Prefest

Prefest is a prescription medication used after menopause to reduce moderate to severe hot flashes, treat moderate to severe menopausal changes in and around the vagina, and help reduce your chances of getting osteoporosis (thin weak bones). Prefest contains two hormones, estradiol and norgestimate, and belongs to a group of drugs called estrogen and progestin combinations. Prefest works as a hormone replacement to relieve issues caused by hormonal changes. 

Prefest comes in tablet form and is usually taken once daily, with or without food. 

Common side effects of Prefest include headache, breast pain, and irregular vaginal bleeding or spotting.

Do not use estradiol and norgestimate if you are pregnant.

You should not take this medicine if you have any of the following conditions: liver disease, a recent stroke or heart attack, unusual vaginal bleeding, a history of breast or uterine cancer, if you have ever had a blood clot, or if you may be pregnant.

Smoking can increase your risk of blood clots, stroke, or heart attack while taking estradiol and norgestimate, especially if you are older than 35.

Estradiol and norgestimate should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

Smoking can increase your risk of blood clots, stroke, or heart attack while taking estradiol and norgestimate, especially if you are older than 35 years of age. Your risk increases the more you smoke. You should not take this medicine if you smoke and are older than 35 years of age.

This medicine can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking estradiol and norgestimate.

You should not take this medicine if you are allergic to estradiol or norgestimate, or if you have:

• liver disease;

• abnormal vaginal bleeding that has not been checked by a doctor;

• a history of hormone-related cancer such as breast or uterine cancer;

• a recent history of heart attack or stroke;

• if you have ever had a blood clot (especially in your lung or your lower body); or

• if you are pregnant.

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

• heart disease, high blood pressure;

• high cholesterol or triglycerides;

• risk factors for coronary artery disease (such as diabetes, smoking, being overweight, or a family history of coronary artery disease);

• asthma;

• kidney disease;

• epilepsy or other seizure disorder;

• migraines;

• lupus;

• gallbladder disease;

• endometriosis;

• a thyroid disorder;

• a history of jaundice caused by pregnancy or birth control pills;

• high levels of calcium in your blood; or

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system).

Estradiol and norgestimate 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. Ask your doctor about your individual risk.

FDA pregnancy category X. This medicine can harm an unborn baby or cause birth defects. Do not use estradiol and norgestimate if you are pregnant or may become pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are taking this medicine.

Estradiol and norgestimate can pass into breast milk and may harm a nursing baby. Estrogens may also slow breast milk production. You should not breast-feed while you are taking this medication.

Do not smoke while taking this medicine, especially if you are older than 35 years of age.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Chest pain or pressure.
• Shortness of breath.
• Coughing up blood.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• Very upset stomach or throwing up.
• Very bad dizziness or passing out.
• Change in eyesight.
• Bulging eyes.
• Change in how contact lenses feel in the eyes.
• A lump in the breast, breast soreness, or nipple discharge.
• Breast pain.
• Vaginal itching or discharge.
• Vaginal bleeding that is not normal.
• Low mood (depression).
• Memory problems or loss.
• Swelling in hands or feet.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

The Prefest® regimen provides for a single oral tablet to be taken once daily. The peach tablet containing 1 mg estradiol, USP is taken on days one through three of therapy; the white tablet containing 1 mg estradiol, USP and 0.09 mg norgestimate, USP is taken on days four through six of therapy. This pattern is then repeated continuously to produce the constant estrogen/intermittent progestogen regimen of Prefest.

The estrogenic component of Prefest is estradiol, USP. It is a white, crystalline solid, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The structural formula is as follows:

 

C18H24O2                            M.W. 272.38

The progestational component of Prefest is micronized norgestimate, USP a white powder which is chemically described as 18,19-dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-. The structural formula is as follows:

C23H31NO3                              M.W. 369.50

Each tablet for oral administration contains 1 mg estradiol, USP alone or 1 mg estradiol, USP and 0.09 mg of norgestimate, USP. The inactive ingredients are as follows:

The estradiol, USP tablet contains anhydrous lactose, croscarmellose sodium, FD&C yellow no. 6 aluminum lake, magnesium stearate and microcrystalline cellulose.

The estradiol and norgestimate tablet contains anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.

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, 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.

Norgestimate is a derivative of 19-nortestosterone and binds to androgen and progestogen receptors, similar to that of the natural hormone progesterone; it does not bind to estrogen receptors. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacokinetics:

Absorption:

Estradiol reaches its peak serum concentration (Cmax) at approximately 7 hours in postmenopausal women receiving Prefest (Table 1). Norgestimate is completely metabolized; its primary active metabolite, 17-deacetylnorgestimate, reaches Cmax at approximately 2 hours after dose (Table 1). Upon co-administration of Prefest with a high fat meal, the Cmax values for estrone and estrone sulfate were increased by 14% and 24%, respectively, and the Cmax for 17-deacetylnorgestimate was decreased by 16%. The AUC values for these analytes were not significantly affected by food.

