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| Medication |
Strength |
Quantity |
| FemHRT (ethinyl estradiol/norethindrone) |
1mg/5mcg |
140 |
FemHRT
Norethindrone Acetate--Ethinyl Estradiol
FemHRT - FemHRT Side Effects - FemHRT Information
Pharmacology: FemHRT is a continuous dosage regimen of an estrogen-progestin combination for oral administration as hormone replacement therapy (HRT). FemHRT manages hypoestrogenic states, especially those associated with menopause, and following oophorectomy.
Estrogen drug products, including ethinyl estradiol, act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, arterial wall and bone of women.
Progestins, including norethindrone, 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 CNS. Norethindrone produces similar endometrial changes to those of the naturally occurring hormone progesterone.
Clinical Pharmacology of Estrogen: 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 interconversion, 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 µg 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. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.
Estrogen replacement therapy decreases the rate of bone loss in menopausal women; evidence of estrogen receptors on bone cells suggests there is a direct effect of estrogen on bone. Estrogens also have direct effects on arterial walls through genomic and non-genomic effects.
Clinical Pharmacology of Progestin: It has been established that the inclusion of either cyclic or continuous progestin, including norethindrone, in hormone replacement therapy inhibits endometrial proliferation induced by estrogen. The inhibition of endometrial proliferation is associated with a reduction in risk of endometrial hyperplasia and the attendant risk of carcinoma in women with intact uteri.
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.
Pharmacokinetics: Absorption and Bioavailability: Norethindrone acetate (NA) and ethinyl estradiol (EE) are rapidly 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 a bioavailability of approximately 64% for norethindrone and 55% for ethinyl estradiol. Bioavailability of FemHRT tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of FemHRT with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food.
The full pharmacokinetic profile of FemHRT (0.5 mg NA/2.5 µg EE and 1 mg NA/5 µg EE) was not characterized due to assay sensitivity limitations. Multiple-dose pharmacokinetics of 1 mg NA/10 µg EE tablets were studied in 18 postmenopausal women. Mean plasma concentrations of norethindrone and ethinyl estradiol are shown in Figure 1 and pharmacokinetic parameters are found in Table I. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for the 1 mg NA/5 µg EE (1/5) and 1 mg NA/10 µg EE (1/10) tablets are slightly more than proportional to dose when compared to the 0.5 mg NA/2.5 µg EE (0.5/2.5) tablet, which is largely explained by higher sex hormone binding globulin (SHBG) concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the FemHRT 0.5/2.5 and FemHRT 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentration for the NA/EE 1/10 tablet.
Distribution: Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin (SHBG), whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. FemHRT increases serum SHBG concentrations approximately 2.6-fold over pretreatment values.
Metabolism: Norethindrone acetate is rapidly deacetylated to norethindrone after oral administration and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. 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 is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone is equivalent to oral administration of 2.8 µg 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: 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/h/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of NA 1 mg/EE 10 µg tablets are approximately 13 hours and 24 hours, respectively.
Pivotal Clinical Trials: The safety and efficacy of FemHRT have been studied in 2 placebo-controlled clinical trials of 12- to 16-weeks duration for treatment of vasomotor symptoms, a 2-year placebo-controlled study for vasomotor symptoms, prevention of osteoporosis and endometrial safety, and a 1-year reference-controlled study for confirming endometrial safety vs a frequently used estrogen-progestin combination of conjugated equine estrogen and medroxyprogesterone acetate (Premarin/MPA).
Vasomotor Symptoms: Two placebo-controlled, multicentre, randomized clinical trials were conducted to determine the safety and efficacy of FemHRT on reducing the frequency of hot flushes.
In Study 376-368, the effect of FemHRT in reducing vasomotor symptoms was established in postmenopausal women who reported symptoms during a 2-week baseline period, with a mean frequency of >40 hot flushes/week. Subjects received FemHRT 0.5/2.5, 1/5, or placebo for a period of 16 weeks. At the end of the study, both FemHRT 0.5/2.5 and 1/5 groups differed significantly from placebo in mean reduction in frequency of hot flushes/week (Figure 2).
Study 376-390: A 12-week placebo-controlled, multicentre, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes/day upon study entry.
