Ethinyl estradiol and norethindrone - Dosage, Side effects, Brand Names

Ethinyl estradiol and norethindrone is a combination oral contraceptive pill that is primarily used to prevent pregnancy (as an oral hormonal contraceptive drug).

Ethinyl estradiol and norethindrone Uses:

  • Acne vulgaris (Estrostep Fe, Tilia Fe, Tri-Legest Fe):

    • Used for the treatment of moderate acne vulgaris in females at least 15 years.
    • Limitations of use:
    • When used for acne, use only in females 15  or more than years who have achieved menarche, who also desire combination hormonal contraceptive therapy, are unresponsive to topical treatments, have no contraindications to combination hormonal contraceptive use, and plan to stay on therapy for ≥6 months.

  • Contraception:

    • Used for the Prevention of pregnancy.
    • Limitations of use: The efficacy of some products has not been established in women with a BMI longer than 35 kg/m².

  • Osteoporosis prevention (female) (femhrt, Jevantique Lo, Jinteli):

    • Used for the prevention of postmenopausal osteoporosis.
    • Limitations of use: For use only in women at significant risk of postmenopausal osteoporosis; consider the use of nonestrogen medications.

  • Vasomotor symptoms associated with menopause (femhrt, Jevantique Lo, Jinteli):

    • Used for the treatment of moderate to severe vasomotor symptoms associated with menopause.

  • Off Label Use of Ethinyl estradiol and norethindrone in Adults:

    • Abnormal uterine bleeding (acute)
    • Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne
    • Dysmenorrhea
    • Hirsutism
    • Menstrual bleeding (menorrhagia)

Ethinyl estradiol and norethindrone Dose in Adults

Ethinyl estradiol and norethindrone Dose in the treatment of Abnormal uterine bleeding, acute (off-label):

  • Oral: Ethinyl estradiol 0.035 mg/norethindrone 1 mg thrice a day for a weak.

Ethinyl estradiol and norethindrone Dose in the treatment of Acne:

  • Adolescents ≥15 years of age and Adults:

    • Females: Oral (Estrostep Fe, Tilia Fe, TriLegest Fe):
      • Refer to dosing for contraception

Ethinyl estradiol and norethindrone Dose in the treatment of Contraception:

  • Females:

    • One tablet once a day.

  • Schedule 1 (Sunday starter):

    • Dose begins on first Sunday after the onset of menstruation;
    • if the menstrual period starts on Sunday, take the first tablet that very same day. (This schedule is not preferred for all products [eg, Generess Fe, Lo Loestrin Fe]).
    • With a Sunday start, an additional method of contraception should be used until after the first weak of consecutive administration (all products).

  • Schedule 2 (Day 1 starter):

    • Dose starts on the first day of the menstrual cycle taking 1 tablet once in a day.

Additional contraceptive dosing considerations:

  • Switching from a different contraceptive:

    • Oral contraceptive:
      • Start on the same day that a new pack of the previous oral contraceptive would have been taken.
    • Transdermal patch, vaginal ring, injection:
      • Start on the day the next dose would have been due.
    • IUD or implant:
      • Start on the day of removal.
      • A backup method of contraception should be used for the first weak if IUD is not removed on the first day of the menstrual cycle.
    • Use after first-trimester abortion or miscarriage:
      • Therapy may be started immediately.
      • If not started within 5 days, a back-up method of contraception should be used for the first weak.
    • Use after childbirth (in women who are not breastfeeding) or after second-trimester abortion or miscarriage:
      • Therapy may be started for 4 or more than 4 weeks postpartum.
      • Pregnancy should be ruled out prior to treatment if menstrual periods have not restarted.
      • An additional method of contraception (nonhormonal) should be used until after the first weak of consecutive administration.
      • Also, refer to prescribing information for product specific information for general guidance.

  • Missed or late doses:

    • If one dose is late ( less than 24 hours since the dose should have been taken) or if one dose is missed (24 to <48 hours since the dose should have been taken):
      • Take the dose as soon as possible.
      • Continue remaining doses at the usual time (even if that means 2 doses on the same day).
    • If 2 or more than 2 consecutive doses are missed (≥48 hours since dose should have been taken):
      • Take the most recently missed dose as soon as possible, discard any other missed doses.
      • Continue remaining doses at the usual time (even if that means taking 2 doses on the same day);
      • use back-up contraception until hormonal pills have been taken for 7 consecutive days.
      • If doses were missed during the last week of hormonal (active) tablets (eg, days 15 to 21 of a 28-day pack), omit the hormone-free interval by finishing the current pack and starting a new pack.
      • If unable to start a new pack immediately, back up contraception is needed until hormonal pills from a new pack have been taken for 7 consecutive days.
      • Consider the use of emergency contraception in some situations (refer to guidelines for details).
    • Also, refer to prescribing information for product specific information.

Ethinyl estradiol and norethindrone Dose in the Postmenopausal indications:

  • General dosing guidelines:

    • When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health.
    • Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer.
    • Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis.
    • Adjust dose based on patient response.

Ethinyl estradiol and norethindrone Dose in the prevention  of Osteoporosis:

  • Females:

    • Oral (femhrt, Jevantique Lo, Jinteli):
      • One tablet once in a day.

Ethinyl estradiol and norethindrone Dose in the treatment of Vasomotor symptoms associated with menopause:

  • Females:

    • Oral (femhrt, Jevantique Lo, Jinteli):
      • Initial: One tablet once in a day.

Ethinyl estradiol and norethindrone Dose in Childrens

Ethinyl estradiol and norethindrone Dose in the treatment of Acne:

  • Adolescent females ≥15 years:

    • Oral (Estrostep Fe, Tilia Fe, Tri-Legest Fe): Refer to adult dosing for contraception; not to be used prior to menarche

Ethinyl estradiol and norethindrone Dose in the treatment of Contraception:

  • Females:

    • Oral: Refer to adult dosing; not to be used prior to menarche.

