etonogestrel/ethinyl estradiol

Action and Spectrum

Actions and Spectrum: 

etonogestrel is a synthetic progestin hormone that acts similarly to natural progesterone. Its primary mechanism of action is to suppress ovulation, the release of an egg from the ovary during the menstrual cycle. By inhibiting ovulation, etonogestrel prevents the availability of an egg for fertilization, reducing the risk of pregnancy. Additionally, etonogestrel thickens the cervical mucus, making it more difficult for sperm to penetrate the cervix and reach the egg. 

ethinyl estradiol is a synthetic estrogen hormone that mimics the effects of natural estrogen in the body. One of its key actions is to suppress the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. This suppression inhibits the maturation of eggs in the ovaries and, combined with the progestin, prevents ovulation. 

Spectrum of Activity 

etonogestrel and ethinyl estradiol combination pills are highly effective as a reversible method of contraception, providing reliable birth control when taken as directed. The combination pills do not protect against sexually transmitted infections (STIs) and should be used alongside barrier methods, such as condoms, for dual protection. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Vaginitis (13.8%) 

Headache (11.2%) 

1-10% 

Vaginal discharge (5.7%) 

Vaginal discomfort (4%) 

Dysmenorrhea (3.5%) 

Acne (2.4%) 

Nausea (5.9%) 

Increased weight (4.9%) 

Breast discomfort (3.8%) 

Abdominal pain (3.2%) 

Decreased libido (2%) 

Black Box Warning

Black box warning: 

• Cardiovascular Risks: Combination oral contraceptives have been associated with an increased risk of blood clots (venous thromboembolism), heart attacks, and strokes, particularly in individuals with other risk factors such as smoking, hypertension, and obesity. 
• Cigarette Smoking: Smoking while using combination oral contraceptives increases the risk of severe cardiovascular side effects, especially in women over 35 years of age. 

Contraindication / Caution

Contraindications/caution: 

• History of Blood Clots: etonogestrel and ethinyl estradiol combination pills have a slightly increased risk of blood clots compared to non-users. 
• Known or Suspected Breast Cancer: These contraceptive pills are contraindicated in individuals with known or suspected breast cancer because of the potential for hormonal stimulation of breast tissue. 
• Severe Liver Disease: Liver disease can impair the metabolism of hormones, and these pills should not be used in individuals with severe liver dysfunction or liver tumors. 
• History of Cardiovascular Disorders: Individuals with a history of heart attacks, strokes, angina, or certain heart valve disorders may have an increased risk of cardiovascular events with hormonal contraceptives and should discuss alternative contraceptive options with their healthcare provider. 
• Uncontrolled Hypertension (High Blood Pressure): Hormonal contraceptives can sometimes lead to elevated blood pressure, and individuals with uncontrolled hypertension should avoid using these pills. 
• Migraine with Aura: People with a history of migraines with neurological symptoms known as aura should avoid hormonal contraceptives because they can increase the risk of stroke in this population. 
• Diabetes with Vascular Complications: Hormonal contraceptives can worsen vascular complications in individuals with diabetes, particularly those with diabetic retinopathy or nephropathy. 
• Smokers over 35: Smoking while using hormonal contraceptives, especially in individuals over 35, increases the risk of cardiovascular complications. 

Caution: 

• Use Caution in Patients with Diseases Exacerbated by Fluid Retention (e.g., migraine, diabetes, renal dysfunction, and epilepsy). 
• Consider Postpartum Thromboembolism Risk and Ovulation Timing. 
• The Vaginal Ring (NuvaRing) may not be suitable for women with conditions that make the vagina more susceptible to irritation or ulceration. 
• NuvaRing users have reported Toxic Shock Syndrome (TSS); seek medical evaluation and treatment if TSS symptoms occur. 
• Do not use the product in women with severe liver disease (e.g., acute viral hepatitis or decompensated cirrhosis of the liver); monitor liver function and discontinue use if jaundice develops. 
• Use Caution with Concomitant Hepatitis C Treatment; discontinue use before starting specific drug regimens. 
• Monitor Blood Pressure, especially in older women or with extended duration of use; discontinue use if blood pressure rises significantly. 
• Hypersensitivity reactions of anaphylaxis and angioedema have been reported; discontinue use and treat accordingly. 
• Carefully monitor prediabetic and diabetic women using the product; CHCs may decrease glucose tolerance. 
• Consider alternative contraception for women with uncontrolled dyslipidemia. 
• Consider discontinuation for an increased frequency or severity of migraines during CHC use. 
• Breast Cancer: Epidemiology studies have not found a consistent association between combined oral contraceptives (COCs) and breast cancer risk. However, some studies report a small increase in risk among current users. 

Pregnancy / Lactation

Pregnancy considerations: These pills should not be used if a person is already pregnant. They are not intended for use as emergency contraception but are meant for ongoing contraception in non-pregnant individuals. 

Lactation: Excretion of the drug in human breast milk is known. 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

Combined oral contraceptives containing etonogestrel and ethinyl estradiol are taken daily to provide continuous hormone levels throughout the menstrual cycle. By combining progestin and estrogen, these pills offer a highly effective and reversible method of contraception. They prevent pregnancy by inhibiting ovulation, thickening cervical mucus, and altering the uterine lining to make it less receptive to implantation. 

