancer: The risk of endometrial cancer is decreased in patients using combination hormonal contraceptives. Patients awaiting treatment for endometrial cancer may use combination hormonal contraceptives (CDC [Curtis 2016b]).

• Gallbladder disease: Combination hormonal contraceptives may cause a small increased risk of gallbladder disease or may worsen existing gallbladder disease (CDC [Curtis 2016b]).

• Hepatic impairment: Contraceptive steroids may be poorly metabolized in patients with hepatic impairment. Discontinue if jaundice develops during therapy or if liver function becomes abnormal. Consider use of combination hormonal contraceptives in patients with mild (compensated) cirrhosis; do not use in patients with severe (decompensated) cirrhosis (CDC [Curtis 2016b]).

• Hepatitis: Initiation of combination hormonal contraceptives is not recommended in patients with acute viral hepatitis or during a flare. Continued use in patients with chronic hepatitis has not been shown to increase the rate or severity of cirrhotic fibrosis or hepatocellular carcinoma. Continued use in patients who are carriers has not been shown to trigger liver failure or severe hepatic dysfunction (CDC [Curtis 2016b]).

• Hereditary angioedema: Estrogens may induce or exacerbate symptoms of hereditary angioedema.

• Hypertension: The risk of hypertension may be increased with age, dose, and duration of use. Do not use combination hormonal contraceptives in patients with hypertension and vascular disease, or persistent blood pressure values ≥160 mm Hg systolic or ≥100 mm Hg diastolic. The risks of use may not outweigh the benefits of treatment in patients with less severe hypertension (140 to 159 mm Hg systolic or 90 to 99 mm Hg diastolic) or those with hypertension that is adequately controlled (CDC [Curtis 2016a]). Consider other risk factors for cardiovascular disease (eg, older age, smoking, diabetes) when prescribing contraceptives (CDC [Curtis 2016b]). Monitor blood pressure in patients with well-controlled hypertension; discontinue therapy if blood pressure rises significantly.

• Migraine: Evaluate new, recurrent, severe or persistent headaches. Use of combination hormonal contraceptives may be considered in patients who have migraines without aura (including menstrual migraines) (CDC [Curtis 2016b]).

• Ovarian cancer: The risk of ovarian cancer is decreased in patients using combination hormonal contraceptives (CDC [Curtis 2016b]; SGO/ASRM [Chen 2019]). Oral contraceptives may be used to reduce the risk of ovarian cancer in at risk patients with BRCA1 and BRCA2 mutations who do not have a personal history of breast cancer (SGO/ASRM [Chen 2019]). Patients awaiting treatment for ovarian cancer may use combination hormonal contraceptives (CDC [Curtis 2016b]).

• Solid organ transplant: Use of combination hormonal contraceptives is not recommended in patients with complicated organ transplants; although data are limited, serious medical complications have been reported (eg, graft failure, rejection, cardiac allograft vasculopathy) requiring discontinuation of the contraceptive (CDC [Curtis 2016b]).

• Systemic lupus erythematosus: Patients with systemic lupus erythematosus (SLE) are at an increased risk for heart disease, stroke, and VTE. Do not use combination hormonal contraceptives in patients with SLE who have positive (or unknown) antiphospholipid antibodies, due to an increased risk of arterial and venous thrombosis (CDC [Curtis 2016b]).

Concurrent drug therapy issues:

• Testosterone: All available forms of contraception can be considered for patients receiving gender-affirming testosterone therapy after evaluating patient preferences and medical conditions (Bonnington 2020; Krempasky 2020). However, it has been suggested to use contraceptive products containing lower daily doses of ethinyl estradiol (10 to 20 mcg) to decrease the risk of possible adverse reactions when testosterone therapy is used with combination hormonal contraceptives (Bonnington 2020).

Special populations:

• Body weight: This product has not been studied in patients with a BMI >30 kg/m². Available evidence suggests efficacy of combination hormonal contraceptives may be decreased in patients with a BMI ≥30 kg/m²; however, reductions in effectiveness are considered minimal and information is conflicting. In this population, use of combination hormonal contraceptives may increase the risk of VTE. In general, the benefits of combination hormonal contraceptives may outweigh the risks in patients who otherwise are eligible for this method (CDC [Curtis 2016b]). Consult product labeling.

• Smoking: Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use. This risk increases with age, particularly in patients >35 years of age, and with the number of cigarettes smoked.