Pregnancy Risk Factor X

  • Pregnant women should not use this product.
  • Breastfeeding should be stopped at 4 weeks post-birth for women who have chosen not to breastfeed.
  • Combination hormonal contraceptives should be stopped in women 21 days after delivery due to increased risk of venous embolism (VTE).
  • Postpartum day 42 sees a decrease in the risk to baseline.
  • To prevent pregnancy, combination hormonal contraceptives can be used. If pregnancy does occur, treatment should be stopped.
  • Combination hormonal contraceptives are generally not associated with any adverse effects on the fetus or mother if used inadvertently early in pregnancy.
  • According to the manufacturer, combination hormonal contraceptives are sho
  • Combination hormonal contraceptives should be used in women 21 to 42 days after birth.
  • Women who use combination hormonal contraceptives must take into account the risk factors for VTE.

Breastfeeding: Ethinyl estradiol, norethindrone

  • The manufacturer suggests that contraceptives containing estrogen be used until the child is weaned. This will reduce milk production.
  • Breastfeeding women should not start combination hormonal contraceptives within 21 days of delivery due to an increased risk for venous embolism (VTE).
  • Breast milk may contain contraceptive steroids.
  • Breastfeeding mothers who use combination hormonal contraceptives have not reported any adverse health effects or persistent effects on infant growth and illness.
  • Postpartum day 42 sees a decrease in the risk to baseline.
  • Combination hormonal contraceptives should be used in women 21 to 42 days after birth. Women who use combination hormonal contraceptives must take into account the risk factors for VTE.
  • When starting treatment for breastfeeding women, it is important to consider the risks and benefits of combination hormonal contraception.

Ethinyl estradiol and norethindrone Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied). Use with caution and monitor blood pressure closely.

Ethinyl estradiol and norethindrone Dose in Liver disease:

Its use is contraindicated in patients with hepatic impairment.

Menopausal vasomotor symptoms and osteoporosis prevention:

Common Side Effects of Ethinyl estradiol and norethindrone:

  • Endocrine & metabolic:

    • Increased sex hormone-binding globulin

Less Common Side Effects of Ethinyl estradiol and norethindrone:

  • Cardiovascular:

    • Edema

  • Central Nervous System:

    • Headache

  • Gastrointestinal:

    • Abdominal Pain

  • Genitourinary:

    • Mastalgia
    • Endometrial Hyperplasia

Contraception And Acne:

Common Side Effects Of Ethinyl Estradiol And Norethindrone:

  • Endocrine & Metabolic:

    • Change In Menstrual Flow
    • Amenorrhea

  • Genitourinary:

    • Breakthrough Bleeding
    • Spotting

Less Common Side Effects Of Ethinyl Estradiol And Norethindrone:

  • Central Nervous System:

    • Headache
    • Migraine
    • Depression
    • Mood Changes
    • Mood Disorder
    • Anxiety

  • Dermatologic:

    • Acne Vulgaris

  • Endocrine & Metabolic:

    • Heavy Menstrual Bleeding
    • Weight Changes
    • Weight Gain

  • Gastrointestinal:

    • Nausea
    • Vomiting
    • Abdominal Pain

  • Genitourinary:

    • Vulvovaginal Candidiasis
    • Abnormal Uterine Bleeding
    • Dysmenorrhea
    • Uterine Cramps
    • Abnormal Cervical Or Vaginal Papanicolaou Smear
    • Bacterial Vaginosis
    • Breast Tenderness
    • Mastalgia
    • Irregular Menses
    • Vaginal Hemorrhage

Frequency of Side effects Not Defined:

  • Cardiovascular:

    • Hypertension

  • Endocrine & Metabolic:

    • Decreased Libido

Contraindications to Ethinyl estradiol and norethindrone:

Combination hormonal contraceptives

  • Hypersensitivity to Ethinyl estradiol or norethindrone or any other component of the formulation
  • Breast cancer or another estrogen- or progestin sensitive cancer (currently or in the past);
  • Hepatic tumors (benign and malignant) or hepatic diseases;
  • pregnancy;
  • Undiagnosed abnormal uterine bleeding
  • concomitant use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

Women at high risk for arterial or vein thrombotic disease, such as women with:

  • Cerebrovascular Disease
  • Coronary artery disease
  • Diabetes mellitus and vascular disease
  • DVT or PE (current and/or historical of);
  • hypertension (uncontrolled);
  • Headaches with focal neurological symptoms
  • Migraine headaches with aura, migraine headaches, if you are >35 years old
  • Women over 35 years old who smoke;
  • Hypercoagulopathies (inherited and acquired);
  • Thrombogenic valvular and thrombogenic rhythm disorders of the heart (eg subacute bacteria endocarditis, valvular disease, atrial fibrillation).

Canadian labeling: Additional contraindications not in US labeling

  • Angina pectoris (current or historical of) or myocardial injury (current or historic of);
  • steroid-dependent jaundice, cholestatic jaundice
  • Any ocular lession that results from ophthalmic vessels disease (partial or complete loss of sight, or visual field defect)
  • Migraine with focal aura (currently or in the past);
  • Pancreatitis in association with severe hypertriglyceridemia (current and/or history of);
  • severe dyslipoproteinemia;
  • Persistent blood pressure >=160mm Hg systolic, or >=100mm Hg diastolic
  • Women with an acquired or hereditary predisposition to arterial or vein thrombosis may be:
    • factor V Leiden mutation,
    • activated protein C (APC-) resistance,
    • antithrombin-III-deficiency,
    • protein C deficiency,
    • protein S deficiency,
    • Hyperhomocysteinemia (eg due to MTHFR C677T and A1298 mutations)
    • Prothrombin mutation G20210A
    • antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant);
    • coadministration with paritaprevir, ritonavir, ombitasvir (with or without dasabuvir)

