Brevinor-1
Brevinor-1 Uses, Dosage, Side Effects, Food Interaction and all others data.
Ethinylestradiol was first synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering. It was developed in an effort to create an estrogen with greater oral bioavailability. These properties were achieved by the substitution of an ethinyl group at carbon 17 of estradiol. Ethinylestradiol soon replaced mestranol in contraceptive pills.
Ethinylestradiol was granted FDA approval on 25 June 1943.
Ethinylestradiol is a synthetic estrogen that decreases luteinizing hormone to decrease endometrial vascularization, and decreases gonadotrophic hormone to prevent ovulation. It has a long duration of action as it is taken once daily, and a wide therapeutic index as overdoses are generally not associated with serious adverse effects. Patients should be counselled regarding the risks of thrombotic events.
Norethisterone has typical effects of a progestogen and converts the endometrium from the proliferative to the secretory phase. It may also have some oestrogenic, anabolic and androgenic activities, but these may not be significant. Norethisterone delays onset of periods and controls abnormal uterine bleeding. It also has contraceptive effects due to negative feedback inhibition of pituitary gonadotropin thus preventing ovulation.
Norethisterone is a synthetic oral progestin used for contraception or to treat other hormone-related conditions such as menopausal symptoms and endometriosis. As a synthetic progestin, norethisterone acts similarly to endogenous progesterone but with a much higher potency - it acts at the pelvic level to alter cervical and endometrial function, as well as via the inhibition of pituitary hormones that play a role in follicular maturation and ovulation. A small increase in the risk of developing breast cancer has been observed in patients using combined oral contraceptives, with some evidence also implicating progestin-only pills - patients starting hormonal contraception should be advised of this risk and should employ routine breast self-examinations to check for evidence of any developing masses.
| Trade Name | Brevinor-1 |
| Generic | norethisterone + ethinylestradiol |
| Type | |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | Australia |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Ethinylestradiol is an estradiol used as a contraceptive.
Ethinylestradiol is combined with other drugs for use as a contraceptive, premenstrual dysphoric disorder, moderate acne, moderate to severe vasomotor symptoms of menopause, prevention of postmenopausal osteoporosis.
Norethisterone is used for:
- Dysfunctional uterine bleeding (DUB)
- Premenstrual syndrome (PMS), Mastopathy
- Timing of menstruation
- Endometriosis
- Menorrhagia
Brevinor-1 is also used to associated treatment for these conditions: Menopausal Osteoporosis, Mild to Moderate Acne, Premenstrual Dysphoric Disorder ( PMDD), Moderate Acne vulgaris, Moderate, severe, Vasomotor Symptoms caused by Menopause, Contraception, Folate supplementation therapyEndometriosis related pain, Moderate to Severe Vasomotor Symptoms, Osteoporosis, Postmenopausal Osteoporosis, Vulvovaginal Atrophy, Hypoestrogenism, Moderate, severe, Vasomotor Symptoms caused by Menopause, Contraception, Hormone Replacement Therapy, Oral Contraceptives
How Brevinor-1 works
Ethinylestradiol is a synthetic estrogenic compound. Use of estrogens have a number of effects on the body including reduced bone density. Combined oral contraceptives suppress ovulation by suppressing gonadotrophic hormone, thickening cervical mucus to prevent the travel of sperm, and preventing changes in the endometrium required for implantation of a fertilized egg. Ethinylestradiol decreases luteinizing hormone, decreasing vascularity in the endometrium. It also increases sex hormone binding globulin.
On a molecular level, progestins like norethisterone exert their effects on target cells via binding to progesterone receptors that result in downstream changes to target genes. Target cells are found in the reproductive tract, breast, pituitary, hypothalamus, skeletal tissue, and central nervous system. Contraceptive efficacy is derived mainly from changes to the cervical mucus, wherein norethisterone increases the cell content and viscosity of the mucous to impede sperm transport and migration. Norethisterone also induces a variety of changes to the endometrium - including atrophy, irregular secretion, and suppressed proliferation - that make it inhospitable for implantation. Working via a negative feedback loop, norethisterone also acts on both the hypothalamus and anterior pituitary to suppress the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Suppression of these hormones prevents follicular development, ovulation, and corpus luteum development.
When used as a component of hormone replacement therapy in menopausal women, norethisterone’s value is mainly in suppressing the growth of the endometrium. As estrogen stimulates endometrial growth, the unopposed use of estrogen in postmenopausal women with an intact uterus can lead to endometrial hyperplasia which can increase the risk of endometrial cancer. The addition of a progestin to a hormone replacement therapy in this population protects against this endometrial hyperplasia and, therefore, lowers the risk associated with the use of hormone replacement therapies.
Norethisterone, along with other progestins and endogenous progesterone, has a low affinity for other steroid receptors, such as the androgen receptor and glucocorticoid receptor. While affinity and agonistic activity at these receptors is minimal, it is thought that androgen receptor agonism is responsible for some of the adverse effects observed with progestin use (e.g. acne, serum lipid changes).
Dosage
Brevinor-1 dosage
Breast cancer: 40 mg daily increasing to 60 mg daily if no regression is noted.
Contraception: 0.35 mg daily, or 0.5-1 mg daily when combined with oestrogen. As acetate: 0.6 mg daily, or 1-1.5 mg daily when combined with oestrogen.
Premenstrual syndrome: 5 mg tid on days 16-25 of cycle.
Progestogen component of menopausal hormonal replacement therapy: 0.7 mg as a continuous daily dose. As acetate: 1 mg daily for 10-12 days of a 28-day cycle.
