norethindrone acetateethinyl estradiol tablets WARNING - PDF document

(norethindrone acetate/ethinyl estradiol tablets) WARNING 5 years of treatment with conjugated equine estrogens (CE 0.625 mg) combined with 2.5mg medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see Other doses of conjugated estrogens with medroxyprogesterone, and other combinations of estrogens DESCRIPTION 1/5 is a continuous dosage regimen of a progestin-estrogen combination for oral administration. Each white D-shaped tablet contains 1 OH H C Revised January 5, 2004 2 O O H O H C H Norethindrone Acetate Molecular Formula: CCLINICAL PHARMACOLOGY for the development and maintenance of the female reproductive system and secondary sex characteristics. Alt exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is s

ubstantially more potent than 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 d form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects ofsimilar to those of endogenous estrogens. teinizing 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. Progestin compounds enhance cellular differentiati, increasing local metabolism of estrogens to less active metabolites, target cells by binding to specific

progesterone receptors that interact wielements 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. has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. The addition of continuous administration of progestin to an estrogen regimen reduced the incidence of endometrial hyperplasia, and the attendant risk of carcinoma in women with intact uteri. Norethindrone acetate (NA) is completely and rarethindrone after oral administration, and the disposition of norethindrone acetate is indistadministered norethindrone. N

orethindrone acetate afrom 1/5 tablets, with maximum plasma concentragenerally occurring 1 to 2 hours postpass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for Revised January 5, 2004 4 Figure 1. Mean Steady-State (Day 87) PlConcentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Time (hours) 06121824 Mean Plasma Ethinyl Estradiol Concentration (pg/mL) 051520253040 Time (hours) 06121824 Mean Plasma Norethindrone Concentration (ng/mL) 02468 Revised January 5, 2004 6 Special Populations Geriatrics The pharmacokinetics of 1/5 have not been studied in a geriatric population. The effect of race on the pharmacokinetics of Patients with Renal Insufficiency 1/5 has not been evaluated. In premenopausal women with chronic renal failure undergoin

g peritoneal dialysis who received multiple doses of an one, plasma ethinyl estradiol concentrations were unchanged compared to concentrations in premenopausal women with normal renal function Patients with Hepatic Impairment estradiol and norethindrone may be poorly metabolized in patients with impaired liver function (see Drug Interactions Effects on Vasomotor Symptoms A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate torandomization. On average, patients had 12 hot flashes per day upon study entry.A total of 65 women were randomized to receive 1/5 and 66 women were randomized to the placebo group. The efficacy of 1/5 for the treatment of moderate to severe vasomotor symptoms (VMS) is demonstrated in Figure 2. Revi

sed January 5, 2004 8 Table 2. Endometrial Biopsy Results After 12 and 24 Months of TreatmentNumber of Patients Biopsied at Baseline 5 mcg estradiol MONTH 12 Patients Biopsied (%) 113 (84) 110 (77) 114 (82) Insufficient Tissue 30 45 20 Atrophic Tissue 60 41 2 Proliferative Tissue 23 24 91 Endometrial Patients Biopsied (%) 94 (70) 102 (71) 107 (77) Insufficient Tissue 35 37 17 Atrophic Tissue 38 33 2 Proliferative Tissue 20 32 86 Endometrial All patients with endometrial hyperplasia were carried forward for all time points Irregular Bleeding/Spotting The cumulative incidence of amenorrhea, defined as 1/5 and placebo arms. Results are shown in Figure 3. Figure 3. Patients With Cumulative AmenorrheaObservation Carried Forward Month 1Month 3Month 6Month 9Month 12 Placebo (N =137) femhrt 1/5 (N=146) Re

vised January 5, 2004 11 seases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial cancer as the primary adverse outcome studied. A “gCHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, after an average Table 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE TM rogesterone) SUBSTUDY OF WHI n = 8102 Relative Risk Absolute Risk per 10,000 Person-years CHD events

