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Activella Tablets (Novo Nordisk)
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Activella® is a single tablet containing an estrogen, estradiol (E 2 ), and a progestin, norethindrone acetate (NETA), for oral administration. Each tablet contains 1 mg estradiol and 0.5 mg norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin.
Estradiol (E 2 ) is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 (10)-triene-3, 17(beta)-diol hemihydrate with the empirical formula of C 18 H 24 O 2 , 1/2 H 2 O and a molecular weight of 281.4. The structural formula of E 2 is as follows:
Norethindrone acetate (NETA) is a white or yellowish-white crystalline powder. Its chemical name is 17(beta)-acetoxy-19-nor-17(alpha)-pregn-4-en-20-yn-3-one with the empirical formula of C 22 H 28 O 3 and a molecular weight of 340.5. The structural formula of NETA is as follows:
Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes and bind to and activate the nuclear estrogen receptor, a DNA-binding protein that is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, that 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, and bone in women.
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 µg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion in peripheral tissues of androstenedione which is secreted by the adrenal cortex, to estrone. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) through a negative feedback mechanism, and estrogen replacement therapy acts 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, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.
The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. The addition of a progestin, in adequate doses and appropriate duration, to an estrogen replacement regimen reduces the incidence of endometrial hyperplasia, and the attendant risk of carcinoma in women with intact uterus.
Estradiol is well absorbed through the gastrointestinal tract. Following oral administration of Activella® (estradiol/norethindrone acetate tablets), peak plasma estradiol concentrations are reached slowly within 5-8 hours. When given orally, estradiol is extensively metabolized (first-pass effect) to estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogens. After oral administration, norethindrone acetate is rapidly absorbed and transformed to norethindrone. It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 0.5-1.5 hours. The oral bioavailability of estradiol and norethindrone following administration of Activella® when compared to a combination oral solution is 53% and 100%, respectively. The pharmacokinetic parameters of estradiol (E 2 ). estrone (E 1 ), and norethindrone (NET) following single oral administration of Activella® in 25 volunteers are summarized in TABLE 1.
Following continuous dosing with once-daily administration of Activella® (estradiol/norethindrone acetate tablets), serum levels of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33-47% above levels following single dose adminstration. Unadjusted circulating levels of E 2 , E 1 , and NET during Activella® treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.
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. Estradiol circulates in the blood bound to sex-hormone-binding globulin (SHBG) (37%) and to albumin (61%), while only approximately 1-2% is unbound. Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).
METABOLISM AND EXCRETION
Estradiol: 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. The half-life of estradiol following single dose administration of Activella® (estradiol/norethindrone acetate tablets) is 12-14 hours.
Norethindrone Acetate: The most important metabolites of norethindrone are isomers of 5(alpha)-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates. The terminal half-life of norethindrone is about 8-11 hours.
Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone. Similarly, no relevant interaction of norethindrone on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study.
A single-dose study in 24 healthy postmenopausal women was conducted to investigate any potential impact of administration of Activella® with and without food. Administration of Activella® with food did not modify the bioavailability of estradiol, although increases in AUC 0-72 of 19% and decreases in C max of 36% for norethindrone were seen.
Activella® is effective in reducing the number of moderate-to-severe vasomotor symptoms in postmenopausal women. In a 12-week radomized clinical trial involving 92 subjects, Activella® was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 12 in both the Activella® and the 1 mg estradiol group compared to placebo (see Figure 2).
Activella® (estradiol/norethindrone acetate tablets) reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E 2 + 0.1 mg NETA (n=294), 1 mg E 2 + 0.25 mg NETA (n=291), and Activella® [1 mg E 2 + 0.5 mg NETA] (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects. The results of the 1 mg estradiol unopposed arm compared to Activella® are shown in TABLE 2.
During the initial months of therapy, irregular bleeding or spotting occurred with Activella® treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Activella®, fewer than 3% of women reported bleeding (see Figure 3).
INFORMATION REGARDING LIPID EFFECTS
A 12-month, placebo-controlled clinical trial in 80 postmenopausal Caucasian women at low risk for cardiovascular disease compared the effects of Activella® to placebo on lipid parameters. These results are shown in TABLE 3.
EFFECT ON BONE MINERAL DENSITY
The results of two randomized, multicenter, calcium-supplemented (500-1000 mg/day), placebo-controlled, 2 year clinical trials have shown that Activella® (estradiol/norethindrone acetate tablets) is effective in preventing bone loss in postmenopausal women. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo. In a European trial, 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo.
Approximately 58% and 67% of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DEXA).
A summary of the results comparing Activella® and placebo from the two prevention trials is shown in Table 4.
The overall difference in mean percentage change in BMD at the lumbar spine between Activella® and placebo was 5.9% in the US trial (1000 mg/day calcium) and 6.3% in the European trial (500 mg/day calcium). Activella® also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials is displayed in Figure 4.
