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Ethinyl estradiol tablets for oral use

Summary about Ethinyl estradiol

Ethinyl Estradiol is a semisynthetic estrogen. Ethinyl estradiol binds to the estrogen receptor complex and enters the nucleus, activating DNA transcription of genes involved in estrogenic cellular responses. This agent also inhibits 5-alpha reductase in epididymal tissue, which lowers testosterone levels and may delay progression of prostatic cancer. In addition to its antineoplastic effects, ethinyl estradiol protects against osteoporosis. In animal models, short-term therapy with this agent has been shown to provide long-term protection against breast cancer, mimicking the antitumor effects of pregnancy.

Ethinyl estradiol is marketed mostly as a combination oral contraceptive under several brand names such as Alesse, Tri-Cyclen, Triphasil, and Yasmin. The FDA label includes a black box warning that states that combination oral contraceptives should not be used in women over 35 years old who smoke due to the increased risk of serious cardiovascular side effects.

Combined oral contraceptives (COC) are a common treatment for polycystic ovary syndrome (PCOS) and have a long history of use in this group of patients. Adolescents and women with PCOS have a number of different clinical symptoms that play a role in their daily quality of life. Excessive hair growth, irregular and unpredictable menses, acne and weight gain are all part of the clinical constellation seen in this population. COC has long been considered a first line of therapy for women experiencing these symptoms and who do not wish to get pregnant. 

 

 

The key mechanism of COC action is folliculogenesis inhibition through either suppression of pituitary gonadtorophin secretion or direct influence on ovarian function when the COC agent has weaker anti-gonadotrapin activity. COC can also lead to a decrease in circulating albumin levels, leading to a decrease in dehydroepiandrosterone sulphate (DHEAS), which is strongly bound to albumin and androgen production and a decrease in peripheral androgen production through an inhibition of 5α reductase in the skin and a subsequent decrease in dihydrotestosterone levels. The combined effect is an overall decrease in gonadotropins and resulting androgens, which is a major goal of PCOS treatment. In addition, the estrogen component of COC increases sex hormone binding globulin (SHBG) production by the liver, which in turn reduces the circulating levels of free testosterone and its bioavailability.

 

 

Ethinyl estradiol

Active Ingredient

Ethinyl estradiol

Administration Route

Oral

Alcohol Warning

The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction, which is unpredictable.

Available Strength

0,02 mg, 0,05 mg, 0,5 mg

Breastfeeding Warning

Use is not recommended.

Excreted into human milk: Yes

Clinical Pharmacology

Pharmacodynamics

Ethinyl estradiol is a synthetic derivative of the natural estrogen estradiol. It is one of two estrogens currently used in oral contraceptive pills. The other, mestranol, is converted to ethinyl estradiol before it is biologically active. Ethinyl estradiol and norethindrone are used together as an oral contraceptive agent.

Pharmacokinetics 

Absorption: Rapid and complete

Protein binding: 98.3%, primarily bound to albumin

Metabolism: Hepatic; forms metabolites

Bioavailability: ~83%; Bioavailability of ethinyl estradiol is increased with biphasic and triphasic preparations

Half-life elimination: 26 ± 6.8 hours

Time to peak: 1.5 ± 0.8 hours; Time to peak varies by day in cycle for biphasic and triphasic preparations

Excretion: rine and feces (as metabolites)

Cost

No data

Dosage Form

Tablets  of 0,02 mg, 0,05 mg, 0,5 mg for oral use

Dose Schedule

In general, estrogen should be given cyclically and in some cases with progestogen or androgen to avoid overstimulation of breast and endometrial tissues. The addition of sufficient progestogen to promote conversion of the endometrium is mandatory in those patients who are receiving sufficient unopposed estrogen to cause vaginal bleeding or endometrial hyperplasia. Obviously, abnormal vaginal bleeding in such patients is an indication for prompt diagnostic measures.

For the relief of menopausal symptoms, administer 5 or 10 g of ethinyl estradiol daily for 21 days, followed by a 7 day period without medication.

Dosage may require adjustment as therapy progresses. Use the lowest effective dosage and assess the requirement for estrogen therapy periodically.

Drug Class

G03AA — Progestogens and estrogens

Drug Unit

mg 

Food Warning

Minor interaction. Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

Included In
Health Insurance Plan

No data.