Products for postmenopausal indications

  • Hypersensitivity to any ingredient of the formulation, anaphylactic reaction or angioedema.
  • Undiagnosed abnormal Genital Bleeding;
  • DVT or PE (current and/or historical of);
  • Active or past history of arterial embombolic disease (eg stroke, MI);
  • Breast cancer (known, suspected, or history of);
  • An estrogen-dependent tumor (known, suspected)
  • Hepatic impairment or disease
  • known antithrombin deficiencies, known protein C and protein S;
  • pregnancy

Canadian labeling: Additional contraindications not in US labeling

  • Endometrial hyperplasia
  • Classic migraine
  • lactation

Warnings and precautions

  • Breast cancer: [US Boxed Warn]

    • Data from the Women's Health Initiative (WHI), shows that postmenopausal women who use conjugated estrogens (CE) and medroxyprogesterone (MPA) have a higher risk of developing invasive breast cancer.
    • Increased breast density may be associated to hormone therapy. An increase in abnormal mammogram findings that require further evaluation has been reported using estrogen alone or in combination.
    • Patients with breast cancer or bone metastases may experience severe hypercalcemia from estrogen use. If this happens, discontinue estrogen.
    • This risk decreases when therapy is stopped, according to observational studies.
    • The WHI study found no evidence of an increase in breast cancer risk for women who had a hysterectomy with CE.
    • Postmenopausal women receiving hormone therapy could be at greater risk for breast cancer due to their estrogen or progestin doses, timing of therapy initiation, length of therapy, route of administration and patient characteristics.
    • Combination hormonal contraceptives have not been proven to reduce breast cancer risk in women who are at high risk due to their family history or susceptibility genes (BRCA1, BRCA2)
    • Breast cancer is a hormone sensitive tumor. Women with a history of breast cancer or a recent diagnosis may have a worse prognosis if they use combination hormonal contraceptives.
    • Patients with breast cancer history or symptoms are advised to avoid this medication.

  • Cervical cancer:

    • Combination hormonal contraceptives may be used by women who are awaiting treatment for cervical carcinoma.
    • Combination hormonal contraceptives have been linked to a slight increase in cervical cancer risk. However, the evidence is inconsistent and could be due to other risk factors.
    • Theoretically, it may influence the prognosis for existing diseases.

  • Chloasma

    • Treatment should be avoided for women who are susceptible to chloasma and other risk factors.
    • Hormone replacement therapy, hormonal combination contraceptives, and sun exposure are all triggers for chloasma.

  • Cholestasis:

    • Cholesteasis risk may increase if there has been a history of cholestasis in pregnancy, or with prior oral contraceptive use.

  • Dementia: [US Boxed Warning]

    • To prevent dementia, it is not a good idea to use estrogens without or with progestin.
    • The Women's Health Initiative Memory Study, (WHIMS), found that women aged >=65 years were more likely to develop dementia if they took CE either alone or in combination.
    • Hormone therapy is not recommended for any age in order to treat or prevent cognitive decline or dementia.
    • The WHI memory studies were performed on women over 65 years old. It is not known if the findings can be applied to younger postmenopausal women.

  • Endometrial Cancer: [US Boxed Warn]

    • Endometrial cancer is more likely to occur in women who have an intact uterus.
    • A progestin may be added to estrogen therapy to reduce the risk of endometrial Hyperplasia, which is a precursor of endometrial carcinoma.
    • To rule out malignancy in women who have undiagnosed abnormal vaginal blood flow, it is important to perform appropriate diagnostic tests, including endometrial sampling, if necessary.
    • A progestin should not be used if low doses are being administered locally to treat vaginal atrophy. However, there are insufficient long-term data (>1 years) supporting this recommendation.
    • Women who use combination hormonal contraceptives have a lower risk of developing endometrial carcinoma.
    • Combination hormonal contraceptives may be used by women who are awaiting treatment for endometrial carcinoma.
    • There is no evidence to suggest that natural estrogens have a different risk profile than synthetic estrogens of equivalent estrogen doses.
    • Endometrial cancer risk appears to be dependent on the duration and dose of treatment. It is highest for patients who have been using therapy for more than 5 years. This may continue even after discontinuation.

  • Endometriosis:

    • Post-hysterectomy with estrogen therapy unopposed has led to malignant transformation of the remaining endometrial implants.
    • Women with endometriosis after hysterectomy should consider adding a progestin.
    • Estrogens may exacerbate endometriosis.

  • The Lipid Effects

    • Combination hormonal contraceptives can increase the risk of pancreatitis in women with hypertriglyceridemia and a family history.
    • Women with uncontrolled dyslipidemia should consider alternative contraception.
    • Combination hormonal contraceptives can adversely affect lipid levels, especially serum triglycerides.
    • Combination hormonal contraceptives can increase the risk of pancreatitis in women with hypertriglyceridemia and a family history.
    • Women with uncontrolled dyslipidemia should consider alternative contraception.

  • Ovarian cancer:

    • The information available regarding the risk of ovarian carcinoma and the use of estrogen/progestin therapy or menopausal estrogen is not consistent.
    • An association may exist, but the risk of developing a serious condition is unlikely. The duration of therapy can also influence the likelihood of an association.
    • Women who use combination hormonal contraceptives have a lower risk of developing ovarian cancer.
    • Women with BRCA1 or BRCA2 mutations may have to use oral contraceptives to lower their risk of developing ovarian cancer.
    • Combination hormonal contraceptives may be used by women awaiting treatment for ovarian carcinoma.

  • Retinal vascular embolism:

    • If you experience an undiagnosed loss of vision, proptosis or diplopia, or retinal vessels lesions, discontinue use immediately and get checked for retinal vein embolism.

