VANCI TABLETS

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
• Management of acne
• Management of hirsutism

Mechanism of action

Drospirenone and ethinyl estradiol in combination suppress the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation. Drospirenone also alters cervical mucus consistency, hindering sperm movement, and reducing the likelihood of embryo implantation. Its anti-mineralocorticoid activity, achieved through blocking aldosterone receptors, promotes sodium and water excretion. Furthermore, its antiandrogenic activity inhibits dihydrotestosterone (DHT) binding to its receptor, reducing androgen synthesis in the ovaries, which aids in treating acne and hirsutism.

Pharmacodynamics

Drospirenone inhibits follicle maturation and ovulation, leading to effective pregnancy prevention. Its antiandrogen effects improve conditions like acne and hirsutism. When combined with ethinyl estradiol, it positively influences the plasma lipid profile. Drospirenone is associated with fewer adverse effects typical of progesterone contraceptives, such as breast tenderness and mood swings. However, it may increase the risk of venous thromboembolism and hyperkalemia, especially in smokers or women over 35, necessitating caution in high-risk populations.

Pharmacokinetics

Drospirenone is well-absorbed after oral administration, with peak plasma concentrations usually occurring within 1-2 hours. It has a half-life of approximately 30 hours, allowing for once-daily dosing in combination oral contraceptive formulations. The drug is metabolized in the liver, primarily via cytochrome P450 enzymes, and its metabolites are excreted primarily through urine. Due to its antimineralocorticoid properties, caution is advised in patients with renal impairment or those on medications that may increase potassium levels.

Contra-indications

• Pregnancy
• Severe liver disease
• History of thrombosis or thromboembolic disorders
• Known or suspected breast cancer or other hormone-sensitive malignancies
• Uncontrolled hypertension
• Hyperkalemia

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Mood changes
• Weight gain
• Vaginal bleeding irregularities
• Increased risk of venous thromboembolism

Interactions

• dronedarone+drospirenone: Unknown (increases exposure)
• cobicistat+drospirenone: Unknown (increases exposure)
• crizotinib+drospirenone: Unknown (increases exposure)
• idelalisib+drospirenone: Unknown (increases exposure)
• imatinib+drospirenone: Unknown (increases exposure)
• letermovir+drospirenone: Unknown (increases exposure)
• nilotinib+drospirenone: Unknown (increases exposure)

Precautions

• Monitor for signs of hyperkalemia, especially in patients with renal impairment or those on potassium-sparing diuretics
• Assess risk factors for thromboembolic events, especially in women over 35 years and smokers
• Regular monitoring of blood pressure

Pregnancy

Drospirenone is contraindicated in pregnancy. It should not be used during this time due to potential risks to the fetus.

Breast-feeding

Drospirenone may be excreted in breast milk. Caution is advised when administering to breastfeeding women, and it is recommended to consult healthcare providers.

Storage

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

Formulations

• Oral tablets containing drospirenone, often in combination with ethinyl estradiol

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.

Mechanism of action

Drospirenone and ethinyl estradiol in combination suppress the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation. Other changes induced by this drug which may aid in the prevention of pregnancy include alterations in cervical mucus consistency, hindering sperm movement, and lowering the chance of embryo implantation. Drospirenone is an analog of the diuretic spironolactone, which exerts anti-mineralocorticoid activity, blocking aldosterone receptors, which increases sodium and water excretion. Studies in animals have demonstrated that drospirenone administration leads to antiandrogenic activity. This activity helps to oppose the effects of naturally occurring androgens, inhibiting the binding of dihydrotestosterone (DHT) to its receptor, and preventing androgen synthesis in the ovaries, helping to treat acne and hirsutism. Drospirenone may also decrease the level of edema in sebaceous follicle during the second half of the menstrual cycle, when acne often appears. Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation). Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity. Acne vulgaris is a skin condition with a multifactorial etiology including androgen stimulation of sebum production. While the combination of ethinyl estradiol and drospirenone increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the antiandrogenic activity of drospirenone on acne is not known. .... The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This pro

Pharmacodynamics

Drospirenone inhibits the maturation of follicles and inhibits ovulation, preventing pregnancy. It has antiandrogen effects, improving acne and hirsutism. When combined with ethinyl estradiol, it has been shown to have favorable effects on the plasma lipid profile. Due to its similarity to naturally occurring progesterone, drospirenone is thought to be associated with a lower incidence of progesterone contraceptive related adverse effects, such as breast tenderness and mood swings. **A note on venous thromboembolism risk and antimineralcorticoid effects** As with other oral contraceptives, the risk of venous thromboembolism and cardiovascular events may be increased when drospirenone is taken. The risk is especially higher in smokers and women aged 35 and older. Women taking this drug should be advised not to smoke. In addition, drospirenone, due to its antimineralcorticoid effects, may increase the risk of hyperkalemia. Patients at high risk for hyperkalemia should not be administered this drug. Consult the official prescribing information for detailed and updated information on the cardiovascular and other risks associated with drospirenone use.

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.