DUOFEM COMBINATION PRODUCT TABLET

Indications

• Menopausal symptoms
• Osteoporosis prophylaxis
• Irregular menstruation
• Vulvovaginal atrophy
• Postmenopausal urogenital conditions

Dosage

Adults: The typical adult dosage of estradiol is 2 mg daily, initiated on day 1-5 of the menstrual cycle or at any time if cycles have ceased or are infrequent, taken with

Mechanism of action

Estradiol exerts its effects by binding to estrogen receptors, specifically estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), as well as the G protein-coupled estrogen receptor (GPER). This binding triggers the receptor-ligand complex to translocate to the nucleus, where it regulates gene transcription and the synthesis of specific proteins that mediate estradiol's physiological effects.

Pharmacodynamics

Estradiol acts on estrogen receptors to alleviate vasomotor symptoms such as hot flashes and urogenital symptoms including vaginal dryness. It has beneficial effects on bone density by inhibiting bone resorption and improving plasma lipid profiles. Additionally, estradiol decreases follicle-stimulating hormone (FSH) levels by suppressing its formation in the anterior pituitary gland. Notably, it may increase the risk of cardiovascular events, venous thromboembolism, and stroke, necessitating caution in high-risk populations.

Pharmacokinetics

Estradiol is rapidly absorbed when administered orally, with a bioavailability affected by first-pass metabolism in the liver. It is extensively metabolized in the liver, conjugated to form estrone and estrone sulfate, and eliminated through urine. The half-life of estradiol varies depending on the route of administration, with peak plasma concentrations occurring within 1-3 hours post-administration. Continuous use can lead to accumulation and requires careful monitoring of therapy duration and dosage adjustments.

Contra-indications

• History of thromboembolic disorders
• Known or suspected estrogen-dependent tumors
• Undiagnosed abnormal genital bleeding
• Severe liver dysfunction
• Pregnancy

Adverse effects

• Nausea
• Headaches
• Weight changes
• Breast tenderness
• Mood alterations
• Vaginal discharge
• Oedema
• Skin reactions
• Thromboembolic events
• Cerebrovascular accidents
• Endometrial hyperplasia
• Angioedema

Interactions

• Antiepileptics (carbamazepine, phenytoin, etc.) may decrease efficacy of estradiol
• Bosentan may decrease efficacy of estradiol
• Modafinil may decrease efficacy of estradiol
• Rifamycins may decrease efficacy of estradiol
• St. John's Wort may decrease efficacy of estradiol
• Ritonavir may decrease efficacy of estradiol

Precautions

• Monitor for signs of thromboembolic events
• Evaluate for endometrial hyperplasia in women with a uterus
• Consider cardiovascular risks before initiating therapy
• Assess liver function prior to use
• Use with caution in patients with a history of depression

Pregnancy

Estradiol is contraindicated in pregnancy due to potential harm to the fetus and increased risk of thromboembolic events.

Breast-feeding

Estradiol is excreted in breast milk; caution is advised when used by nursing mothers as it may affect milk production.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets (1 mg, 2 mg)
• Vaginal ring (continuous use, replaced every 3 months)

Indications

• Contraception
• Regulation of menstrual cycles
• Management of polycystic ovary syndrome
• Management of endometriosis

Dosage

Children: Refer to the BNF for Children for appropriate pediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing guidelines, as doses may vary based on formulation and indication.

Mechanism of action

Ethinyl estradiol exerts its effects by binding to estrogen receptors in target tissues, leading to changes in gene expression. This action promotes the development of secondary sexual characteristics and regulates the menstrual cycle. It also inhibits ovulation by suppressing gonadotropin release from the pituitary gland, thereby reducing follicular maturation and ovum release.

Pharmacodynamics

Ethinyl estradiol influences the reproductive system by stabilizing the endometrial lining, making it less conducive to implantation. It also affects the cervical mucus, making it thicker and less penetrable to sperm. The pharmacodynamic effects are dose-dependent, contributing to contraceptive efficacy and menstrual regulation.