  • Thromboembolic disorders

    • If you experience an arterial or vein thrombotic event, discontinue using combination hormonal contraceptives.
    • Women who use combined hormonal contraceptives have a higher risk of developing thrombotic events if they are older than 35 years.
    • Combination hormonal contraceptives can also increase the risk for arterial thrombosis (eg MI, stroke). Women with a history or ischemic heart disease should not use them.
    • Oral contraceptives may increase the risk of venous thromboembolism (risk is greatest during the 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 Ethinylestradiol.
    • Women who have inherited thrombophilias, such as protein C or S deficiency and factor V Leiden mutation, antithrombin deficiencies, or prothrombin mutation, may be at greater risk for venous thromboembolism.
    • Combination hormonal contraceptives are not recommended for women at high risk of venous or arterial thrombotic diseases.

  • Vaginal bleeding

    • There may be occasional missed periods.
    • Unresolved vaginal bleeding is a sign of malignancy and pregnancy.
    • Combination hormonal contraceptives may cause amenorrhea and oligomenorrhea, particularly if the condition was not present previously.
    • In the initial 3 months of therapy, it is possible to experience intra-cyclic bleeding or breakthrough.

  • Abnormal uterine bleeding:

    • A specific treatment for chronic or acute abnormal uterine bleeding (AUB), due to ovulatory dysfunction (not structure-caused) should be considered.
    • Also, consider medical contraindications to the available therapies. Consider if simultaneous contraception or pregnancy is required.

  • Cardiovascular disease: [US-Boxed Warning]

    • To prevent heart disease, estrogens should not be combined with or without progestin.
    • Data from the Women's Health Initiative studies has shown that CE has an increased risk for stroke and deep vein thrombosis.
    • There has also been a reported increase in DVT, stroke and pulmonary emboli (PE) in postmenopausal females between 50 and 79 years old.
    • Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE).
    • You should manage your risk factors well. If you suspect that adverse cardiovascular events may occur, stop using the medication immediately.
    • Before you start treatment for menopausal symptoms, take into account the age, cardiovascular, metabolic, and other risk factors of patients with diabetes.
    • Women at high risk for arterial or vein thrombotic disease may find it contraindicated to use combination hormonal contraceptives.
    • Transdermal administration is preferred to treat vasomotor symptoms associated with menopause in patients at high risk for developing thrombotic events.
    • Women with an active DVT, PE, or arterial thromboembolic diseases (stroke and MI) are not recommended.
    • Patients with cardiovascular risk factors (eg hypertension, low HDL and high LDL cholesterol, older age, diabetes, or women who smoke) should be cautious about using combination hormonal contraceptives.

  • Depression

    • Patients with a history or depression should be cautious; discontinue use if severe depression recurs.

  • Diabetes:

    • Contraceptive use should not be used in women who have concomitant neuropathy, nephropathy, retinopathy or other vascular conditions.
    • Before you start treatment for menopausal symptoms, take into account the age, cardiovascular, metabolic, and other risk factors of patients with diabetes.
    • Women with diabetes mellitus or vascular disease should not use combination hormonal contraceptives.
    • This may impair glucose tolerance. Women with diabetes and prediabetes should be cautious.
    • Combination oral contraceptives have a limited effect on insulin requirements and are not effective for long-term diabetes control in women who do not have nonvascular diseases.

  • Fluid retention can lead to more severe diseases

    • Patients with fluid retention-related diseases, such as cardiac or renal dysfunction, should be cautious.

  • Epilepsy:

    • Epilepsy can be aggravated if you are careful.

  • Gallbladder disease

    • Postmenopausal estrogen use may increase the risk of gallbladder diseases that require surgery.
    • Combination hormonal contraceptives can increase the risk of gallbladder diseases or worsen existing gallbladder diseases.

  • Hepatic adenomas and carcinomas

    • Combination hormonal contraceptives can cause hepatic tumors (rare). A rupture could lead to fatal intra-abdominal bleeding.
    • A higher risk of developing hepatocellular carcinoma in the long term (rare).
    • Preexisting hepatic cancers are not recommended.

  • Hepatic impairment

    • Women with hepatic impairment may not be able to process estrogens properly.
    • If jaundice occurs during treatment or if the liver function is abnormal, discontinue use.
    • Preexisting hepatic diseases are contraindicated.
    • Combination hormonal contraceptives can be used for women with mild (compensated), but not severe (decompensated), cirrhosis.

  • Hepatitis

    • Women with chronic hepatitis have not been shown to experience an increase in the severity or rate of cirrhotic fibrisis.
    • It has been proven that continued use of a drug by women who are carriers does not cause liver disease or severe hepatic dysfunction.
    • Combination hormonal contraceptives are not recommended for women suffering from acute viral hepatitis, flares, or other severe conditions.

  • Hepatic hemomangiomas

    • Patients with hepatic hemomangiomas should be cautious; it may worsen the condition.

  • Hereditary angioedema:

    • Women with hereditary angioedema may experience angioedema symptoms from exogenous estrogens.

  • Hypertension:

    • Hypertension risk may increase with age, dosage, and length of use.
    • Women with mild hypertension (140-159 mmHg systolic, 90-99 mmHg diastolic) and women with moderate hypertension (140-159 mmHg systolic; or hypertension controlled to an acceptable level) may not be at risk.
    • When prescribing contraceptives, it is important to consider other risk factors such as older age, smoking, and diabetes.
    • The manufacturer warns against use in women with uncontrolled hypertension. They recommend monitoring women with well-controlled hypertension. Stop taking the medication if your blood pressure increases significantly.
    • Women with hypertension or vascular disease or persistent blood pressure levels >=160mm Hg Systolic or >=100mm Hg Diastolic should not use combination hormonal contraceptives.

  • Hypoparathyroidism:

    • Hypoparathyroidism patients should be cautious as estrogen-induced hypocalcemia can occur.

  • Migraine

    • Assess new, persistent, severe or recurring headaches.

  • Otosclerosis

    • Women with migraines without aura, including menstrual migraines, may consider using combination hormonal contraceptives.
    • If >35 years old, it is not recommended to be used in women suffering from headaches that have focal neurological symptoms or migraine headaches without or with aura.
    • Patients with otosclerosis should exercise caution.

  • Porphyria

    • Patients with porphyria should be cautious as it can worsen the condition.

