NOVELLA

Indications

• Contraception
• Hormone replacement therapy
• Management of menstrual disorders
• Treatment of acne in women
• Regulation of menstrual cycles

Dosage

Children: Refer to the BNF for Children for specific dosing information applicable to pediatric patients

Adults: The typical adult dosing for contraceptive purposes is one tablet daily, usually taken for 21 days followed by a 7-day break, during which withdrawal bleeding occurs. Refer to specific product guidelines for variations in dosing.

Mechanism of action

Ethinylestradiol works by binding to estrogen receptors in estrogen-responsive tissues, leading to a suppression of gonadotrophic hormones, which in turn inhibits ovulation. It thickens cervical mucus to impede sperm travel and alters the endometrial lining, making it less suitable for implantation. Additionally, it decreases luteinizing hormone levels, reducing endometrial vascularization, and increases sex hormone binding globulin levels.

Pharmacodynamics

As a synthetic estrogen, ethinylestradiol exhibits properties similar to endogenous estrogens, affecting various tissues in the body. It modulates the menstrual cycle by decreasing the secretion of luteinizing hormone and preventing ovulation, thus demonstrating a selective action with a long duration of effect when administered daily. The therapeutic index is wide, typically allowing for safe use at recommended doses, although there is a notable risk of thrombotic events associated with estrogen use.

Pharmacokinetics

Ethinylestradiol is well-absorbed after oral administration, undergoing first-pass metabolism in the liver, which influences its bioavailability. It has a half-life that allows for once-daily dosing, leading to stable plasma concentrations. Metabolism occurs primarily in the liver, and it is excreted in urine as metabolites. The drug's pharmacokinetic profile supports its use in contraceptive regimens, ensuring effective hormone levels are maintained throughout the dosing period.

Contra-indications

• History of thromboembolic disorders
• Severe hypertension
• Active liver disease
• Known or suspected pregnancy
• Estrogen-dependent tumors

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Weight gain
• Mood changes
• Thromboembolic events

Interactions

• Antibiotics may reduce the effectiveness of ethinylestradiol
• Anticonvulsants may decrease plasma concentrations
• St. John's Wort may reduce effectiveness

Precautions

• Monitor for signs of thromboembolism
• Caution in patients with a history of migraines
• Monitor blood pressure regularly
• Consider risks versus benefits in patients with liver disease

Pregnancy

Ethinylestradiol is contraindicated during pregnancy due to potential harm to the fetus.

Breast-feeding

Use is not recommended during breastfeeding as it may reduce milk production.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Tablets
• Combined oral contraceptive formulations

Indications

• Contraception
• Emergency contraception
• Menorrhagia management

Dosage

Children: For females of childbearing potential, the dosage for emergency contraception is the same as for adults, 1.5 mg as a single dose. For long-term contraception, consult the BNF

Adults: For emergency contraception, a single dose of 1.5 mg should be taken as soon as possible after unprotected intercourse, preferably within 12 hours but no later than 72 hours. For contraception, the recommended dose may vary based on the specific formulation and patient needs, refer to the BNF for specific guidelines.

Mechanism of action

Levonorgestrel suppresses gonadotropins, inhibiting ovulation by binding to progesterone and androgen receptors, and slowing the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This leads to the suppression of the luteinizing hormone (LH) surge necessary for ovulation. Additionally, it increases the thickness of cervical mucus, hindering sperm movement and survival, and induces changes in the endometrium that prevent implantation of a fertilized egg.

Pharmacodynamics

Levonorgestrel effectively prevents pregnancy through multiple mechanisms: by interfering with ovulation, fertilization, and implantation. The emergency contraceptive tablet is approximately 89% effective when taken within 72 hours after unprotected intercourse, while IUDs releasing levonorgestrel demonstrate over 99% effectiveness. It also serves a therapeutic role in preventing endometrial carcinoma associated with unopposed estrogen therapy.

Pharmacokinetics

Levonorgestrel is rapidly absorbed after oral administration, with peak plasma concentrations typically achieved within 1 to 2 hours. It has a half-life of approximately 24 hours and is metabolized in the liver. The drug is primarily excreted via urine and feces, and its pharmacokinetic profile can be affected by certain enzyme-inducing medications.

Contra-indications

• Pregnancy
• Severe liver disease
• Known or suspected hormone-sensitive malignancies
• Undiagnosed vaginal bleeding

Adverse effects

• Nausea
• Vomiting
• Fatigue
• Headache
• Dizziness
• Breast tenderness
• Mood changes
• Abdominal pain
• Changes in menstrual bleeding

Interactions

• Antiepileptics (carbamazepine, eslicarbazepine, fosphenytoin, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, topiramate) may decrease efficacy
• Bosentan may decrease efficacy
• Ritonavir may decrease efficacy
• Lamotrigine may decrease effects
• Modafinil may decrease efficacy
• St. John's Wort may decrease efficacy
• Rifamycins may decrease efficacy
• Ulipristal may decrease efficacy

Precautions

• Monitor for ectopic pregnancy in women with a history of ectopic pregnancy or pelvic inflammatory disease
• Consider alternative contraceptive methods in cases of severe obesity
• Use caution in women with a history of thromboembolic disorders
• Regular follow-up is necessary to monitor for side effects and efficacy

Pregnancy

Levonorgestrel is contraindicated in pregnancy. It is not effective once implantation has occurred.

Breast-feeding

Levonorgestrel is excreted in breast milk, but it is considered safe for use during breastfeeding. However, it is advisable to take the medication just after breastfeeding to minimize exposure to the infant.

Storage

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

Formulations

• Levonorgestrel 1.5 mg oral tablet for emergency contraception
• Levonorgestrel intrauterine device (IUD) releasing 20 micrograms per day

Mechanism of action

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. 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. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens. 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 complex (eg, specifically the surface topography of AF-2 for raloxifene) compared with the estrogen (estradiol)-estrogen receptor complex. A second estrogen receptor also has been identified, and existence of at least 2 estrogen receptors (ER-alpha, ER-beta) may contribute to the tissue-specific activity of selective modulators. While the role of the estrogen receptor in bone, cardiovascular tissue, and the CNS continues to be studied, emerging evidence indicates that the mechanism of action of estrogen receptors in these tissues differs from the manner in which estrogen receptors function in reproductive tissue. /Estrogen General Statement/ Intracellular cytosol-binding proteins for estrogens have been identified in estrogen-responsive tissues including the female genital organs, breasts, pituitary, and hypothalamus. The estrogen-binding protein complex (ie, cytosol-binding protein and estrogen) distributes into the cell nucleus where it stimulates DNA, RNA, and protein synthesis. The presence of these receptor proteins is responsible for the palliative response to e

Pharmacodynamics

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.

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.