Pharmacokinetics

Ethinyl estradiol is well-absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 to 2 hours after oral administration. It undergoes extensive first-pass metabolism in the liver, resulting in a bioavailability of approximately 40-60%. The drug is primarily metabolized by cytochrome P450 enzymes, particularly CYP3A4, and has a half-life of about 13 to 27 hours. Ethinyl estradiol is excreted mainly in urine and feces.

Interactions

• fostemsavir + ethinylestradiol from a combined hormonal contraceptive: Moderate (increases concentration)

Pregnancy

Ethinyl estradiol is generally not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Ethinyl estradiol may pass into breast milk; caution is advised.

Storage

Store at room temperature, away from light and moisture.

Indications

• Contraception
• Management of menstrual disorders
• Hormonal replacement therapy
• Prevention of endometrial carcinoma

Dosage

Adults: For contraception, the usual dosage is one tablet containing 0.3 mg of norgestrel taken orally once daily. For emergency contraception, norgestrel is typically administered as a single dose of 1.5

Mechanism of action

Norgestrel acts by binding to progesterone and androgen receptors, which suppresses gonadotropins and inhibits ovulation. It slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, thereby reducing the luteinizing hormone (LH) surge that is necessary for ovulation. Additionally, norgestrel increases the thickness of cervical mucus, making it more difficult for sperm to enter the uterus, and induces changes in the endometrium that prevent implantation of a fertilized egg.

Pharmacodynamics

Norgestrel effectively prevents pregnancy by interfering with ovulation, fertilization, and implantation. The oral contraceptive containing norgestrel is approximately 89% effective when used within 72 hours after unprotected intercourse. Long-acting forms such as intrauterine devices (IUDs) and implants that release norgestrel demonstrate over 99% efficacy in preventing pregnancy. Furthermore, norgestrel helps prevent endometrial carcinoma in women receiving unopposed estrogen therapy.

Pharmacokinetics

Following oral administration, norgestrel is rapidly absorbed, with peak plasma concentrations typically reached within 1 to 2 hours. It has a half-life of approximately 33 hours, allowing for once-daily dosing in contraceptive regimens. Norgestrel undergoes hepatic metabolism, primarily through the cytochrome P450 system, and is excreted in urine and feces. Its bioavailability can be influenced by factors such as food intake and individual metabolic variations.

Contra-indications

• Pregnancy
• Unexplained vaginal bleeding
• Active liver disease
• Thromboembolic disorders
• Known or suspected breast cancer

Adverse effects

• Nausea
• Vomiting
• Breast tenderness
• Headache
• Irregular menstrual bleeding
• Fatigue
• Dizziness

Interactions

• Antibiotics (e.g., rifampicin, rifabutin)
• Anticonvulsants (e.g., carbamazepine, phenytoin)
• HIV protease inhibitors (e.g., ritonavir)
• St. John's Wort

Precautions

• Use with caution in patients with a history of depression
• Monitor for signs of thromboembolic events
• Consider risks versus benefits in patients with cardiovascular disease
• Assess for potential drug interactions

Pregnancy

Levonorgestrel is contraindicated in pregnancy. It is not effective for terminating an existing pregnancy and should not be used as an abortifacient.

Breast-feeding

Levonorgestrel is excreted in breast milk. It is generally considered safe to use during breastfeeding, but monitoring of the infant for any potential effects is advisable.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets (e.g., emergency contraceptive)
• Intrauterine device (IUD)
• Implantable contraceptive

Mechanism of action

Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women. Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems. Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. ... After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Estrogens have an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression. Biologic response is initiated when estrogen binds to a ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription through specific estrogen response elements (ERE) of target gene promoters; subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains (ie, AF-1 and AF-2) of the receptor. The estrogen receptor also mediates gene transcription using different response elements (ie, AP-1) and other signal pathways. Recent advances in the molecular pharmacology of estrogen and estrogen receptors have resulted in the development of selective estrogen receptor modulators (eg, clomiphene, raloxifene, tamoxifen, toremifene), agents that bind and activate the estrogen receptor but that exhibit tissue-specific effects distinct from estrogen. Tissue-specific estrogen-agonist or -antagonist activity of these drugs appears to be related to structural differences in their estrogen receptor