• Surgery: Whenever possible, discontinue estrogens at least 4 weeks prior to and through 2 weeks following elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Other warnings/precautions:

• HIV infection protection: Combination hormonal contraceptives do not protect against HIV infection or other sexually transmitted diseases (CDC [Curtis 2016a]; CDC [Curtis 2016b]).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Natazia: Estradiol valerate 3 mg [2 tablets]; dienogest 2 mg and estradiol valerate 2 mg [5 tablets]; dienogest 3 mg and estradiol valerate 2 mg [17 tablets]; estradiol valerate 1 mg [2 tablets]; 2 inactive tablets

Generic Equivalent Available: US

Pricing: US

Tablets (Natazia Oral)

3/2-2/2-3/1 mg (per each): $10.62

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Take tablets at the same time each day in the order presented in the blister pack. Do not delay administration by >12 hours. Instruct patients not to take more than 2 tablets in any 1 day. Use a nonhormonal contraceptive (eg, condom or spermicide) for the first 9 days of therapy. If patient is unsure of number of tablets missed, continue taking 1 tablet each day and use a back-up form of contraception.

According to the manufacturer, in case of vomiting or diarrhea within 3 to 4 hours of taking a colored tablet, treat as if the dose was missed (or can take another tablet of the same color from an extra blister pack). Additional guidelines are available (Ref).

Administration: Pediatric

Oral: Tablets should be taken at the same time each day in the order presented in the blister pack. Do not delay administration by >12 hours. Patients should be instructed not to take more than 2 tablets in any one day. A nonhormonal contraceptive (eg, condom, spermicide) should be used for the first 9 days of therapy. If patient is unsure of number of tablets missed, they should continue taking one tablet each day and use a back-up form of contraception.

**Missed or Late Doses of Estradiol/Dienogest**
If ≤12 hours late, take tablet as soon as remembering and take the next tablet at the usual time.
If >12 hours late, instructions vary by day of cycle and number of tablets missed:
If missed ONE dose:	Days 1 to 17: Take missed tablet immediately; take next tablet at usual time (may require 2 tablets that day); use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. Days 18 to 24: Do not continue using current blister pack (throw away); take day 1 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. Days 25 to 28: Take missed tablet immediately; take next tablet at usual time (may require 2 tablets that day); continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.
If missed TWO doses in a row:	Days 1 to 17: Do not take missed tablets; start by taking the tablet for the day it was first noticed that the tablet was missed; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 17 and 18, follow directions for missed tablets on days 17 to 25. Days 17 to 25: Do not continue using current blister pack (throw away); take day 3 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 25 and 26, follow directions for missed tablets on days 25 to 28. Days 25 to 28: Do not continue using current blister pack (throw away); start a new pack on the same day, or start a new pack the day it would normally be started; continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 2]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use: Labeled Indications

Abnormal uterine bleeding, nonacute: Treatment of nonacute abnormal uterine bleeding (ie, heavy menstrual bleeding) in patients without organic pathology who choose to use an oral contraceptive as their method for contraception.

Contraception: For the prevention of pregnancy.

Limitations of use: For use in patients who may become pregnant; not for use prior to menarche or postmenopause. Efficacy has not been evaluated in patients with a BMI >30 kg/m².

Use: Off-Label: Adult

Acne; Dysmenorrhea (primary and secondary to endometriosis); Menstrual suppression; Polycystic ovary syndrome in patients with menstrual irregularities and hirsutism/acne

Medication Safety Issues

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Adalimumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy

Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination

Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Aprepitant: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration with aprepitant, and to continue back-up contraception for 28 days after discontinuing aprepitant to ensure contraceptive reliability. Risk D: Consider therapy modification

Asparaginase Products: Hormonal Contraceptives may enhance the thrombogenic effect of Asparaginase Products. Management: Consider discontinuing hormonal contraceptives and using an alternative contraceptive method in patients treated with asparaginase products. Risk D: Consider therapy modification

Asunaprevir: May decrease the serum concentration of Hormonal Contraceptives. Management: Use of a high-dose oral contraceptive (at least 30 mcg of ethinyl estradiol combined with norethindrone) is recommended when combined with asunaprevir. Consider an additional barrier method when other forms of contraception are used with asunaprevir. Risk D: Consider therapy modification

Atazanavir: May decrease the serum concentration of Hormonal Contraceptives. Specifically, atazanavir/ritonavir may decrease concentrations of estrogens. Atazanavir may increase the serum concentration of Hormonal Contraceptives. Specifically, atazanavir alone may increase concentrations of estrogens and atazanavir alone or boosted may increase concentrations of progestins. Management: Dose adjustment of hormonal contraceptives or use of alternative or additional nonhormonal contraceptive may be needed when combined with atazanavir. See full interact monograph for details. Atazanavir/cobicistat with drospirenone is contraindicated. Risk D: Consider therapy modification

Bimekizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Brigatinib: May decrease the serum concentration of Hormonal Contraceptives. Management: Use a non-hormonal contraceptive during brigatinib use and for at least 4 months after the last brigatinib dose. Males with partners of reproductive potential should use contraception during treatment with brigatinib and for 3 months after brigatinib use. Risk D: Consider therapy modification

C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy

Carfilzomib: Hormonal Contraceptives may enhance the thrombogenic effect of Carfilzomib. Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib, especially patients using carfilzomib in combination with dexamethasone, lenalidomide plus dexamethasone, or daratumumab plus dexamethasone. Risk D: Consider therapy modification

Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy

Chlorprothixene: Estrogen Derivatives may enhance the adverse/toxic effect of Chlorprothixene. Estrogen Derivatives may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy

Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Cobicistat: May decrease the serum concentration of Hormonal Contraceptives. Specifically, cobicistat may decrease serum concentrations of estrogens. Cobicistat may increase the serum concentration of Hormonal Contraceptives. Specifically, cobicistat may increase serum concentrations of progestins. Management: Use alternative or additional nonhormonal forms of contraception when estrogen-containing hormonal contraceptives are combined with cobicistat. Progestin-only contraceptives can be used without back up, but monitor for progestin toxicities. Risk D: Consider therapy modification

Colchicine: May enhance the adverse/toxic effect of Hormonal Contraceptives. Risk C: Monitor therapy

Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy

Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

CYP3A4 Inducers (Weak): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy

Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination

Efavirenz: May decrease the serum concentration of Hormonal Contraceptives. Management: Use a back-up method during coadministration, and to continue back-up contraception for 12 weeks after stopping efavirenz to ensure contraceptive reliability. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Risk D: Consider therapy modification

Elagolix: Hormonal Contraceptives may diminish the therapeutic effect of Elagolix. Specifically, estrogen-containing hormonal contraceptives may diminish the therapeutic effects of elagolix. Elagolix may decrease the serum concentration of Hormonal Contraceptives. Specifically, concentrations of progestins may be decreased with elagolix therapy. Elagolix may increase the serum concentration of Hormonal Contraceptives. Specifically, concentrations of ethinyl estradiol may be increased with elagolix therapy. Management: Use an alternative, nonhormonal contraceptive during treatment with elagolix and for at least 28 days following discontinuation of elagolix treatment. Use of elagolix 200 mg twice daily with an estrogen-containing hormonal contraceptive is not recommended Risk D: Consider therapy modification

Elexacaftor, Tezacaftor, and Ivacaftor: Hormonal Contraceptives may enhance the adverse/toxic effect of Elexacaftor, Tezacaftor, and Ivacaftor. Specifically, the risk for rash may be increased. Risk C: Monitor therapy

Encorafenib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk X: Avoid combination

Etravirine: May decrease the serum concentration of Hormonal Contraceptives. Specifically, progestin concentrations may decrease. Etravirine may increase the serum concentration of Hormonal Contraceptives. Specifically, estrogen concentrations may increase. Risk C: Monitor therapy

Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination

Exenatide: Hormonal Contraceptives may diminish the therapeutic effect of Exenatide. Exenatide may decrease the serum concentration of Hormonal Contraceptives. Management: Administer oral hormonal contraceptives at least one hour prior to exenatide. Monitor blood glucose more frequently when patients treated with exenatide initiate therapy with a hormonal contraceptive. Increases in exenatide doses may be needed. Risk D: Consider therapy modification

Felbamate: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing felbamate to ensure contraceptive reliability. Risk D: Consider therapy modification

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination

Flibanserin: Hormonal Contraceptives may increase the serum concentration of Flibanserin. Risk C: Monitor therapy

Fosaprepitant: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration with fosaprepitant, and to continue back-up contraception for 28 days after discontinuing fosaprepitant to ensure contraceptive reliability. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Griseofulvin: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing griseofulvin to ensure contraceptive reliability. Risk D: Consider therapy modification

Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider therapy modification

Guanethidine: Estrogen Derivatives may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination

Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy

Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy

Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination

Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Ivosidenib: May decrease the serum concentration of Hormonal Contraceptives. Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Risk D: Consider therapy modification