The efficacy of FemHRT for the treatment of moderate to severe vasomotor symptoms (VMS) is demonstrated in Figure 3 (reduction in frequency of hot flushes) and Figure 4 (reduction in intensity of hot flushes). Reduction in mean frequency of hot flushes with FemHRT was significantly greater than placebo from Weeks 2 and 3, for FemHRT 1/5 and 0.5/2.5 doses, respectively. Similarly, reduction in mean intensity of hot flushes with FemHRT was significantly greater than placebo from Weeks 3 and 6, for FemHRT 1/5 and 0.5/2.5 doses, respectively.
on Bone Mineral Density: A 2-year, placebo-controlled, multicentre, randomized clinical trial was conducted to determine the safety and efficacy of various combinations of NA and EE on maintaining bone mineral density, protecting the endometrium, and to determine the effects on lipids. This trial is referred to as the CHART Study (376-359): Continuous Hormones As Replacement Therapy. Patients were randomized to either placebo, FemHRT 0.5/2.5, 1/5, or matching unopposed EE doses (2.5 or 5 µg). All participants received 1000 mg of elemental calcium supplement daily.
In the CHART Study (376-359), trabecular bone mineral density (BMD) was assessed at lumbar spine using quantitative computed tomography. Bone mineral density was maintained with FemHRT 0.5/2.5 dose, while the NA/EE 1/5 dose resulted in a significant increase in BMD at each annual assessment. The increase in BMD seen with the FemHRT 1/5 dose was statistically significantly different than the 5 µg EE dose group at Months 12 and 24. There was a significant decrease in BMD in the placebo group (Figure 5).
Over a 24-month treatment period, patients in the FemHRT 0.5/2.5 and 1/5 groups had positive significant differences in BMD of 5.8% (p=0.0026) and 9.8% (p=0.0001) respectively, versus the placebo group (absolute difference, adjusted mean % change from baseline). The changes in BMD versus the placebo group were 4.1% (p=0.0449) and 4.9% (p=0.0116), in patients receiving unopposed 2.5 and 5 µg EE, respectively, over the same time period.
on Endometrium: CHART Study (376-359): Biopsies were obtained at 6-month intervals in the CHART Study. Baseline biopsies were classified as normal (in approximately 95% of subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up biopsies were obtained in approximately 70 to 80% of patients in each arm of the study after 12 and 24 months of therapy. All unopposed EE groups reported at least 1 case of hyperplasia with the highest incidence at the highest dose. No hyperplasia was detected in any of the FemHRT treatment groups (Table III).
The extent of endometrial proliferation was quantified using Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) and a severity score was assigned (1=Atrophic; 2=mildly proliferative; 3=moderately proliferative; 4=markedly proliferative; 5=hyperplastic). There was a dose-related increase in severity score with unopposed ethinyl estradiol use, while the endometrial status of all NA/EE dose combinations was similar to placebo.
Endometrial Safety Data from Study 376-401: Study 376-401 was a randomized, double-blind, comparative, 1-year multicentre study in healthy postmenopausal women, to assess the safety and protective effect on the endometrium, of FemHRT 1/5, EE alone 5 µg, placebo, or 0.625 mg Premarin/2.5 mg MPA. In addition, all subjects received 1000 mg of elemental calcium supplement daily.
Endometrial biopsies were obtained at baseline and all subjects were required to have no evidence of either hyperplasia or markedly proliferative endometrial tissue in order to be eligible for the study. The results from this study replicate those obtained from the CHART Study (376-359), i.e., at the end of 1 year no cases of hyperplasia were observed in subjects receiving FemHRT 1/5. The additional experience from this comparative, controlled clinical trial provides further support for the protective endometrial effects of FemHRT.
Bleeding and/or Spotting: CHART Study (376-359): Figure 6 shows the incidence of bleeding and/or spotting, as determined after 24-month observations in the CHART Study. The number of FemHRT patients reporting bleeding and/or spotting decreased steadily to 13% by end of the study.
HDL-C/LDL-C ratios increased in all FemHRT treated subjects after 12-months and 24-months therapy, but did not appear to be dose-related. The atherogenic index, which was in the low-risk range for this age group (Total-C/HDL-C <4.5), remained stable in all FemHRT treatment groups. Thus the overall effect of FemHRT on the serum lipid profile in menopausal women was considered improved or neutral.
Effects on Coagulation Parameters: In Study 376-390, Factor VII and plasminogen activator inhibitor-1 decreased from baseline in a dose-related manner, but remained within the normal laboratory reference range for postmenopausal women who were randomized to FemHRT. Fibrinogen and partial thromboplastin time did not change from baseline for any of the NA/EE combination groups.
Indications: Intended for continuous administration as hormone replacement therapy.