1.29 (1.02-1.63) 30 37 Non-fatal MI 1.32 (1.02-1.72) 23 30 CHD death 1.18 (0.70-1.97) 6 7 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than 0.92 (0.74-1.14) 40 37 1.15 (1.03-1.28) 151 170 Deep vein thrombosis 2.07 (1.49-2.87) 13 26 0.66 (0.44-0.98) 15 9 0.77 (0.69-0.86) 170 131 adapted from JAMA, 2002; 288:321-333 includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorecta

l cancer, hip fracture, or death due to other causes not included in Global Index * nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the "global index," absolute excess rigroup treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 perscancers and 5 fewer hip fractures. The absolute excemortality (See BOXED WARNINGEstrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous Revised January 5, 2004 13 per 10,000 women per year. If feasible, estrogens should be discontinued at least 4-6 weeks before surgery of t

he type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Induction of Malignant Neoplasms Estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. In the CE/MPA subsinvasive breast cancer (38 vs 30 per 10,000 woman-years) after an average of 5.2 years of treatment was observed in women receiving CE/MPA compared to women receiving placebo. The increased risk of breast cancer became apparent after 4 years on CE/MPA. The women reporting prior postmenopausal use of estrogens and/or r relative risk for breast cancer associated with CE/MPA than Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens . Th

is association was reanalyzed in original data from 51 studies that and without progestins. In the rving breast cancer diagnosed became tment, and subsided after treatment had been discontinued for 5 years or longer. Some later studies have suggested that postmenopausal treatment breast cancer more than treatment with estrogen A postmenopausal woman without a uterus who retherapy, and should not be exposed unnecessarily to progestins. All postmenopausal women should receive yearly breast exams by a healthcare provider and perform monthly self-examinations. In addition, mammography examinations should be scThe reported endometrial cancer risk among users of of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The g

reatest risk appears associated with prolonged use, with increased to 10 years or more, and this risk has been shown to persist for at least 15 years after cessation of estrogen treatment. Results from a 2-year clinical study of 1/5 on endometrial section of this label. Clinical surveillance of all women taking progestin/estrogen 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 abnormaevidence that “natural” estrogens are more or less hazardous than “synthetic” estrogens at equivalent 3. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in womenpostmenopausal estrogen has been reported. Revised January 5, 2004

15 Ovarian cancer n or more years, has been associated with an increased risk of ovarian cancer in some epidemiosignificant association. Data are insufficient to determine whether there is an increased risk with combined estrogen/progestin therapy in postmenopausal women. Endometriosis may be exacerbated with administration of estrogens. Uterine Bleeding and Mastodynia Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia. In cases of undiagnosed abnormal uterine bleeding, adequate diagnostic measures are indicated (see Impaired Liver FunctionEstrogens and progestins may be poorly metabolized in patients with impaired liver function. For tic jaundice associated with past caution should be exercised and in the case of recurrenc

e, medication should be discontinued. The pathologist should be advised of progestin/estrogen therapy when relevant specimens are submitted. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Some studies have shown that women taking estrgulability, primarily related to decreased antithrombin activity. This

effpronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have changes in coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies (of primarily conjugated estrogen users) report no such increase. There is insufficient information on hypercoagulability in women who have had previous thromboembolic disease, therefore, femhrt 1/5 is contraindicated in such women.Familial Hyperlipoproteinemia Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.Depression depression recurs to a serious

degree. Revised January 5, 2004 17 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 certain drugs containing ethinyl estradiol (eg, oral contraceptives containing ethinyl estradiol). In addition, drugs containing ethinyl estradiol may induce the Decreased plasma concentrations of acetaminophen and increased clearance of temazapam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with certain ethinyl-estradiol containing drug products (eg, oral contraceptives containing ethinyl estradiol). E. Carcinogenesis, MutagenesiLong-term continuous administration of natural and synthetic estrogens

in certain animal species increases the frequency of carcinomas of the breastBOXED WARNING, CONTRAINDICATIONS AND WARNINGSF. Pregnancy be used during pregnancy (see CONTRAINDICATIONSG. Nursing Mothers As a general principle, the admimothers should be done only when clearly necessary since many drugs are excreted in human milk. Estrogen administration to nursing nd quality of the milk. Dehave been identified in the milk of mothers receive effect of this on the nursing infant has not been determined1/5 is administered to nursing mothers. ADVERSE REACTIONS BOXED WARNING, WARNINGS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 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 e events that appear to be related to drug use and for approximating rates. Adverse events reported in controlled clinical studies of �Reported at a Frequency of 5% of Patients with femhrt 1/5 % of Patients Revised January 5, 2004 19 DOSAGE AND ADMINISTRATION Use of estrogen, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3 to 6 month intervals) to determine if treatment is still necessary (See BOXED WARNING) For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases o