EFFECT ON BONE TURNOVER
Activella® (estradiol/norethindrone acetate tablets) significantly reduced serum and urine markers of bone turnover with a marked decrease in bone resorption makers (e.g., urinary pyridinoline crosslinks Type 1 collagen C-telopeptide, pyridinoline, deoxypyridinoline) and to a lesser extent in bone formation markers (e.g., serum osteocalcin, bone-specific alkaline phosphatase, C-terminal propetide of Type 1 collagen). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 24-month treatment period.
INDICATIONS AND USAGE
Activella® therapy is indicated in women with an intact uterus for the:
Most prospective studies of efficacy for the osteoporosis prevention indication have been carried out in white postmenopausal women, without stratification by other risk factors, and tend to show a universally beneficial effect on bone. Since estrogen administration is associated with risk, patient selection must be individualized based on the balance of risks and benefits.
Case-control studies have shown an approximately 60-percent reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years after menopause. Studies also suggest that estrogen reduces the rate of vertebral fractures. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. White and Asian women are at higher risk for osteoporosis than black women, and thin women are at a higher risk than heavier women, who generally have higher endogenous estrogen levels. Early menopause is one of the strongest predictors for the development of osteoporosis. Other factors associated with osteoporosis include genetic factors (small build, family history), lifestyle (cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body weight and dietary calcium intake).
The mainstays of prevention and management of osteoporosis are weight-bearing exercise, adequate calcium intake, and, when indicated, estrogen. 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. The average calcium intake in the USA is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake.
Estrogens/progestins combined should not be used in women under any of the following conditions or circumstances.
ALL WARNINGS BELOW PERTAIN TO THE USE OF THIS COMBINATION PRODUCT.
Based on experience with estrogens and/or progestins:
Based on experience with estrogens and/or progestins:
Based on experience with estrogens:
Based on experience with progestins:
INFORMATION FOR THE PATIENT
See text of Patient Package Insert which appears after the HOW SUPPLIED section.
DRUG/LABORATORY TEST INTERACTIONS
The following interactions have been observed with estrogen therapy, and/or Activella® (estradiol/norethindrone acetate tablets):
CARCINOGENESIS, MUTAGENESIS, and IMPAIRMENT OF INFERTILITY
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See CONTRAINDICATIONS and WARNINGS ).
PREGNANCY CATEGORY X:
Estrogens/progestins should not be used during pregnancy. (See CONTRAINDICATIONS and WARNINGS ).
Detectable amounts of estradiol and norethindrone acetate have been identified in the milk of mothers receiving these products and has been reported to decrease the quantity and the quality of the milk.
As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Activella® (estradiol/norethindrone acetate tablets) did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
(See WARNINGS regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, elevated blood pressure, thromboembolic disorders, cardiovascular disease, visual abnormalities, and hypercalcemia and PRECAUTIONS regarding cardiovascular disease).
Adverse events reported by investigators in the Phase 3 studies regardless of causality assessment are shown in TABLE 5.
The following adverse reactions have been reported with estrogen and/or progestin therapy:
Genitourinary system: changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, increase in size of uterine leiomyomata, vaginal candidiasis, changes in amount of cervical secretion, premenstrual-like syndrome, cystitis-like syndrome.
Breasts: tenderness, enlargement.
Gastrointestinal: nausea, vomiting, changes in appetite, cholestatic jaundice, abdominal pain, flatulence, bloating, increased incidence of gallbladder disease.
Skin: chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, itching, skin rash and pruritus.
Cardiovascular: changes in blood pressure, cerebrovascular accidents, deep venous thrombosis and pulmonary embolism.
CNS: headache, migraine, dizziness, depression, chorea, insomnia, nervousness.
Eyes: steepening of corneal curvature, intolerance to contact lenses.
Miscellaneous: increase or decrease in weight, aggravation of porphyria, edema, changes in libido, fatigue, allergic reactions, back pain, arthralgia, myalgia.
Acute Overdose: Serious ill effects have not been reported following acute ingestion of large doses of estrogen/progestin-containing oral contraceptives by young children. Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
Activella® (estradiol/norethindrone acetate tablets) therapy consists of a single tablet to be taken once daily. For the treatment of moderate to severe vasomotor symptoms associated with the menopause, treatment of vulvar and vaginal atrophy, and the prevention of postmenopausal osteoporosis - Activella® 1 mg E 2 / 0.5 mg NETA daily. The doses of 17beta-estradiol and norethindrone acetate in Activella® may not be the lowest effective dose-combination for the prevention of osteoporosis.
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 abnormal vaginal bleeding.
Activella®, 1 mg estradiol and 0.5 mg norethindrone acetate, is a white, film-coated tablet, engraved with NOVO 288 on one side and the APIS bull on the other. It is round, 6 mm in diameter and bi-convex.
Activella® is supplied as:
28 tablets in a calendar dial pack dispenser NDC 0169-5174-02.
Store in a dry place protected from light. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
[See USP Controlled Room Temperature]
Activella® is a trademark owned by
Novo Nordisk A/S
Revised July 2003
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
Novo Nordisk AS
2880 Bagsvaerd, Denmark