  • Transplantation of solid-organs:

    • Even though data is scarce, serious medical complications were reported by women who have had to undergo complicated organ transplants (eg rejection, graft failure and cardiac allograft vasculopathy).
    • Combination hormonal contraceptives are not recommended for women who have had multiple organ transplants.

  • Systemic lupus, erythematosus

    • SLE women are more at risk for heart disease, stroke and VTE.
    • Patients with systemic Lupus Erythematosus (SLE) should be cautious. This could worsen the condition.
    • Women with SLE should not use combination hormonal contraceptives if they have antiphospholipid antibodies. This is because there is a greater risk of arterial or venous embolism.

Ethinyl estradiol and norethindrone: Drug Interaction

Risk Factor C (Monitor therapy)

Ajmaline

Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased.

Anthrax Immune Globulin (Human)

Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human).

Antidiabetic Agents

Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.

Ascorbic Acid

May increase the serum concentration of Estrogen Derivatives.

C1 inhibitors

Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors.

C1 inhibitors

Progestins may enhance the thrombogenic effect of C1 inhibitors.

Chenodiol

Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative.

CloZAPine

CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

Corticosteroids (Systemic)

Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic).

CYP3A4 Inducers (Moderate)

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

CYP3A4 Inhibitors (Moderate)

May increase the serum concentration of Estrogen Derivatives.

CYP3A4 Inhibitors (Strong)

May increase the serum concentration of Estrogen Derivatives.

Dantrolene

Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene.

Deferasirox

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Erdafitinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Flibanserin

Estrogen Derivatives (Contraceptive) may increase the serum concentration of Flibanserin.

Flibanserin

Progestins (Contraceptive) may increase the serum concentration of Flibanserin.

Guanethidine

Estrogen Derivatives (Contraceptive) may diminish the therapeutic effect of Guanethidine.

Herbs (Estrogenic Properties)

May enhance the adverse/toxic effect of Estrogen Derivatives.

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca)

May enhance the adverse/toxic effect of Progestins.

Immune Globulin

Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin.

Lenalidomide

Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide.

Metreleptin

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Metreleptin may increase the serum concentration of Estrogen Derivatives (Contraceptive).

Metreleptin

May decrease the serum concentration of Progestins (Contraceptive). Metreleptin may increase the serum concentration of Progestins (Contraceptive).

Mivacurium

Estrogen Derivatives may increase the serum concentration of Mivacurium.

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.

Proguanil

Ethinyl Estradiol may diminish the therapeutic effect of Proguanil.

ROPINIRole

Estrogen Derivatives may increase the serum concentration of ROPINIRole.

Sarilumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Selegiline

Estrogen Derivatives (Contraceptive) may increase the serum concentration of Selegiline.

Selegiline

Progestins (Contraceptive) may increase the serum concentration of Selegiline.

Siltuximab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Succinylcholine

Estrogen Derivatives may increase the serum concentration of Succinylcholine.

Thalidomide

Estrogen Derivatives (Contraceptive) may enhance the thrombogenic effect of Thalidomide.

Thalidomide

Progestins (Contraceptive) may enhance the thrombogenic effect of Thalidomide.

Thalidomide

Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide.

Theophylline Derivatives

Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline.

Thyroid Products

Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products.

Tocilizumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Ursodiol

Estrogen Derivatives may diminish the therapeutic effect of Ursodiol.

Valproate Products

Estrogen Derivatives (Contraceptive) may decrease the serum concentration of Valproate Products.

Voriconazole

May decrease the metabolism of Estrogen Derivatives (Contraceptive). Estrogen Derivatives (Contraceptive) may increase the serum concentration of Voriconazole.

Voriconazole

May increase the serum concentration of Progestins (Contraceptive). Progestins (Contraceptive) may increase the serum concentration of Voriconazole.

Risk Factor D (Consider therapy modification)

Acitretin

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Given the potential for progestin-only preparations to fail to prevent pregnancy during acitretin therapy, such products should not be relied upon. Alternative, nonhormonal forms of contraception must be employed during acitretin therapy.

Anticoagulants

Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations.

Anticoagulants

Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations.

Aprepitant

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use of a non-hormone-based contraceptive is recommended.

Aprepitant

May decrease the serum concentration of Progestins (Contraceptive). Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose.

Armodafinil

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: The manufacturer recommends that patients use nonhormonal contraceptives, in addition to or in place of hormonal contraceptives, during and for one month following treatment with armodafinil.

Artemether

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether.

Artemether

May decrease the serum concentration of Progestins (Contraceptive). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether.

Asunaprevir

May decrease the serum concentration of Ethinyl Estradiol. Management: For patients using hormone-based contraception, a high-dose oral contraceptive containing at least 30 mcg of ethinyl estradiol combined with norethindrone acetate/norethindrone is recommended during treatment with asunaprevir.

Atazanavir

May increase the serum concentration of Progestins (Contraceptive). However, atazanavir may lead to decreased ethinyl estradiol concentrations and decreased effectiveness of oral contraceptive products. Management: Consider an alternative or additional method of contraception, particularly with combined estrogen/progestin products. Depot medroxyprogesterone acetate may be used without a need for additional contraception.

Barbiturates

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a non-hormonal contraceptive is recommended.

Barbiturates

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended.

Bexarotene (Systemic)

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form).

Bexarotene (Systemic)

May decrease the serum concentration of Progestins (Contraceptive). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form).

Bile Acid Sequestrants

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Administer estrogen-based oral contraceptives at least 1 to 4 hours prior to or 4 to 6 hours after administration of a bile acid sequestrant.

Bile Acid Sequestrants

May decrease the serum concentration of Progestins (Contraceptive). Management: Administer oral progestin-containing contraceptives at least 1 to 4 hours prior to or 4 to 6 hours after administration of a bile acid sequestrant.

Bosentan

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone.

Bosentan

May decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone.

Brigatinib

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Females of childbearing potential should use an alternative, non-hormonal contraceptive during brigatinib therapy and for at least 4 months after the final brigatinib dose.