Interacting Drugs

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

  • Dasabuvir
  • Ombitasvir
  • Paritaprevir
  • Ritonavir
  • Tranexamic Acid

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Anagrelide
  • Aprepitant
  • Boceprevir
  • Bosentan
  • Bupropion
  • Carbamazepine
  • Ceritinib
  • Conivaptan
  • Dabrafenib
  • Darunavir
  • Dexamethasone
  • Donepezil
  • Encorafenib
  • Enzalutamide
  • Fosaprepitant
  • Fosnetupitant
  • Fosphenytoin
  • Glecaprevir
  • Griseofulvin
  • Isotretinoin
  • Ivosidenib
  • Lesinurad
  • Lixisenatide
  • Lumacaftor
  • Mitotane
  • Modafinil
  • Nafcillin
  • Netupitant
  • Nevirapine
  • Oxcarbazepine
  • Paclitaxel
  • Paclitaxel Protein-Bound
  • Phenobarbital
  • Phenytoin
  • Pibrentasvir
  • Piperaquine
  • Pitolisant
  • Pixantrone
  • Prednisone
  • Primidone
  • Rifabutin
  • Rifampin
  • St John’s Wort
  • Sugammadex
  • Theophylline
  • Tizanidine
  • Topiramate
  • Valproic Acid

Is Available Generically

Yes. 

Is Proprietary

No.

Label Details

https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB00977.pdf?1371680618 

Legal Status

Legal.

Is not subject to the Controlled Substances Act.

Manufacturer

Schering Plough

Maximum Intake

10 g for 21 days

Mechanism of Action

Estrogens diffuse into their target cells and interact with a protein receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. This cascade is initiated by initially binding to the estrogen receptors. The combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH).

Non Proprietary Name

Ethinyl estradiol

Overdosage

Overdose may cause following side effects:
  • Breast pain (in females and males)
  • fast heartbeat
  • fever
  • hives
  • hoarseness
  • increased breast size (in females and males)
  • irritation of the skin
  • itching of the skin
  • joint pain, stiffness, or swelling
  • rash
  • redness of the skin
  • shortness of breath
  • swelling of the eyelids, face, lips, hands, or feet
  • swelling of the feet and lower legs
  • tightness in the chest
  • troubled breathing or swallowing
  • weight gain (rapid)
  • wheezing

Pregnancy Category


If a woman becomes pregnant while taking this drug, therapy should be withdrawn immediately.AU TGA pregnancy category: B3
US FDA pregnancy category: XAU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Pregnancy Warning

Use is contraindicated in pregnant women. Hormonal contraceptives are used to prevent pregnancy; treatment should be discontinued if pregnancy occurs. In general, the use of combination hormonal contraceptives, when inadvertently used early in pregnancy, have not been associated adverse fetal or maternal effects

Prescribing Info

https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB00977.pdf?1371680618

Prescription Status

Prescription only

Proprietary Name

Quartete, Alesse, Tri-Cyclen, Triphasil, Yasmin.

Related Drugs

Estradiol, Dienogest, Chlormadinone, Nomegestrol

RxCUI

312880

2186

1233720

218591

210142

210141

4124

16728

210140

Warning

Vascular risks: Stop Ethynil estradiol if a thrombotic event occurs. Stop using this drug at least 4 weeks before and through 2 weeks after major surgery. Start Ethynil estradiol no earlier than 4 weeks after delivery, in women who are not breastfeeding.

Liver disease: Discontinue Ethynil estradiol if jaundice occurs. 

High blood pressure: Do not prescribe Ethynil estradiol for women with uncontrolled hypertension or hypertension with vascular disease. 

Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Ethynil estradiol. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. 

Headache: Evaluate significant change in headaches and discontinue Ethynil estradiol if indicated. (5.6)

Uterine bleeding: Evaluate irregular bleeding or amenorrhea

 

References:

Drugs.com [Internet]. Ethynil estradiol Information from Drugs.com; c1996-2019 [Updated: 6 December 2018, Cited: 7 December 2019]. Available from: https://www.drugs.com/pregnancy/ethinyl-estradiol.html

Drugbank.ca [Internet]. Ethynil estradiol Information from Drugbank.ca; c1996-2019 [Updated: 6 December 2019, Cited: 7 December 2019]. Available from: https://www.drugbank.ca/drugs/DB00977

Mathur R, Levin O, Azziz R. Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome. Ther Clin Risk Manag. 2008;4(2):487–492. doi:10.2147/tcrm.s6864

Hofmann B, Reinecke I, Schuett B, Merz M, Zurth C. Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive. Int J Clin Pharmacol Ther. 2014;52(12):1059–1070. doi:10.5414/CP202064

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