Pharmacodynamics:  

etonogestrel (progestin): 

• Progesterone Receptor Agonist: etonogestrel acts as an agonist at progesterone receptors. Binding to these receptors exerts progestogenic effects similar to natural progesterone. 
• Suppression of Ovulation: One of the primary pharmacodynamic actions of etonogestrel is the inhibition of ovulation. It suppresses the release of luteinizing hormone (LH) from the pituitary gland, which prevents the dominant follicle in the ovary from maturing and releasing an egg (ovulation). 
• Cervical Mucus Thickening: etonogestrel thickens the cervical mucus, making it more difficult for sperm to penetrate the cervix and reach the egg in the fallopian tubes. 
• Endometrial Changes: etonogestrel alters the endometrial lining, reducing its receptivity to implantation in case fertilization occurs. 

ethinyl estradiol (estrogen): 

• Estrogen Receptor Agonist: ethinyl estradiol acts as an agonist at estrogen receptors. It mimics the effects of natural estrogen in the body. 
• Suppression of Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH): ethinyl estradiol suppresses the secretion of FSH and LH from the pituitary gland. This prevents the development and maturation of follicles in the ovaries and inhibits ovulation. 
• Endometrial Stabilization: ethinyl estradiol helps stabilize the endometrial lining of the uterus, reducing the likelihood of breakthrough bleeding and ensuring proper cycle control. 

Pharmacokinetics: 

Absorption 

etonogestrel is absorbed rapidly and entirely after subdermal insertion of contraceptive implants, such as Nexplanon. Once inserted, etonogestrel is released into the bloodstream at a controlled rate, providing contraceptive efficacy for an extended period. ethinyl estradiol is well-absorbed from the gastrointestinal tract after oral administration in combination with oral contraceptive pills. 

Distribution 

Both etonogestrel and ethinyl estradiol are extensively distributed in the bloodstream. They are bound to proteins, with ethinyl estradiol having a high protein-binding capacity (98%) and etonogestrel being approximately 32% bound to sex hormone-binding globulin (SHBG) and 66% to albumin. 

Metabolism 

etonogestrel undergoes metabolism in the liver via the CYP3A4 enzyme to form metabolites. ethinyl estradiol is metabolized in the liver by cytochrome P450 enzymes, primarily CYP3A4, to form various metabolites. 

Elimination and Excretion 

Both etonogestrel and ethinyl estradiol and metabolites are primarily excreted in the urine and feces. 

Adminstartion

Administration: 

Intravaginal administration 

Initial Use and Timing:  

• Before using the intravaginal ring for the first time, consider the possibility of ovulation and conception.  
• Insert one NuvaRing in the vagina; it should remain in place continuously for three weeks (21 days). 
• Remove the ring after three weeks for a one-week break, during which withdrawal bleeding is common. 
• A new ring should be inserted one week after the last ring was removed to maintain contraceptive efficacy. 

Starting NuvaRing: 

• It can be started on the first day of menstrual bleeding. 
• Alternatively, it can be started on Days 2-5 of the menstrual cycle, but in this case, a barrier method should be used for the first seven days of the ring’s use in the first cycle. 

Switching from Other Contraceptives: 

• Switching from other combination hormonal contraceptives (CHCs) at any time is possible, but it must be done no later than the day after the customary gap of hormone-free time. 
• Switching from progestin-only contraceptives requires specific instructions and additional barrier method use for the first seven days. 

Use after Abortion, Miscarriage, or Childbirth: 

• Different timing rules apply after abortion, miscarriage, or childbirth, considering the risk of thromboembolism and pregnancy. 

Inadvertent Removal or Expulsion: 

• The effectiveness of the contraceptive ring is unaffected if it accidentally falls out and is placed outside the vagina for less than three hours. The ring should be thoroughly cleaned before being reinserted.  
• During weeks 1 and 2, if the ring is removed for over three hours, employ a barrier technique until the ring has been worn consistently for seven days. Week 3’s instructions are precise. 

Prolonged Ring-Free Interval or Prolonged Use of the Ring: 

• Prolonged ring-free intervals or prolonged use of the ring beyond four weeks require specific actions to rule out pregnancy and ensure contraceptive efficacy. 

Ring Breakage: 

• If the ring breaks or disconnects, vaginal discomfort or expulsion may occur. Discard the ring and replace it with a new one. 

Missed Menstrual Period: 

• Adherence to the prescribed regimen is important. If there are missed menstrual periods, rule out pregnancy as appropriate. 

Use with Other Vaginal Products:  

• Using a diaphragm as a backup contraceptive method is not recommended as it may interfere with the correct placement of the ring. Tampons do not affect the systemic absorption of hormones released by the ring. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: etonogestrel/ethinyl estradiol 

Why do we use etonogestrel/ethinyl estradiol? 

etonogestrel and ethinyl estradiol are synthetic hormones combined with oral contraceptive pills and contraceptive devices like the intravaginal ring (e.g., NuvaRing). Their primary use is to prevent pregnancy. When used correctly and consistently, they are highly effective at preventing ovulation, thickening cervical mucus to impede sperm penetration, and altering the uterine lining to prevent implantation if fertilization occurs. 

Combination oral contraceptives containing etonogestrel and ethinyl estradiol can be used for the following non-contraceptive benefits: 

• Menstrual Cycle Regulation: Combination oral contraceptives can help regulate menstrual cycles, making them more predictable and reducing the intensity of menstrual cramps and flow. 
• Reduced Menstrual Pain: They can alleviate symptoms of dysmenorrhea (painful periods) by suppressing ovulation and reducing the release of prostaglandins responsible for uterine contractions. 
• Acne Treatment: Combining oral contraceptives may improve acne in some individuals by regulating hormones contributing to acne development. 
• Management of Hormonal Imbalance: They can be used to address conditions like polycystic ovary syndrome (PCOS), a hormonal disorder affecting ovulation and menstrual regularity. 
• Endometriosis Management: Combination oral contraceptives can help control the growth of endometrial tissue outside the uterus, reducing pain and inflammation associated with endometriosis. 
• Premenstrual Syndrome (PMS) Relief: By regulating hormone levels, they can alleviate symptoms of PMS like mood swings, bloating, and breast tenderness.