FemHRT is indicated for: relief of menopausal and postmenopausal symptoms occurring in naturally or surgically induced estrogen deficiency states; symptomatic treatment of vulvar and vaginal atrophy associated with menopause; prevention of osteoporosis in naturally occurring or surgically induced estrogen-deficiency states in addition to other important therapeutic measures such as adequate diet with sufficient calcium intake and regular exercise.
FemHRT is recommended for use only in patients with an intact uterus, since the regimen includes a progestin whose role is to prevent endometrial hyperplasia.
Estrogen replacement therapy reduces bone resorption and retards or halts postmenopausal bone loss. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that in the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.
At skeletal maturity there are sex and race differences in both the total amount of bone present and its density, in favor of men. Thus, women are at higher risk than men because they start with less bone mass and, for several years following natural or induced menopause, the rate of bone mass decline is accelerated. White and Asian women are also at higher risk than Black women.
Early menopause is one of the strongest predictors for development of osteoporosis. In addition, other factors affecting the skeleton which are associated with osteoporosis include genetic factors (small build, family history), endocrine factors (nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, type 1 diabetes), lifestyle (cigarette smoking, alcohol abuse, sedentary lifestyles), and nutrition (below average body weight, low dietary calcium intake).
The mainstays of prevention and management of osteoporosis are estrogen, an adequate lifetime calcium intake, and exercise. Postmenopausal women absorb dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. By comparison, premenopausal women require about 1000 mg/day and the average calcium intake in North America is 400 to 600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful.
Weight-bearing exercise and nutrition may be important adjuncts to the prevention and management of osteoporosis. Immobilization and prolonged bed rest produce rapid bone loss, while weight-bearing exercise has been shown both to reduce bone loss and to increase bone mass. The optimal types and amount of physical activity that would prevent osteoporosis have not been established; however, in 2 studies, an hour of walking and running exercises 2 or 3 times weekly significantly increased lumbar spine bone mass.
Contraindications: In patients with any of the following disorders: Active hepatic dysfunction or disease, especially of the obstructive type. Personal history of known or suspected estrogen/progestin-dependent neoplasia, such as breast or endometrial cancer. Endometrial hyperplasia. Undiagnosed abnormal genital bleeding. Known or suspected pregnancy. A history of cerebrovascular accident, coronary thrombosis, or in the presence of classical migraine. Active thrombophlebitis, thrombosis, or thromboembolic disorders. Partial or complete loss of vision due to ophthalmic vascular disease. Known or suspected hypersensitivity to any components of the medication.
Warnings: Endometrial Hyperplasia and Endometrial Carcinoma: There is evidence from several studies that estrogens unopposed by progestins increase the risk of carcinoma of the endometrium in humans. FemHRT provides plasma norethindrone levels within the appropriate range to counteract the effects of ethinyl estradiol on the endometrium.
In the CHART Study (376-359) (See Pharmacology, Pivotal Clinical Trials), it has been demonstrated that when norethindrone acetate is administered with ethinyl estradiol, the incidence of endometrial hyperplasia (a possible precursor of endometrial cancer) is reduced to the level observed in placebo users. No cases of endometrial hyperplasia were detected with FemHRT 0.5/2.5 and 1/5 doses administered for 2 years. FemHRT 0.5/2.5 and 1/5 treatment groups did not differ from placebo with regard to the degree of endometrial proliferation.
Study 376-401 (see Pharmacology, Pivotal Clinical Trials) assessed the safety and endometrial protective effect of FemHRT 1/5 in healthy, postmenopausal women. At the end of 1 year, there were no cases of endometrial hyperplasia reported with FemHRT 1/5.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Breast Cancer: The available epidemiological data on the use of estrogen/progestin combination products in menopause are still inconclusive and hence it is not possible as yet to evaluate fully the effects of these products on breast cancer.
Breast cancers found in women using hormone replacement therapy (HRT) are more likely to be localized to the breast than those found in non-users.
It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease. There is a need for caution in prescribing estrogens for women with known risk factors associated with the development of breast cancer, such as a strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy). Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.
It is recommended that women deemed to be at high risk undergo a mammography before starting HRT, and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.
The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. It is important that the modest increase in risk of breast cancer in women taking HRT for over 5 years be discussed with the patient and weighed against its known benefits.
Instructions for regular self-examination of the breasts should be included in this counselling.
Venous Thromboembolism: Epidemiological studies have suggested that hormone replacement therapy is associated with an increased relative risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. This increase in risk was found only in current HRT users and did not persist in former users. For healthy women, this amounts to a risk of one extra case of VTE each year for every 5000 patients taking HRT.
Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition) and severe obesity (body mass index >30 kg/m 2). The risk of VTE also increases with age.
The risk of VTE may be temporarily increased with prolonged immobilization, major elective surgery or post-traumatic surgery, or major trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised.
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, FemHRT therapy should be discontinued immediately.
Precautions: Before FemHRT is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial thickness should be evaluated by ultrasound or by endometrial biopsy, when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.
The first follow-up examination should be done within 3 to 6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made every 6 to 12 months and should include at least those procedures outlined above.
It is important that patients are encouraged to practice frequent self-examination of the breasts.
Abnormal vaginal bleeding that is prolonged, irregular or heavy, occurring during therapy should prompt diagnostic measures like endometrial biopsy or dilation and curettage (D&C) to rule out the possibility of uterine malignancy and the treatment should be reevaluated.
Pre-existing uterine leiomyoma may increase in size during estrogen use. This is usually minimal, especially in patients who are well past the menopause. Growth, pain or tenderness of uterine leiomyoma requires prompt evaluation and, if necessary, discontinuation of medication.
Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.
Caution is advised in patients with a history of estrogen-related jaundice and pruritus. If cholestatic jaundice develops during treatment with FemHRT, the drug should be discontinued and appropriate investigations carried out.
Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication.
If feasible, hormone replacement therapy should be discontinued at least 4 weeks before major surgery or during periods of prolonged immobilization, since these events may be associated with an increased risk of thromboembolism.
Women using hormone replacement therapy sometimes experience increased blood pressure which, in most cases, returns to normal upon discontinuing the drug. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be evaluated and FemHRT therapy may have to be discontinued.
Estrogens may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. Treatment should be stopped if there is an increase in epileptic seizures. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.
Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus, estrogens should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.
A worsening of glucose tolerance and lipid metabolism have been observed in a significant percentage of peri- and postmenopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.
Women with familial hypertriglyceridemia need special surveillance. Lipid lowering measures are recommended before starting treatment in these women.
Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see the section under Laboratory Test Interactions.
Drug Interactions : No drug-drug interaction studies have been conducted with FemHRT. The following section contains information on drug interactions with ethinyl estradiol-containing products (specifically, oral contraceptives) that have been reported in the published literature. It is unknown whether such interactions occur with FemHRT or drug products containing other types of estrogens.
Estrogens may diminish the effectiveness of anticoagulants, antidiabetic and antihypertensive agents.
Preparations inducing liver enzymes (e.g., barbiturates, hydantoins, carbamazepine, meprobamates, phenylbutazone or rifampin) may interfere with the activity of orally administered estrogens.
The metabolism of ethinyl estradiol is increased by rifampin and anticonvulsants such as phenobarbital, phenytoin and carbamazepine.
Ascorbic acid and acetaminophen (gram doses) may increase AUC and/or plasma concentration of ethinyl estradiol. Coadministration of atorvastatin and ethinyl estradiol-containing oral contraceptives increased AUC values for ethinyl estradiol by 20%.
Clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.
Drug products containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone and theophylline have been reported with concomitant administration of oral contraceptives containing ethinyl estradiol. In addition, these drugs containing ethinyl estradiol may induce the conjugation of other compounds.
Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid have been noted when these drugs were administered with oral contraceptives containing ethinyl estradiol.
It was found that some herbal products (e.g., St. John's Wort) which are available as OTC products might affect metabolism, and therefore, efficacy and safety of estrogen/progestin combination products.
Physicians and other health-care providers should be aware of other non-prescription products concomitantly used by the patient, including herbal£ and natural£ products made widely available through Health Food and pharmacy outlets.
Laboratory Test Interactions : The results of certain endocrine and liver function tests may be affected by estrogen-containing products: Increased sulfobromophthalein retention. Increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III. Increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T4) as measured by column or radioimmunoassay; free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively; free or biologically active hormone concentrations are unchanged. Reduced response to the metopirone test. Reduced serum folate concentration. Increased serum triglyceride and phospholipid concentration.
The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for 2 to 4 weeks. The pathologist should be informed that the patient is receiving estrogen-progestin therapy when relevant specimens are submitted.
Pregnancy: Estrogens/progestins should not be used during pregnancy (see Contraindications).
Renal Insufficiency: The effect of renal disease on the disposition of FemHRT has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.
Hepatic Impairment: The effect of hepatic disease on the disposition of FemHRT has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function (see Contraindications).
Geriatrics: The pharmacokinetics of norethindrone and ethinyl estradiol were not affected by age, (age range 40 to 62 years), in the postmenopausal population studied.
