PREMPAC-C 0.625MG TABLET

Indications

• Menopausal symptoms
• Vulvar and vaginal atrophy
• Prevention of osteoporosis in postmenopausal women
• Hypoestrogenism due to hypogonadism or castration

Dosage

Children: Conjugated estrogens are not typically indicated for use in the pediatric population. Refer to specialized resources for any off-label use.

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

Mechanism of action

Conjugated estrogens exert their effects primarily through binding to estrogen receptors, leading to the activation of estrogen-responsive genes. This binding triggers a cascade of biological responses that promote the development and maintenance of female reproductive tissues, regulation of the menstrual cycle, and other systemic effects such as bone density maintenance and modulation of cholesterol levels.

Pharmacodynamics

The pharmacodynamics of conjugated estrogens involve their role in modulating gene expression within estrogen-responsive tissues. They help to alleviate symptoms associated with menopause, such as hot flashes and vaginal dryness, and play a critical role in bone health by inhibiting osteoclast activity, thus reducing bone resorption and helping to prevent osteoporosis.

Pharmacokinetics

Following oral administration, conjugated estrogens are absorbed through the gastrointestinal tract. They undergo first-pass metabolism in the liver, which can affect their bioavailability. The half-life of conjugated estrogens varies, but they generally have a half-life of several hours. They are metabolized primarily in the liver and excreted in urine. The pharmacokinetics can be influenced by factors such as age, liver function, and concurrent medications.

Contra-indications

• Known hypersensitivity to conjugated estrogens or any of the excipients
• Estrogen-dependent neoplasms, including breast cancer
• Undiagnosed abnormal genital bleeding
• Active or past venous thromboembolic disorders
• Severe liver dysfunction or disease
• Pregnancy

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Abdominal cramps
• Bloating
• Mood changes
• Increased risk of thromboembolic events
• Hypertension
• Cholestatic jaundice
• Gallbladder disease

Interactions

• Anticoagulants may have altered effects
• Certain anticonvulsants may reduce efficacy of estrogen therapy
• Rifampicin and other enzyme inducers may decrease effectiveness
• St. John's Wort may decrease hormone levels

Precautions

• Monitor patients for signs of thromboembolic disorders
• Assess risk factors for cardiovascular disease
• Evaluate liver function before and during treatment
• Consider individual patient history of breast cancer or other estrogen-sensitive conditions

Pregnancy

Conjugated estrogens are contraindicated in pregnancy due to risk of fetal harm.

Breast-feeding

Conjugated estrogens may be excreted in breast milk; use with caution in breastfeeding women.

Storage

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

Formulations

• Oral tablets
• Injectable forms

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

Indications

• Hormone replacement therapy in menopausal women
• Contraception in combination with progestins
• Management of estrogen receptor-positive breast cancer
• Treatment of hypogonadism in women

Mechanism of action

Oestrogens exert their effects by binding to oestrogen receptors (ERα and ERβ) located in various tissues, including reproductive organs, bones, and the cardiovascular system. Upon binding, the oestrogen-receptor complex translocates to the nucleus, where it regulates the transcription of target genes involved in cell growth, differentiation, and metabolism. This action influences various physiological processes such as menstrual cycle regulation, bone density maintenance, and lipid metabolism.

Pharmacodynamics

Oestrogens have multiple effects on different tissues. In the reproductive system, they promote the growth and maturation of the endometrium, regulate ovulation, and maintain pregnancy. In bone tissue, oestrogens inhibit osteoclast activity, reducing bone resorption and helping to maintain bone density. They also have a positive effect on lipid profiles by increasing high-density lipoprotein (HDL) and decreasing low-density lipoprotein (LDL) levels, thus providing cardiovascular protection.

Pharmacokinetics

Oestrogens are absorbed well after oral administration, with peak plasma concentrations occurring within a few hours. They undergo extensive first-pass metabolism in the liver, resulting in variable bioavailability. Oestrogens are primarily metabolized in the liver through conjugation, forming glucuronides and sulfates, which are then excreted in the urine. The elimination half-life varies depending on the specific oestrogen used, but typically ranges from a few hours to a day. Oestrogens can also be administered via transdermal patches, intramuscular injections, or vaginal routes to bypass first-pass metabolism.

Contra-indications

• Known or suspected pregnancy
• Active or past history of thromboembolic disorders
• Severe liver disorders
• Estrogen-dependent tumors
• Uncontrolled hypertension
• Undiagnosed vaginal bleeding
• History of stroke or myocardial infarction

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Mood changes
• Weight gain
• Increased risk of thromboembolic events
• Hypertension
• Chloasma
• Gastrointestinal disturbances

Interactions

• Anticonvulsants (e.g., phenobarbital, phenytoin) which may decrease estrogen levels
• Antibiotics (e.g., rifampicin) that can reduce the efficacy of estrogen
• Corticosteroids which may have altered metabolism when used with estrogens
• Certain herbal supplements (e.g., St. John's Wort) that may affect estrogen activity

Precautions

• Monitor for signs of thromboembolic events
• Consider risk factors for cardiovascular disease
• Assess liver function before and during therapy
• Evaluate the risk of estrogen-dependent tumors
• Use with caution in patients with a history of depression

Pregnancy

Estrogens should not be used during pregnancy as they may cause harm to the fetus.

Breast-feeding

Estrogens can be excreted in breast milk; caution is advised when used during breastfeeding.

Storage

Store in a cool, dry place away from light, at room temperature.

Formulations

• Tablets
• Transdermal patches
• Injectable formulations
• Topical gels or creams

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.