Brigatinib

May decrease the serum concentration of Progestins (Contraceptive). Management: Females of childbearing potential should use an alternative, non-hormonal contraceptive during brigatinib therapy and for at least 4 months after the final brigatinib dose.

CarBAMazepine

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended.

CarBAMazepine

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended.

Carfilzomib

May enhance the thrombogenic effect of Estrogen Derivatives (Contraceptive). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib.

Carfilzomib

May enhance the thrombogenic effect of Progestins (Contraceptive). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib.

Cladribine

May diminish the therapeutic effect of Hormonal Contraceptives. Management: Women using systemically acting hormonal contraceptives should add a barrier method during cladribine dosing and for at least 4 weeks after the last dose in each treatment course.

CloBAZam

May decrease the serum concentration of Estrogen Derivatives (Contraceptive).

CloBAZam

May decrease the serum concentration of Progestins (Contraceptive).

Cobicistat

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider an alternative, nonhormone-based contraceptive in patients receiving cobicistat-containing products.

Cobicistat

May increase the serum concentration of Progestins (Contraceptive). Management: Consider an alternative, nonhormone-based contraceptive in patients receiving cobicistat containing products. Drospirenone is specifically contraindicated with atazanavir and cobicistat.

Colesevelam

May decrease the serum concentration of Ethinyl Estradiol. Management: Oral contraceptives containing ethinyl estradiol and norethindrone should be administered at least 4 hours before colesevelam.

Colesevelam

May decrease the serum concentration of Norethindrone. Management: Oral contraceptives containing ethinyl estradiol and norethindrone should be administered at least 4 hours before colesevelam.

Cosyntropin

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

CYP3A4 Inducers (Strong)

May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.

Dabrafenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).

Dabrafenib

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Females of reproductive potential should use an alternative, highly effective, nonhormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment.

Dabrafenib

May decrease the serum concentration of Progestins (Contraceptive). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment.

Darunavir

May decrease the serum concentration of Norethindrone.

Efavirenz

May decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction.

Elagolix

Estrogen Derivatives (Contraceptive) may diminish the therapeutic effect of Elagolix. Management: Use an alternative, non-hormonal contraceptive during treatment with elagolix and for at least 1 week following discontinuation of elagolix treatment.

Elvitegravir

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider the use of an alternative, non-hormone-based contraceptive, in patients who are being treated with elvitegravir-containing products.

Enzalutamide

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.

Eslicarbazepine

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Alternative non-hormonal means of birth control should be considered for women of child-bearing potential.

Eslicarbazepine

May decrease the serum concentration of Progestins (Contraceptive). Management: Alternative, non-hormonal means of birth control should be considered for women of child-bearing potential.

Exenatide

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Administer oral contraceptives at least one hour prior to exenatide.

Exenatide

May decrease the serum concentration of Progestins (Oral Contraceptive). Management: Administer oral contraceptives at least one hour prior to exenatide.

Felbamate

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended.

Felbamate

May decrease the serum concentration of Progestins (Contraceptive). Management: Contraceptive failure is possible. Use of an alternative, nonhormonal method of contraception is recommended.

Fosamprenavir

Progestins (Contraceptive) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Progestins (Contraceptive). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception.

Fosaprepitant

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with fosaprepitant or aprepitant and for at least one month following the last fosaprepitant/aprepitant dose.

Fosaprepitant

May decrease the serum concentration of Progestins (Contraceptive). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose.

Fosphenytoin

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended.

Fosphenytoin

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended.

Hyaluronidase

Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required.

Ivosidenib

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib.

Ivosidenib

May decrease the serum concentration of Progestins (Contraceptive). Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib.

LamoTRIgine

Estrogen Derivatives (Contraceptive) may decrease the serum concentration of LamoTRIgine. Management: Monitor for increased serum concentrations/effects of lamotrigine in patients in whom a hormonal contraceptive is discontinued/dose decreased (this includes during a pill-free week). A reduced dosage of lamotrigine may be needed.

Lesinurad

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception.

Lesinurad

May decrease the serum concentration of Progestins (Contraceptive). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception.

Lixisenatide

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide.

Lixisenatide

May decrease the serum concentration of Progestins (Contraceptive). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide.

Lomitapide

Ethinyl Estradiol 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.

Lopinavir

May decrease the serum concentration of Progestins (Contraceptive). Lopinavir may increase the serum concentration of Progestins (Contraceptive). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate and etonogestrel implants may be used without a need for additional contraception.

Lorlatinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.

Lumacaftor

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required.

Lumacaftor

May decrease the serum concentration of Progestins (Contraceptive). Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required.

MiFEPRIStone

May diminish the therapeutic effect of Progestins (Contraceptive). MiFEPRIStone may increase the serum concentration of Progestins (Contraceptive). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment.

MiFEPRIStone

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). MiFEPRIStone may increase the serum concentration of Estrogen Derivatives (Contraceptive). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment.

Mitotane

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.

Modafinil

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: The manufacturer recommends that patients use nonhormonal contraceptives, in addition to or in place of hormonal contraceptives, during and for one month following treatment with modafinil.

Mycophenolate

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Average AUC values were unchanged, but there was evidence of substantial patient-to-patient variability in response to this combination. Management: Women of childbearing potential who are receiving mycophenolate mofetil should consider using an alternative and/or additional form of contraception.

Mycophenolate

May decrease the serum concentration of Progestins (Contraceptive). Management: Use of an additional or alternative (nonhormonal) method of contraception should be considered.

Nafcillin

May increase the metabolism of Estrogen Derivatives (Contraceptive). Management: Use of an alternative, nonhormonal form of contraception during nafcillin therapy is recommended.

Nelfinavir

May decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction.

Nevirapine

May decrease the serum concentration of Estrogen Derivatives (Contraceptive).