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 sex hormone binding globulin (SHBG) and albumin. 17-deacetylnorgestimate, the primary active metabolite of norgestimate, does not bind to SHBG, but to other serum proteins. The percent protein binding of 17-deacetylnorgestimate is approximately 99%.

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 the 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 gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate’s primary active metabolite is 17-deacetylnorgestimate.

Excretion:

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Norgestimate metabolites are eliminated in the urine and feces. The half-life (t1/2) of estradiol and 17-deacetylnorgestimate in postmenopausal women receiving Prefest is approximately 16 and 37 hours, respectively.

Drug Interactions:

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Results of a subset population (n=24) from a clinical study conducted in 36 healthy postmenopausal women indicated that the steady state serum estradiol levels during the estradiol plus norgestimate phase of the regimen may be lower by 12 to 18% as compared with estradiol administered alone. The serum estrone levels may decrease by 4% and the serum estrone sulfate levels may increase by 17% during the estradiol plus norgestimate phase as compared with estradiol administered alone. The clinical relevance of these observations is unknown.

Special Populations:

Race and Body Weight:

The effects of race and body weight on the pharmacokinetics of estradiol, norgestimate, and their metabolites were evaluated in 164 healthy postmenopausal women (100 Caucasians, 61 Hispanics, 2 Blacks, and 1 Asian). No significant pharmacokinetic difference was observed between the Caucasian and the Hispanic postmenopausal women. No significant difference due to body weight was observed in women in the 60 to 80 kg weight range. Women with body weight higher than 80 kg, however, had approximately 40% lower peak serum levels of 17-deacetylnorgestimate, 30% lower AUC values for 17-deacetylnorgestimate and 30% lower Cmax values for norgestrel. The clinical relevance of these observations is unknown.

No pharmacokinetic studies were conducted in other special populations.

Table 1. Mean Pharmacokinetic Parameters of E2, E1, E1S and 17d-NGM*  Following Single and Multiple Dosing of Prefest

* E2 = Estradiol, E1 = Estrone, E1S = Estrone Sulfate, 17d-NGM = 17 -deacetylnorgestimate. Baseline uncorrected data are reported for E2, E1 and E1S. † Cmax= peak serum concentration, tmax = time to reach peak serum concentration, AUC (0 to 24 h) = area under serum concentration vs. time curve from 0 to 24 hours after dose, t½ = half life. ‡ NA = Not available or not applicable.
Analyte	Parameter†	Units	First Dose E2	First Dose E2/NGM	Multiple Dose E2	Multiple Dose E2/NGM
E2	C max	pg/mL	27.4	39.3	49.7	46.2
	tmax	h	7	7	7	7
	AUC (0 to 24 h)	pg. h/mL	424	681	864	779
E1	Cmax	pg/mL	210	285	341	325
	t max	h	6	6	341	6
	AUC (0 to 24 h)	pg. h/mL	2774	4153	5429	4957
E1S	Cmax	ng/mL	11.1	13.9	14.9	14.5
	tmax	h	5	4	6	5
	AUC (0 to 24 h)	ng. h/mL	135	180	198	198
17d-NGM	Cmax	pg/mL	NA‡	515	NA	643
	tmax	h	NA	2	NA	2
	AUC (0 to 24 h)	pg. h/mL	NA	2146	NA	5322
	t½	h	NA	37	NA	NA

See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.

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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Table 7. ALL TREATMENT-EMERGENT ADVERSE EVENTS REGARDLESS OF DRUG RELATIONSHIP REPORTED AT A FREQUENCY OF ≥ 5% WITH Prefest

FOUR 12-MONTH CLINICAL TRIALS
	Prefest (Estradiol and Norgestimate) (N = 579) N (%)
Body as a Whole
Back pain	69 (12%)
Fatigue	32 (6%)
Influenza-like symptoms	64 (11%)
Pain	37 (6%)
Digestive System
Abdominal pain	70 (12%)
Flatulence	29 (5%)
Nausea	34 (6%)
Tooth disorder	27 (5%)
Musculoskeletal System
Arthralgia	51 (9%)
Myalgia	30 (5%)
Nervous System
Dizziness	27 (5%)
Headache	132 (23%)
Psychiatric Disorders
Depression	27 (5%)
Reproductive System
Breast pain	92 (16%)
Dysmenorrhea	48 (8%)
Vaginal bleeding (all)	52 (9%)
Vaginitis	42 (7%)
Resistance Mechanism Disorders
Viral infection	35 (6%)
Respiratory System
Coughing	28 (5%)
Pharyngitis	38 (7%)
Sinusitis	44 (8%)
Upper respiratory-tract infection	121 (21%)

The following additional adverse reactions have been reported with estrogen and/or progestin therapy:

1. Genitourinary system.
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, 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. 2. Breasts.
Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. 3. Cardiovascular.
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal.
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas. 5. Skin.
Chloasma or melasma, that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. 6. Eyes.
Retinal vascular thrombosis, intolerance to contact lenses. 7. Central Nervous System.
Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. 8. Miscellaneous.
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.