Femhrt

Femhrt is part of the drug class:

• Progestogens and estrogens, fixed combinations

• It is used to put off soft, brittle bones (osteoporosis) in women after change of life.
• It is used to prevent or lower the signs of the change of life (menopause).
• It may be given to you for other reasons. Talk with the doctor.

Use Femhrt as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• Take this medicine at the same time of day.
• Take with or without food. Take with food if it causes an upset stomach.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you miss taking Femhrt for a few days in a row, call your doctor before you start taking it again.

12.1       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.

12.2       Pharmacodynamics

Currently, there are no pharmacodynamic data known for Femhrt.

12.3       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 Femhrt 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 Femhrt tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of Femhrt 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 Femhrt tablets with food.

The full pharmacokinetic profile of Femhrt tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 post-menopausal 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 NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the Femhrt 0.5/2.5 tablets and Femhrt1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet.

Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets

†  Cmax = 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
‡  ND = Not determined

Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for Femhrt 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 Femhrt 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 40-62 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 NA/10 mcg EE 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.

16.1       How Supplied

Femhrt (norethindrone acetate/ethinyl estradiol tablets) is available in the following strengths and package sizes:

N 0430-0145-14  Blister card of 28 oval white tablets containing 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; imprinted with WC on one side and 145 on the other.

16.2       Storage and Handling

Store at 25º C (77º F); excursions permitted to 15 to 30º C (59 to 86º F) [see USP Controlled Room Temperature].

femhrt contains a combination of ethinyl estradiol and norethindrone. 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.

femhrt is used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. It is also used to prevent osteoporosis.

femhrt may also be used for purposes not listed in this medication guide.

Use femhrt exactly as it was prescribed for you. 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 femhrt 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 femhrt, 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 femhrt.

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.

Avoid smoking while using this medication. Smoking can increase your risk of blood clots, stroke, or heart attack caused by taking hormones.

Applies to ethinyl estradiol / norethindrone: oral capsule liquid filled, oral tablet, oral tablet chewable

Other dosage forms:

• oral tablet, oral tablet chewable

Along with its needed effects, ethinyl estradiol / norethindrone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ethinyl estradiol / norethindrone:

• Abdominal or stomach pain
• absent, missed, or irregular menstrual periods
• anxiety
• change in vision
• changes in skin color
• chest pain or discomfort
• chills
• clay-colored stools
• constipation
• cough
• dark urine
• diarrhea
• dizziness or lightheadedness
• fainting
• fast heartbeat
• fever
• headache
• hives or welts
• itching skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• medium to heavy, irregular vaginal bleeding between regular monthly periods, which may require the use of a pad or a tampon
• nausea and vomiting
• pain or discomfort in the arms, jaw, back, or neck
• pain, tenderness, or swelling of the foot or leg
• pains in the chest, groin, or legs, especially in the calves of the legs
• pounding in the ears
• rash
• redness of the skin
• severe headaches of sudden onset
• slow or fast heartbeat
• sudden loss of coordination or slurred speech
• sudden onset of shortness of breath for no apparent reason
• sudden shortness of breath or troubled breathing
• sweating
• unusual tiredness or weakness
• vomiting of blood

Some side effects of ethinyl estradiol / norethindrone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach cramps
• bloating
• blotchy spots on the exposed skin
• breast enlargement or tenderness
• discouragement
• feeling sad or empty
• irritability
• itching of the vagina or outside genitals
• loss of interest or pleasure
• pain during sexual intercourse
• thick, white curd-like vaginal discharge without odor or with mild odor
• tiredness
• trouble concentrating
• trouble sleeping
• trouble wearing contact lenses