Nevirapine

May decrease the serum concentration of Progestins (Contraceptive). Management: Instruct patients receiving nevirapine to use an alternative or additional nonhormonal contraceptive. Nevirapine product labeling however suggests that depo-medroxyprogesterone acetate may be used as a sole method of contraception.

OXcarbazepine

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal contraceptive is recommended.

OXcarbazepine

May decrease the serum concentration of Progestins (Contraceptive). Management: Contraceptive failure is possible. Use of an additional or alternative, nonhormonal method of contraception is recommended.

Perampanel

May decrease the serum concentration of Progestins (Contraceptive). Management: Patients should use an alternative, nonhormonal-based form of contraception both during the concurrent use of perampanel and for 1 month after discontinuing perampanel.

Phenytoin

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended.

Phenytoin

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended.

Pitolisant

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Management: The combination of hormonal contraceptives with pitolisant should be avoided, and an alternate means of contraception should be used.

Pitolisant

May diminish the therapeutic effect of Progestins (Contraceptive). Management: The combination of hormonal contraceptives with pitolisant should be avoided, and an alternate means of contraception should be used.

Pitolisant

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.

Pomalidomide

May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations.

Pomalidomide

Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations.

Primidone

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended.

Protease Inhibitors

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use oral contraceptives containing at least 35mcg ethinyl estradiol with atazanavir/ritonavir, or no more than 30mcg in patients receiving atazanavir alone. Use of an alternative, non-hormonal contraceptive is recommended with other protease inhibitors. Exceptions: Indinavir.

Retinoic Acid Derivatives

May diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical).

Rifamycin Derivatives

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal contraceptive is recommended.

Rifamycin Derivatives

May decrease the serum concentration of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended.

Rufinamide

May decrease the serum concentration of Ethinyl Estradiol.

Rufinamide

May decrease the serum concentration of Norethindrone.

Saquinavir

May decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction.

St John's Wort

May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Consider an alternative to St John's wort if possible. If this combination is used, an alternative, nonhormonal contraceptive is recommended.

St John's Wort

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Consider using a product other than St John's wort. Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended.

St John's Wort

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.

Sugammadex

May decrease the serum concentration of Progestins (Contraceptive). 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.

Sugammadex

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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.

Tipranavir

Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception.

Tipranavir

May increase the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction.

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.

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).

Topiramate

May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Risk appears greatest for higher topiramate doses (200 mg/day or greater). Some have recommended using at least 50 mcg/day of ethinyl estradiol, but the effectiveness of this is unclear. Consider a nonhormonal form of contraception.

Topiramate

May decrease the serum concentration of Progestins (Contraceptive). Management: Caution patients that this combination may be associated with reduced contraceptive effectiveness. Consider adding an additional (non-hormonal) contraceptive method.

Vitamin K Antagonists (eg, warfarin)

Estrogen Derivatives (Contraceptive) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products.

Vitamin K Antagonists (eg, warfarin)

Progestins (Contraceptive) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive.

Risk Factor X (Avoid combination)

Anastrozole

Estrogen Derivatives may diminish the therapeutic effect of Anastrozole.

Antihepaciviral Combination Products

Ethinyl Estradiol may enhance the hepatotoxic effect of Antihepaciviral Combination Products. Management: Use of ethinyl estradiol must be discontinued prior to use of this combination; ethinyl estradiol can be restarted 2 weeks after cessation of the antihepaciviral combination product.

Dasabuvir

Ethinyl Estradiol may enhance the hepatotoxic effect of Dasabuvir.

Dehydroepiandrosterone

May enhance the adverse/toxic effect of Estrogen Derivatives.

Encorafenib

May decrease the serum concentration of Estrogen Derivatives (Contraceptive).

Encorafenib

May decrease the serum concentration of Progestins (Contraceptive).

Exemestane

Estrogen Derivatives may diminish the therapeutic effect of Exemestane.

Glecaprevir and Pibrentasvir

Ethinyl Estradiol may enhance the adverse/toxic effect of Glecaprevir and Pibrentasvir. Specifically, the risk for ALT elevation may be increased with this combination.

Griseofulvin

May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible.

Hemin

Estrogen Derivatives may diminish the therapeutic effect of Hemin.

Indium 111 Capromab Pendetide

Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide.

Ixazomib

May decrease the serum concentration of Progestins (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of contraceptive progestins. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment.

Ospemifene

Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene.

Tranexamic Acid

Progestins (Contraceptive) may enhance the thrombogenic effect of Tranexamic Acid.

Tranexamic Acid

Estrogen Derivatives (Contraceptive) may enhance the thrombogenic effect of Tranexamic Acid.

Ulipristal

May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal.

 

Monitoring parameters:

Hormonal contraceptives:

  • Assessment of pregnancy status (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.

If all doses have not been taken on schedule and one menstrual period is missed, the possibility of pregnancy should be considered. If 2 consecutive menstrual periods are missed, access 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.
  • Adequate diagnostic measures should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

Postmenopausal indications:

  • Prior to therapy, baseline risk for breast cancer and CVD.
  • During therapy, age-appropriate breast, and pelvic exams;
  • blood pressure;
  • unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer);
  • serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL);
  • TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement).

Menopausal symptoms:

  • Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate.
  • The duration of treatment should be evaluated at least annually.

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms of menopause Prevention of osteoporosis:

  • Bone density measurement

How to administer Ethinyl estradiol and norethindrone?

Combination hormonal contraceptives:

  • Administer at the same time each day at intervals, not >24 hours; without regard to meals.
  • The Femcon Fe tablet may be chewed or swallowed whole; if chewed, immediately drink a full glass of liquid (240  mL) after swallowing.
  • For some products (eg, Femcon Fe, Generess Fe, Lo Loestrin Fe), if vomiting or diarrhea occurs within 3 to 4 hours of a dose, consider the dose to be missed.
  • For the 21-tablet package, one dose is taken for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken.
  • For the 28-tablet package, one dose is taken daily without interruption.