Information to Be Provided to the Patient: Patients should be advised to read the Information for Patients Using FemHRT as Hormone Replacement Therapy, and to follow the information.
Adverse Effects: Clinical Adverse Experience: Adverse events reported in controlled clinical studies of FemHRT are shown in Table V below.
The following adverse reactions have been reported with estrogens/progestin combinations in general:
Gastrointestinal: nausea, vomiting, abdominal discomfort (cramps, pressure, pain), bloating, gallbladder disorder, asymptomatic impaired liver function, cholestatic jaundice.
Genitourinary: breakthrough bleeding, spotting, change in menstrual flow, dysmenorrhea, vaginal itching/discharge, dyspareunia, dysuria, endometrial hyperplasia, premenstrual-like syndrome, reactivation of endometriosis, cystitis, changes in cervical erosion and amount of cervical secretion.
Skin: chloasma or melasma, which may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, acne.
Endocrine: breast swelling and tenderness, increased blood sugar levels, decreased glucose tolerance, sodium retention.
Cardiovascular/Hematologic: palpitations, isolated cases of thrombophlebitis, thromboembolic disorder, exacerbation of varicose veins, increase in blood pressure (see Warnings and Precautions) coronary thrombosis, altered coagulation tests (see Precautions, Laboratory Test Interactions).
CNS: aggravation of migraine episodes, headaches, mental depression, nervousness, dizziness, fatigue, irritability, neuro-ocular lesions (e.g., retinal thrombosis, optic neuritis).
Ophthalmic: visual disturbances, steepening of the corneal curvature, intolerance to contact lenses, neuro-ocular lesions (see CNS).
Miscellaneous: changes in appetite, changes in body weight, edema, neuritis, change in libido; musculoskeletal pain, including leg pain not related to thromboembolic disease (usually transient, lasting 3 to 6 weeks), may occur.
If adverse symptoms persist, the dose of hormone replacement therapy should be reevaluated.
Overdose: Symptoms: Numerous reports of ingestion of large doses of estrogen products and estrogen-containing oral contraceptives by young children have not revealed acute serious ill effects. Overdosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.
Progestin (norethindrone acetate) overdosage has been characterized by depressed mood, tiredness, acne and hirsutism.
Treatment: In case of overdose or accidental ingestion by children, the physician should observe the patient closely and provide symptomatic treatment. Gastric lavage should be given if considered necessary.
Dosage: FemHRT therapy consists of a single tablet to be taken once daily, without regard to meals.
Treatment of Vasomotor Symptoms: FemHRT 1/5 should be given once daily for the treatment of moderate to severe vasomotor symptoms associated with the menopause. Patients should be reevaluated within 3 to 6 months after initiation of treatment, to assess response to treatment.
Symptomatic Treatment of Vulvar and Vaginal Atrophy Associated With Menopause: FemHRT 1/5 should be given once daily for the treatment of vulvar and vaginal atrophy associated with the menopause. Patients should be reevaluated within 3 to 6 months after initiation of treatment, to assess response to treatment.
Prevention of Osteoporosis: FemHRT 1/5 should be given once daily to prevent postmenopausal osteoporosis (see Pharmacology, Pivotal Clinical Trials: Effect on Bone Mineral Density). Response to therapy can be assessed by measurement of bone mineral density.
Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring vaginal bleeding. Patients should be evaluated at least annually for breast abnormalities and more often, if there are any symptoms.
Information for the Patient: See Blue Section--Information for the Patient FemHRT£.
Supplied: Each white tablet, D-shaped debossed with PD£ on one side and 144£ on the other side, contains: norethindrone acetate 1 mg and ethinyl estradiol 5 µg. Nonmedicinal ingredients: calcium stearate, cornstarch, lactose monohydrate and microcrystalline cellulose. Blister cards of 28. Store at controlled room temperature, 15 to 25°C.
IMPORTANT NOTE: THE FOLLOWING INFORMATION IS INTENDED TO SUPPLEMENT, NOT SUBSTITUTE FOR, THE EXPERTISE AND JUDGMENT OF YOUR PHYSICIAN, PHARMACIST OR OTHER HEALTHCARE PROFESSIONAL. IT SHOULD NOT BE CONSTRUED TO INDICATE THAT USE OF THE DRUG IS SAFE, APPROPRIATE, OR EFFECTIVE FOR YOU. CONSULT YOUR HEALTHCARE PROFESSIONAL BEFORE USING THIS DRUG.
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