Fyavolv

Name: Fyavolv

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What Is Fyavolv?

Ethinyl estradiol is a form of estrogen. Estrogen is a female sex hormone necessary for many processes in the body.

Norethindrone is a form of progesterone. Progesterone is a female hormone important for the regulation of ovulation and menstruation.

Ethinyl estradiol and norethindrone is a combination medicine used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. It is also used to prevent osteoporosis.

Estradiol and norethindrone may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have any of the following conditions: a history of stroke or blood clot, circulation problems, a hormone-related cancer such as breast or uterine cancer, abnormal vaginal bleeding, if you have recently had a stroke or heart attack, if you have had your uterus removed (hysterectomy), or if you have ever had an allergic reaction to birth control pills or other hormones.

Do not use if you are pregnant.

Ethinyl estradiol and norethindrone may increase your risk of developing a condition that may lead to uterine cancer. Call your doctor at once if you have any unusual vaginal bleeding while using this medicine.

Ethinyl estradiol and norethindrone should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions. Long-term use may also increase your risk of breast cancer or blood clot.

Do not use ethinyl estradiol and norethindrone if you are pregnant. Use effective birth control, and tell your doctor right away if you become pregnant.

You should not use this medicine if you are allergic to it, or if you have:

abnormal vaginal bleeding that a doctor has not checked;
a hormone-related cancer such as breast or uterine cancer;
a history of heart attack, stroke, or blood clot (especially in your lung or your lower body);
a hereditary clotting deficiency (protein C, protein S, or antithrombin);
a history of having your uterus removed (hysterectomy);
liver disease; or
a history of liver problems or jaundice caused by birth control pills or other hormones.

Ethinyl estradiol and norethindrone will not prevent heart disease, heart attack, stroke, breast cancer, or dementia, and may actually increase your risk of developing these conditions. Long-term use may also increase your risk of breast cancer or blood clot. Talk with your doctor about your individual risks.

To make sure ethinyl estradiol and norethindrone is safe for you, tell your doctor if you have:

continued vaginal bleeding after menopause;
high blood pressure or heart disease;
a thyroid disorder;
lupus;
hereditary angioedema;
endometriosis;
bone cancer;
high cholesterol or triglycerides (a type of fat in the blood);
gallbladder disease;
diabetes;
high or low levels of calcium in your blood;
asthma;
epilepsy or other seizure disorder;
migraines; or
risk factors for coronary artery disease (such as diabetes, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, being older than 40, or if you have had a hysterectomy).

Ethinyl estradiol and norethindrone can pass into breast milk and may harm a nursing baby. This medicine may also slow breast milk production. Do not use if you are breast-feeding a baby.

Fyavolv Dosage

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Try to take this medicine at the same time each day.

Use ethinyl estradiol and norethindrone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

This medicine may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin to take while you are using ethinyl estradiol and norethindrone, to help lower this risk. Report any unusual vaginal bleeding right away.

Your doctor should check your progress on a regular basis (every 3 to 6 months) to determine whether you should continue this treatment. Self-examine your breasts for lumps on a monthly basis, and have regular mammograms.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medicine for a short time. Any doctor or surgeon who treats you should know that you are using ethinyl estradiol and norethindrone.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include nausea, vomiting, or vaginal bleeding.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling:

Cardiovascular Disorders[see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)] .
Malignant Neoplasms[see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.2)] .

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported by ≥5 percent of subjects in controlled clinical studies of norethindrone acetate and ethinyl estradiol are shown in Table 1.

Table 1. Associated Adverse Reactions Reported by ≥5 Percent of Subjects by Body System*

* The total number of subjects for each body system may be less than the number of subjects with AEs in that body system because a subject may have had more than one AE per body system
BODY SYSTEM/ Adverse Reaction		Number (Percent) of Subjects
	Placebo N = 247	Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 N = 244	Norethindrone Acetate and Ethinyl Estradiol 1/5 N = 258
BODY AS A WHOLE	23 (12.8)	30 (16.9)	30 (15.7)
Edema – Generalized	10 (4.0)	12 (4.9)	11 (4.3)
Headache	12 (4.9)	14 (5.7)	16 (6.2)
DIGESTIVE SYSTEM	8 (4.4)	17 (9.6)	25 (13.1)
Abdominal Pain	3 (1.2)	13 (5.3)	14 (6.8)
UROGENITAL SYSTEM	20 (11.1)	34 (19.2)	45 (23.6)
Breast Pain	9 (3.6)	22 (9.0)	20 (7.8)

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of norethindrone acetate and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; uterine cancer; vaginal hemorrhage; ovarian cyst; irregular menstruation; metrorrhagia; menorrhagia; dysmenorrhea; uterine enlargement.

Breasts

Tenderness, enlargement, breast pain, nipple pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer; breast disorder; breast mass; breast enlargement.

Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; thrombosis; chest pain; myocardial infarction; cerebrovascular accident (stroke); transient ischemic attack; hemiparesis; increase in blood pressure; irregular heart rate; palpitations; dyspnea.

Gastrointestinal

Nausea, vomiting; cholestatic jaundice; pancreatitis, enlargement of hepatic hemangiomas; bloating, abdominal cramps; abdominal pain; increased incidence of gallbladder disease; cholecystitis; cholelithiasis.

Skin

Chloasma or melasma that may persist when drug is discontinued; generalized erythema; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; rash, pruritus.

Eyes

Retinal vascular thrombosis; visual impairment; intolerance to contact lenses.

Central Nervous System (CNS)

Headache; migraine; dizziness; depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia; paresthesia; insomnia.

Miscellaneous

Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; back pain; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; blood glucose abnormal; fatigue; myalgia; hypersensitivity.

Overdosage

Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Fyavolv with institution of appropriate symptomatic care.

Fyavolv - Clinical Pharmacology

Mechanism of Action

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.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the 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 FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Pharmacodynamics

Currently, there are no pharmacodynamic data known for norethindrone acetate and ethinyl estradiol.

Pharmacokinetics

Absorption

Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablet is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of norethindrone acetate and ethinyl estradiol tablets with food.

The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablet was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol in 18 postmenopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol and 1/10 are slightly more than proportional to dose when compared to 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the norethindrone acetate and ethinyl estradiol 1/10 tablet.

Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets

Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parametersa Following Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets

aCmax = Maximum plasma concentration; tmax = time of Cmax; AUC(0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t½ = Elimination half-life
bND = Not determined
Cmax		tmax	AUC(0-24)	CL/F	t½
Norethindrone	ng/mL	hr	ng·hr/mL	mL/min	hr
Day 1	6.0 (3.3)	1.8 (0.8)	29.7 (16.5)	588 (416)	10.3 (3.7)
Day 87	10.7 (3.6)	1.8 (0.8)	81.8 (36.7)	226 (139)	13.3 (4.5)
Ethinyl	pg/mL	hr	pg·hr/mL	mL/min	hr
Estradiol
Day 1	33.5 (13.7)	2.2 (1.0)	339 (113)	NDb	NDb
Day 87	38.3 (11.9)	1.8 (0.7)	471 (132)	383 (119)	23.9 (7.1)

Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively.

The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40 to 62 years), in the postmenopausal population studied.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol tablets are approximately 13 hours and 24 hours, respectively.

Use in Specific Populations

No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.