Combined hormonal contraceptives may be initiated at any time during the menstrual cycle if it is reasonably sure the woman is not pregnant. Back-up contraception should be used for 7 days unless contraception is initiated within the first 5 days of menstrual bleeding or the woman abstains from sexual intercourse. Combined hormonal contraceptives may be started immediately following or within a weak of a first or second-trimester abortion; backup contraception is needed for 7 days unless contraception is started at the time of the surgical abortion.

Postmenopausal indications:

  • Administer at the same time each day.

Mechanism of action of Ethinyl estradiol and norethindrone:

  • Combination oral contraceptives can inhibit ovulation through a negative feedback mechanism on hypothalamus.
  • This alters the normal pattern gonadotropin production of a follicle stimulating hormone (FSH), and luteinizing hormone from the anterior pituitary.
  • FSH in the follicular phase and a midcycle surge with gonadotropins is inhibited. 
  • Combination hormonal contraceptives can also cause alterations in the genital system, including cervical mucus changes, which makes it difficult for sperm penetration, even if there is ovulation.
  • Endometrium changes can also happen, which could lead to unfavorable conditions for nidation. 
  • Combination hormonal contraceptives may affect the tubal transport and function of the ova through fallopian tubes. 
  • The fertility of sperm may also be affected by progestational drugs.
  • Exogenous estrogen can be used to replace the loss of endogenous estrogen in postmenopausal females. 
  • Women with intact uterus can reduce the risk of endometrial carcinoma and endometrial hyperplasia by adding progestin.

Norethindrone: See individual monograph.

Ethinyl estradiol:

Absorption:

  • Rapid

Bioavailability:

  • 43% to 55%

Protein binding:

  • more than 95 percent to albumin

Metabolism:

  • Hepatic via oxidation and conjugation in GI tract; hydroxylated via CYP3A4 to metabolites; first-pass effect; enterohepatic recirculation; reversibly converted to estrone and estriol

Half-life elimination:

  • 19 to 24 hours

Excretion:

  • Urine (as estriol,estradiol and estrone);
  • feces

International Brand Names of Ethinyl estradiol and norethindrone:

  • Alyacen 1/35
  • Blisovi 24 Fe
  • Blisovi Fe 1.5/30
  • Blisovi FE 1/20
  • Brevicon (28)
  • Briellyn
  • Cyclafem 1/35
  • Cyclafem 7/7/7
  • Dasetta 1/35
  • Dasetta 7/7/7
  • Estrostep Fe
  • Alyacen 7/7/7
  • Aranelle
  • Aurovela 1.5/30
  • Aurovela 1/20
  • Aurovela 24 FE
  • Aurovela FE 1/20
  • Balziva
  • Femcon Fe
  • Femhrt Low Dose
  • Fyavolv
  • Generess FE
  • Gildagia
  • Gildess 1.5/30
  • Gildess 1/20
  • Gildess 24 FE
  • Gildess FE 1.5/30
  • Gildess FE 1/20
  • Hailey 24 Fe
  • Kaitlib Fe
  • Larin 1.5/30
  • Larin 1/20
  • Larin 24 FE
  • Larin Fe 1.5/30
  • Larin Fe 1/20
  • Layolis FE
  • Leena
  • Lo Loestrin Fe
  • Loestrin 1.5/30 (21)
  • Loestrin 1/20 (21)
  • Loestrin Fe 1.5/30
  • Loestrin Fe 1/20
  • Lomedia 24 FE
  • Melodetta 24 Fe
  • Mibelas 24 Fe
  • Microgestin 1.5/30
  • Jevantique Lo
  • Jinteli
  • Junel 1.5/30
  • Junel 1/20
  • Junel FE 1.5/30
  • Junel FE 1/20
  • Junel Fe 24
  • Microgestin 1/20
  • Microgestin 24 Fe
  • Microgestin FE 1.5/30
  • Microgestin FE 1/20
  • Minastrin 24 Fe
  • Modicon (28)
  • Necon 0.5/35 (28)
  • Necon 1/35 (28)
  • Necon 10/11 (28)
  • Necon 7/7/7
  • Norinyl 1+35 (28)
  • Nortrel 0.5/35 (28)
  • Nortrel 1/35 (21)
  • Nortrel 1/35 (28)
  • Nortrel 7/7/7
  • Ortho-Novum 1/35 (28)
  • Ortho-Novum 7/7/7 (28)
  • Ovcon-35 (28)
  • Philith
  • Pirmella 1/35
  • Pirmella 7/7/7
  • Tarina 24 Fe
  • Tarina FE 1/20
  • Tarina FE 1/20 EQ
  • Taytulla
  • Tilia Fe
  • Brevicon 1/35
  • FemHRT
  • Loestrin 1.5/30
  • Lolo
  • Minestrin 1/20
  • Ortho 0.5/35
  • Ortho 1/35
  • Ortho 7/7/7
  • Select 1/35
  • Synphasic
  • Brevinor
  • Covina
  • Estracomb
  • Estragest TTS
  • Eveclin Half
  • Eveprem
  • Eviclin
  • Evorel Cont
  • Evorel Conti
  • Evorel Sequi
  • Evorelconti
  • Lunabell
  • Micropil
  • Tri-Legest Fe
  • Tri-Norinyl (28)
  • Vyfemla
  • Wera
  • Wymzya Fe
  • Zenchent FE
  • Zenchent
  • Brevicon 0.5/35
  • Norimin
  • Ortho 7 7 7
  • Ortho-Novum 1 35
  • Ortho-Novum 1/35
  • Ovysmen
  • Ovysmen 0.5 35
  • Trisequens;
  • Trisequens Forte
  • Ovysmen 1 35
  • Synphase-2
  • Synphasic 28
  • Tri-Sequens
  • Triella
  • Trinovum
  • Trisekvens

Ethinyl estradiol and norethindrone Brand Names in Pakistan:

There is no brand available in Pakistan.

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