Norinyl-1

Uses

Mestranol is a synthetic estradiol found in oral contraceptive pills for contraception and the treatment of other conditions in the female reproductive system, such as dysmenorrhea and dysfunctional uterine bleeding.

Mestranol was used as one of the first oral contraceptives.

Norethisterone is used for:

• Dysfunctional uterine bleeding (DUB)
• Premenstrual syndrome (PMS), Mastopathy
• Timing of menstruation
• Endometriosis
• Menorrhagia

Norinyl-1 is also used to associated treatment for these conditions: Abnormal Uterine Bleeding, Endometriosis, Hypermenorrhea, Menstrual Distress (Dysmenorrhea), Polycystic Ovarian Syndrome, Oral ContraceptivesEndometriosis 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 Norinyl-1 works

Mestranol is the 3-methyl ether of ethinylestradiol. Ethinylestradiol, is a synthetic derivative of estradiol. Ethinylestradiol is orally bio-active and the estrogen used in almost all modern formulations of combined oral contraceptive pills. It binds to (and activates) the estrogen receptor. Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver with a conversion efficiency of 70%.

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. The combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH).

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

Norinyl-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

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

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

The C_max of norethisterone following oral administration of a single dose ranges from 5.39 to 7.36 ng/mL with a T_max of 1-2 hours. AUC_0-24 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 C_max 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

The half-life of norethisterone has been variably estimated as 8-10 hours.

Clearance

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

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

Innovators Monograph

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