Ixazomib: May decrease the serum concentration of Hormonal Contraceptives. More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of hormonal contraceptives. Management: Patients of reproductive potential should use a non-hormonal contraceptive method during treatment with ixazomib and for at least 90 days after the last ixazomib dose. Risk D: Consider therapy modification

LamoTRIgine: Estrogen Derivatives (Contraceptive) may decrease the serum concentration of LamoTRIgine. Management: Larger doses of lamotrigine may be needed when combined with estrogens. Specific dosing recommendations vary based on other concomitant medications and which medication is being initiated or discontinued. See interaction monograph for details. Risk D: Consider therapy modification

Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy

Lixisenatide: Hormonal Contraceptives may diminish the therapeutic effect of Lixisenatide. Lixisenatide may decrease the serum concentration of Hormonal Contraceptives. Management: Administer oral hormonal contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Additionally, monitor blood glucose more frequently when patients treated with lixisenatide initiate therapy with a hormonal contraceptive. Risk D: Consider therapy modification

Lomitapide: Estrogen Derivatives may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 40 mg/day. Risk D: Consider therapy modification

Mavacamten: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative contraceptive that is not sensitive to CYP3A4 induction or a back-up method during coadministration, and to continue back-up contraception for 4 months after stopping mavacamten to ensure contraceptive reliability. Risk D: Consider therapy modification

Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy

MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification

MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification

MiFEPRIStone: May diminish the therapeutic effect of Hormonal Contraceptives. Management: Nonhormonal contraception should be used during, and for 4 weeks following, mifepristone treatment for hyperglycemia due to Cushing syndrome. If used for pregnancy termination, hormonal contraceptives can be used after pregnancy expulsion is confirmed. Risk D: Consider therapy modification

Mitotane: May decrease the serum concentration of Hormonal Contraceptives. Management: Effective nonhormonal contraception is recommended for those of reproductive potential during treatment with mitotane as well as after discontinuation of mitotane for as long as mitotane plasma levels are detectable. Risk X: Avoid combination

Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: Monitor therapy

Mobocertinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination

Mycophenolate: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients of childbearing potential who are taking hormonal contraceptives should use an additional form of barrier contraception during treatment with mycophenolate and for 6 weeks after mycophenolate discontinuation. Risk D: Consider therapy modification

Nirmatrelvir and Ritonavir: May decrease the serum concentration of Hormonal Contraceptives. Specifically, nirmatrelvir and ritonavir may decrease concentrations of estrogens. Nirmatrelvir and Ritonavir may increase the serum concentration of Hormonal Contraceptives. Specifically, nirmatrelvir and ritonavir may increase concentrations of progestins. Management: Use additional nonhormonal forms of contraception (back-up method) when estrogen-containing hormonal contraceptives are combined with nirmatrelvir/ritonavir. Progestin-only contraceptives can be used without back-up, but monitor for progestin toxicities. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Octreotide: May decrease the serum concentration of Hormonal Contraceptives. Management: Women should use an alternative non-hormonal method of contraception or a back-up method when octreotide is combined with hormonal contraceptives. Risk D: Consider therapy modification

Olutasidenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid use of olutasidenib with sensitive or narrow therapeutic index CYP3A4 substrates when possible. If concurrent use with olutasidenib is unavoidable, monitor closely for evidence of decreased concentrations of the CYP3A4 substrates. Risk D: Consider therapy modification

Omaveloxolone: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination

Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Risk X: Avoid combination

OXcarbazepine: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing oxcarbazepine to ensure contraceptive reliability. Risk D: Consider therapy modification

Perampanel: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients should use an alternative, nonhormonal-based form of contraception during the concurrent use of perampanel and for 1 month after discontinuing perampanel. Risk D: Consider therapy modification

Pexidartinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination

Pitolisant: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. Risk D: Consider therapy modification

Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Hormonal Contraceptives. Specifically, protease inhibitors may decrease concentrations of estrogens. Protease Inhibitors may increase the serum concentration of Hormonal Contraceptives. Specifically, protease inhibitors may increase concentrations of progestins. Management: Use alternative or additional nonhormonal forms of contraception when estrogen-containing hormonal contraceptives are combined with protease inhibitors. Progestin-only contraceptives can be used without back up, but monitor for progestin toxicities. Risk D: Consider therapy modification

Raloxifene: Estrogen Derivatives may enhance the adverse/toxic effect of Raloxifene. Risk X: Avoid combination

Repotrectinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination

ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy

Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy

Sugammadex: May diminish the therapeutic effect of Hormonal Contraceptives. Management: Patients receiving any hormonal contraceptive (oral or non-oral) should use an additional, nonhormonal contraceptive method during and for 7 days following sugammadex treatment. Risk D: Consider therapy modification

Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Taurursodiol: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk X: Avoid combination

Tazemetostat: May decrease the serum concentration of Hormonal Contraceptives. Management: Individuals of childbearing potential should use a non-hormonal contraceptive method during treatment with tazemetostat and for 6 months after. Males with partners of childbearing potential should use contraception during treatment and for 3 months after. Risk D: Consider therapy modification

Tetrahydrocannabinol and Cannabidiol: May decrease the serum concentration of Hormonal Contraceptives. Management: Product labeling recommends that patients taking hormonal contraceptives should use an additional, non-hormonal contraceptive or reliable barrier method during treatment with tetrahydrocannabinol and cannabidiol buccal spray. Risk D: Consider therapy modification

Thalidomide: Hormonal Contraceptives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy

Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy

Tirzepatide: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients using oral hormonal contraceptives should switch to a non-oral contraceptive method, or add a barrier method of contraception, for 4 weeks after initiation of tirzepatide and for 4 weeks after each dose escalation of tirzepatide. Risk D: Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification

Tobacco (Smoked): May enhance the adverse/toxic effect of Estrogen Derivatives (Contraceptive). Specifically, the risk of serious cardiovascular events (eg, stroke, venous thromboembolism, myocardial infarction) may be increased. Management: Avoid cigarette smoking in patients who use estrogen containing contraceptives whenever possible. If combined, monitor for signs and symptoms of serious cardiovascular events (eg, stroke, venous thromboembolism, myocardial infarction). Risk D: Consider therapy modification

Topiramate: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing topiramate to ensure contraceptive reliability. Risk D: Consider therapy modification

Tranexamic Acid: Hormonal Contraceptives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination

Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination

Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy

Ustekinumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Vaborbactam: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing meropenem/vaborbactam to ensure contraceptive reliability. Risk D: Consider therapy modification

Valproate Products: Estrogen Derivatives may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Hormonal Contraceptives may increase the serum concentration of Vitamin K Antagonists. Hormonal Contraceptives may decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Voriconazole: Hormonal Contraceptives may increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy

Food Interactions

Food increases C_max of estradiol by 23% and decreases C_max of dienogest by 28%; AUC remains unchanged for both.

Reproductive Considerations

The manufacturer does not recommend use until ≥4 weeks after delivery in patients who choose not to breastfeed or ≥4 weeks after a second trimester abortion.

Due to the increased risk of venous thromboembolism (VTE) postpartum, do not start combination hormonal contraceptives in any patient <21 days following delivery. The risk decreases to baseline by postpartum day 42. In patients who are between 21 and 42 days after delivery, consider risk factors for VTE (eg, age ≥35 years, previous VTE, thrombophilia, immobility, preeclampsia, transfusion at delivery, cesarean delivery, peripartum cardiomyopathy, BMI ≥30 kg/m², postpartum hemorrhage, smoking) (CDC [Curtis 2016b]).

All available forms of contraception, including combination hormonal contraceptives, can be considered for patients on gender-affirming testosterone therapy after evaluating patient preferences and medical conditions (Bonnington 2020; Krempasky 2020).

Pregnancy Considerations

Use is contraindicated during pregnancy. Combination hormonal contraceptives are used to prevent pregnancy; discontinue treatment if pregnancy occurs. In general, the use of combination hormonal contraceptives when inadvertently taken early in pregnancy has not been associated with adverse fetal or maternal effects (CDC [Curtis 2016b]).

Breastfeeding Considerations

Contraceptive steroids may be present in breast milk.

Adverse health outcomes, or consistent effects on infant growth or illness due to exogenous estrogens have not been reported following maternal use of combination hormonal contraceptives in breastfeeding patients (CDC [Curtis 2016b]). Because estrogen containing contraceptives may reduce milk production, the manufacturer recommends use of other forms of contraception until the child is weaned.

Due to the increased risk of venous thromboembolism (VTE) postpartum, do not start combination hormonal contraceptives in breastfeeding patients <21 days following delivery. The risk decreases to baseline by postpartum day 42. In patients who are between 21 and 42 days after delivery, consider risk factors for VTE (eg, age ≥35 years, previous VTE, thrombophilia, immobility, preeclampsia, transfusion at delivery, cesarean delivery, peripartum cardiomyopathy, BMI ≥30 kg/m², postpartum hemorrhage, smoking). Evaluate risks, benefits, and alternatives to combination hormonal contraception when initiating treatment in breastfeeding patients (CDC [Curtis 2016b]).