Endometriosis: 10-25 mg daily continuously for 4-9 month. As acetate: 5-15 mg daily, start at 5 mg daily and increase by 2.5 mg at 14 day intervals. Take continuously for 4-9 month.
Menorrhagia: 10-15 mg daily in a cyclical regimen. Usual dose: 5 mg tid for 10 days as primary treatment, subsequently 5 mg bid on days 19-26 of cycle to prevent recurrence. As acetate: 2.5-10 mg daily in a cyclical regimen, beginning during the assumed latter half of the cycle.
Postponement of menstruation: 5 mg tid starting 3 days before expected onset of menstruation.
Side Effects
Mental depression, cholestatic jaundice, porphyria, epilepsy, migraine, headache, breast discomfort, dizziness, nausea and vomiting, changes in libido, appetite and weight, breakthrough bleeding, changes in menstrual flow, amenorrhoea, oedema, rash, melasma or cholasma, acne, urticaria, abnormal LFTs, moodswings, insomnia, thrombotic and thromoembolic events, optic neuritis, altered lipid profile.
Toxicity
Female patients experiencing and overdose may present with withdrawal bleeding, nausea, vomiting, breast tenderness, abdominal pain, drowsiness, and fatigue. Overdose should be treated with symptomatic and supportive care including monitoring for potassium concentrations, sodium concentrations, and signs of metabolic acidosis.
The oral LD50 in mice 6 g/kg and the TDLo in human women is 42 mg/kg. There have been no reports of serious ill effects following overdose of oral contraceptives, including following ingestion by children. Symptoms of overdosage are likely to be consistent with the adverse effect profile of the contraceptive and may, therefore, include significant nausea and/or vomiting.
Precaution
Hypertension; CVS disease; hepatic impairment; epilepsy; lactation; new onset of migraine-type headache; asthma; renal impairment; history of clinical depression.
Interaction
Concentration may be reduced by CYP450 inducers (e.g. phenobarbital, phenytoin, carbamazepine, rifampicin, rifabutin, nevirapine, efavirenz, tetracyclines, ampicillin, oxacillin, co-trimoxazole) and ritonavir, nelfinavir (usually inhibitors of CYP450 but have inducing properties when used with steroid hormones). May cause additive fluid retention with NSAIDs, vasodilators. Adjustment in antidiabetic, thyroid hormone and anticoagulant therapy may be required.
Volume of Distribution
A 30µg oral dose has an apparent volume of distribution of 625.3±228.7L and a 1.2mg topical dose has an apparent volume of distribution of 11745.3±15934.8L.
The volume of distribution of norethisterone is approximately 4 L/kg. Sulfated metabolites of norethisterone, as well as small quantities of parent drug, have been shown to distribute into breast milk.
Elimination Route
A 30µg oral dose of ethinylestradiol reaches a Cmax of 74.1±35.6pg/mL, with a Tmax of 1.5±0.5h, and an AUC of 487.4±166.6pg*h/mL. A 1.2mg dose delivered via a patch reaches a Cmax of 28.8±10.3pg/mL, with a Tmax of 86±31h, and an AUC of3895±1423pg*h/mL.
The Cmax of norethisterone following oral administration of a single dose ranges from 5.39 to 7.36 ng/mL with a Tmax of 1-2 hours. AUC0-24 values following single oral doses range from approximately 30 to 37 ng*hr/mL. The oral bioavailability of norethisterone is approximately 64%. When applied transdermally, norethisterone is well-absorbed through the skin, reaches steady-state concentrations within 24 hours, and has a Cmax ranging from 617 to 1060 pg/mL at steady state.
Norethisterone is often formulated as norethisterone acetate, which is completely and rapidly deacetylated to norethisterone following oral administration - the disposition of norethisterone acetate is indistinguishable from that of orally administered norethisterone.
Half Life
A 30µg oral dose has a half life of 8.4±4.8h and a 1.2mg topical dose has a half life of 27.7±34.2h.
The half-life of norethisterone has been variably estimated as 8-10 hours.
Clearance
Ethinylestradiol has an intravenous clearance of 16.47L/h, and an estimated renal clearance of approximately 2.1L/h. A 30µg oral dose has a clearance of 58.0±19.8L/h and a 1.2mg topical dose has a clearance of 303.5±100.5L/h.
The plasma clearance of norethisterone has been estimated as 0.4 L/hr/kg, and the intrinsic clearance is approximately 73-81 L/h.
Elimination Route
Ethinylestradiol is 59.2% eliminated in the urine and bile, while 2-3% is eliminated in the feces. Over 90% of ethinylestradiol is eliminated as the unchanged parent drug.
Following administration of radio-labeled norethisterone, slightly more than 50% of the administered dose was eliminated in the urine and 20-40% was eliminated in the feces.
Pregnancy & Breastfeeding use
Pregnancy Category X. Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Contraindication
Norethisterone should not be used in the presence of the conditions listed below, which are derived also from information on other progestogen-only products. Should any of the conditions appear during the use of Norethisterone, the use of the preparation must be discontinued immediately.
- Known or suspected pregnancy
- Lactation
- Thromboembolic processes
- Diabetes mellitus with vascular involvement
- Presence or history of severe hepatic disease as long as liver function values have returned to normal
- Presence or history of liver tumors (benign or malignant)
- Known or suspected sex-hormone dependent malignancies
- Hypersensitivity to the active substances or to any of the excipients
Acute Overdose
Acute toxicity studies performed with norethisterone acetate did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose.
Storage Condition
Store in a cool and dry place, protected from light and moisture. Keep out of reach of children
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