f undiagnosed persistent or recurring abnormal be evaluated for breast abnormalities in accordance with good clinical practice. For the Treatment of Vasomotor Symptoms 1/5 should be given once daily for the treatment of moderate to severe vasomotor symptoms associated with the menopause. Patients should be reevaluated at 3 to 6 month intervals to determine if treatment is still necessary. Prevention of Osteoporosisevent postmenopausal osteoporosis (see Effect on Bone Mineral Density). Response to therapy can be assessed by measurement of bone mineral density. ailable in the following strength and package sizes: N 0430-0544-23 Bottle of 90 D-shaped tablets with 1 estradiol N 0430-0544-14 Blister card of norethindrone acetate and 5 ethinyl estradiol Keep this drug and all drugs out of the reach of chil

dren. °C (77°F); excursions permitted to 15-30 F)[see USP Controlled Room Temperature]. INFORMATION FOR THE PATIENT Please read this PATIENT INFORMATION before you start taking 1/5 and each time you refill femhrt. There may be new information. This information does not take the plhealthcare provider about your medical condition or your treatment. What is the most important information I should know about 1/5 (a combination of estrogen and progestin hormones)? Do not use estrogens and progestins to prevent heart disease, heart attacks, or strokes. Revised January 5, 2004 21 Estrogens increase the risk of certain types us. If you have or had cancer, talk with your 1/5. (see “What are the possible risks and side effects 1/5?”). art attack in the past year.After childbirth or when breast-feedin

g a baby. 1/5 should not be taken to try to stop the breasts from filling with milk after a baby is born. If you have had a hysterectomy (uterus removed). 1/5 contains a progestin to decrease the risk of developing endometrial hyperplasia (an overgrowth of the lining of the uterus that may lead to cancer). If you do not have a uterus, you do not need a progestinIf you are allergic to femhrt 1/5 or any of its ingredients. See the end of this leaflet for a list of Tell your healthcare provider: Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, or problems with youror have high calcium levels in About all the medicines you take, including prescription and nonprescription medicines, vitamin

s, and herbal supplements. Some medicines may affect how may also affect how your other medicines work.If you are going to have surgery or will be on bed rest. You may need to stop taking estrogens How should I take femhrt femhrt 1/5 pill once a day at about the same time each day. If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take two doses at the same time. Estrogens should only be used as long as needed. t you still need treatment with What are the possible risks and side effects of 1/5? Heart Disease1/5 should not be used to treat or prevtaking estrogen/progestin therapy may increase your risk of heart disease. Studies show that taking estrogen/progestin therapy may incre

ase your risk for getting breast cancer. You should have regular breast examinations by a health professional and examine your own breasts monthly. Ask your healthcare provider tobreast exam yourself. If you are over 50 years of age, you should have a mammogram every year. progestin in it. If you take any drug that regular check-ups and report nal bleeding after menopause may be a warning Revised January 5, 2004 23 Have a breast exam and mammogram (breast If members of your family hahave ever had breast lumps or an abnormal mammogram (breast x-ray), you may need more frequent breast examinations. rol (fat in the blood), diabetes, are overweight, provider for ways of lowering your chanBe alert for signs of trouble.symptoms) happen while you are taking femhpains in the calves or chest, sudden shortnes

s of breath, or coughing blood (possible clots in the severe headache or vomiting, dizziness, faintness, or changes in vision or speech, weakness or numbness of an arm or leg (possible clots in the brain or eye) breast lumps (possible breast cancer) yellowing of the skin or whites of the eyes (possible liver problem) pain, swelling, or tenderness in the abdomen (possible gallbladder problem) Other Information Discuss carefully with your doctor or healthcare provider all the possible estrogen and progestin treatment If you take calcium supplements as part of your treatment to help prevdoctor about the amounts recommended. A daily intake of 1500 mg of calcium is often recommended for postmenopausal women. Vitamin D (400 IU daily) may help your body use more of the calcium. Taking estrogens with progestins

may have unhealthy effects on blood sugar, which might make a diabetic condition worse. alone. Do not give your femhrt 1/5 to anyone else. Do not take femhrt 1/5 for conditions for which it was not prescribed. Keep all drugs out of the reach of children. In tor, hospital, or poison control center right away. What are the ingredients in femhrt 1/5? Each white D-shaped tablet contains 1 mg norethindrone acetate [19-No)-] and 5 mcg ethinyl estradiol [19-Norpregna-1,3,5(1)-]. Each tablet also contains calcium stearate, lactose monohydrate, micrThis leaflet provides the most important information about femhrt 1/5. If you want more information, ling. The professional book called “The Physicians’ Desk Reference” or PDR, available in bookstores and public libraries. Duramed Pharmaceuticals, Inc. Revised