Monitoring Parameters

Assessment of pregnancy status (prior to therapy); personal or family history of thrombotic or thromboembolic disorders (prior to therapy); blood pressure (prior to therapy and yearly); weight (optional; BMI at baseline may be helpful to monitor changes during therapy); assess potential health status changes at routine visits (CDC [Curtis 2016a]).

If all doses have not been taken on schedule and 1 menstrual period is missed, consider the possibility of pregnancy. If 2 consecutive menstrual periods are missed, assess pregnancy status before a new dosing cycle is started.

Monitor patient for vision changes; blood pressure; signs and symptoms of thromboembolic disorders; signs or symptoms of depression; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias. Perform adequate diagnostic measures, including endometrial sampling, if indicated, to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

Mechanism of Action

Combination hormonal contraceptives inhibit ovulation and may also cause changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. The four-phasic formulation provides the estrogen in decreasing concentrations and the progestin in increasing concentrations over the 28-day cycle.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: Estradiol: V_d: 1.2 L/kg; Dienogest: V_dss: 46 L

Protein binding: Estradiol: Albumin (60%) and sex hormone binding globulin (38%); Dienogest: Albumin (90%)

Metabolism: Hepatic via CYP3A4

Estradiol: Partially metabolized in the gastrointestinal mucosa, also undergoes significant first-pass metabolism; forms active metabolites (estrone, estrone sulfate, estrone glucuronide)

Dienogest: Forms inactive metabolites

Bioavailability: Dienogest ~91%

Half-life elimination: Estradiol: ~14 hours; Dienogest: ~11 hours

Time to peak: Estradiol: ~6 hours; Dienogest: ~1 hour

Excretion: Urine; feces

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Velbienne;
(AR) Argentina: Azucena | Qlaira;
(AT) Austria: Qlaira | Velbienne;
(BE) Belgium: Laclimella | Velbienne;
(BG) Bulgaria: Qlaira;
(BR) Brazil: Qlaira | Tambella;
(CH) Switzerland: Qlaira;
(CL) Chile: Qlaira | Valerix;
(CO) Colombia: Bellanew | Dadu | Qlaira | Segufem mini;
(CZ) Czech Republic: Qlaira | Velbienne;
(DE) Germany: Ariora | Climodien | Ladivella | Qlaira | Velbienne;
(DO) Dominican Republic: Qlaira;
(EC) Ecuador: Qlaira;
(EE) Estonia: Klimodien;
(ES) Spain: Qlaira;
(FI) Finland: Qlaira;
(FR) France: Qlaira;
(GB) United Kingdom: Qlaira;
(GR) Greece: Qlaira;
(HK) Hong Kong: Qlaira;
(HR) Croatia: Qlaira;
(ID) Indonesia: Qlaira;
(IE) Ireland: Qlaira;
(IL) Israel: Qlair;
(IT) Italy: Klaira | Paudien;
(KE) Kenya: Qlaira;
(KR) Korea, Republic of: Qlaira;
(LT) Lithuania: Klimodien | Qlaira | Velbienne;
(LU) Luxembourg: Laclimella | Velbienne;
(LV) Latvia: Klimodien;
(MA) Morocco: Qlaira | Velbienne;
(MX) Mexico: Qlaira;
(MY) Malaysia: Qlaira;
(NL) Netherlands: Climodien | Qlaira;
(NO) Norway: Climodien | Qlaira;
(NZ) New Zealand: Qlaira;
(PE) Peru: Qlaira;
(PH) Philippines: Qlaira;
(PK) Pakistan: Qlaira;
(PL) Poland: Juvinelle | Qlaira | Velbienne mini;
(PR) Puerto Rico: Natazia;
(PY) Paraguay: Qlaira;
(RO) Romania: Qlaira;
(RU) Russian Federation: Climodien | Qlaira;
(SE) Sweden: Qlaira;
(SG) Singapore: Qlaira;
(SK) Slovakia: Velbienne;
(TR) Turkey: Qlairista;
(UA) Ukraine: Qlaira;
(UY) Uruguay: Emily | Qlaira | Sienna;
(ZA) South Africa: Qlaira

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Topic 15573 Version 306.0

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Estradiol and dienogest: Drug information