Pharmacodynamics

Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia). Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland. **A note on hyper-coagulable state, cardiovascular health, and blood pressure** Estradiol may cause an increased risk of cardiovascular disease, DVT, and stroke, and its use should be avoided in patients at high risk of these conditions. Estrogen induces a hyper-coagulable state, which is also associated with both estrogen-containing oral contraceptive (OC) use and pregnancy. Although estrogen causes an increase in levels of plasma renin and angiotensin. Estrogen-induced increases in angiotensin, causing sodium retention, which is likely to be the mechanism causing hypertension after oral contraceptive treatment.

Mechanism of action

**Mechanism of action on ovulation** Oral contraceptives containing levonorgestrel suppress gonadotropins, inhibiting ovulation. Specifically, levonorgestrel binds to progesterone and androgen receptors and slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This process results in the suppression of the normal physiological luteinizing hormone (LH) surge that precedes ovulation. It inhibits the rupture of follicles and viable egg release from the ovaries. Levonorgestrel has been proven to be more effective when administered before ovulation. **Mechanism of action in cervical mucus changes** Similar to other levonorgestrel-containing contraceptives, the intrauterine (IUD) forms of levonorgestrel likely prevent pregnancy by increasing the thickness of cervical mucus, interfering with the movement and survival of sperm, and inducing changes in the endometrium, where a fertilized ovum is usually implanted. Levonorgestrel is reported to alter the consistency of mucus in the cervix, which interferes with sperm migration into the uterus for fertilization. Levonorgestrel is not effective after implantation has occurred. Interestingly, recent evidence has refuted the commonly believed notion that levonorgestrel changes the consistency of cervical mucus when it is taken over a short-term period, as in emergency contraception. Over a long-term period, however, levonorgestrel has been proven to thicken cervical mucus. The exact mechanism of action of levonorgestrel is not completely understood and remains a topic of controversy and ongoing investigation. *Effects on implantation** The effects of levonorgestrel on endometrial receptivity are unclear, and the relevance of this mechanism to the therapeutic efficacy of levonorgestrel is contentious. Prescribing information for levonorgestrel IUDs state that they exert local morphological changes to the endometrium (e.g. stromal pseudodecidualization, glandular atrophy) that may play a role in their contraceptive activity. **Mechanism of action in hormone therapy** When combined with estrogens for the treatment of menopausal symptoms and prevention of osteoporosis, levonorgestrel serves to lower the carcinogenic risk of unopposed estrogen therapy via the inhibition of endometrial proliferation. Unregulated endometrial proliferation sometimes leads to endometrial cancer after estrogen use. Norgestrel (and more specifically the active stereoisomer levonorgestrel) binds to the progesterone and estrogen receptors within the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins like levonorgestrel will slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge. Loss of the LH surge inhibits ovulation and thereby prevents pregnancy. Combination oral contraceptives act by suppression of gonadotrophins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cer-vical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which may reduce the likelihood of implantation). Progestins enter target cells by passive diffusion and bind to cytosolic (soluble) receptors that are loosely bound in the nucleus. The steroid receptor complex initiates transcription, resulting in an increase in protein synthesis. /Progestins/ Progestins are capable of affecting serum concentrations of other hormones, particularly estrogen. Estrogenic effects are modified by the progestins, either by reducing the availability or stability of the hormone receptor complex or by turning off specific hormone-responsive genes by direct interaction with the progestin receptor in the nucleus. In addition, estrogen priming is necessary to increase progestin effects by upregulating the number of progestin receptors and/or increasing progesterone product

Pharmacodynamics

Levonorgestrel prevents pregnancy by interfering with ovulation, fertilization, and implantation. The levonorgestrel-only containing emergency contraceptive tablet is 89% effective if it is used according to prescribing information within 72 hours after intercourse. The intrauterine and implantable devices releasing levonorgestrel are more than 99% in preventing pregnancy. Levonorgestrel utilized as a component of hormonal therapy helps to prevent endometrial carcinoma associated with unopposed estrogen administration.