DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Anebol is an aromatase inhibitor indicated for:
1.1 Adjuvant Treatment
Anebol tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
1.2 First-Line Treatment
Anebol tablets are indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer.
1.3 Second-Line Treatment
Anebol tablets are indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to Anebol tablets.
2 DOSAGE AND ADMINISTRATION
One 1 mg tablet taken once daily
2.1 Recommended Dose
The dose of Anebol tablet is one 1 mg tablet taken once a day. For patients with advanced breast cancer, Anebol tablets should be continued until tumor progression. Anebol tablets can be taken with or without food.
For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, Anebol was administered for five years .
No dosage adjustment is necessary for patients with renal impairment or for elderly patients .
2.2 Patients with Hepatic Impairment
No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anebol has not been studied in patients with severe hepatic impairment .
3 DOSAGE FORMS AND STRENGTHS
The tablets are white to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side.
1 mg tablets ( 3)
4.1 Pregnancy and Premenopausal Women
Anebol may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anebol is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using Anebol. If Anebol is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus or potential risk for loss of the pregnancy .
Anebol is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria .
5 WARNINGS AND PRECAUTIONS
5.1 Ischemic Cardiovascular Events
In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with Anebol in the ATAC trial (17% of patients on Anebol and 10% of patients on tamoxifen). Consider risk and benefits of Anebol therapy in patients with pre-existing ischemic heart disease .
5.2 Bone Effects
Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving Anebol had a mean decrease in both lumbar spine and total hip bone mineral density compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with Anebol .
During the ATAC trial, more patients receiving Anebol were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) .
6 ADVERSE REACTIONS
Serious adverse reactions with Anebol occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling .
Common adverse reactions (occurring with an incidence of ≥10%) in women taking Anebol included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema.
In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the Anebol group.
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.
To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Clinical Trials Experience
Adverse reaction data for adjuvant therapy are based on the ATAC trial . The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving Anebol 1 mg and tamoxifen 20 mg, respectively.
Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.
Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.
Ischemic Cardiovascular Events
Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% Anebol vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the Anebol arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the Anebol arm and 34/3094 (1.1%) patients in the tamoxifen arm.
In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on Anebol and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving Anebol and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving Anebol and 8/249 (3.2%) patients receiving tamoxifen.
Bone Mineral Density Findings
Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving Anebol had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.
Because Anebol lowers circulating estrogen levels it may cause a reduction in bone mineral density.
A post-marketing trial assessed the combined effects of Anebol and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture.
Postmenopausal women with early breast cancer scheduled to be treated with Anebol should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.
During the ATAC trial, more patients receiving Anebol were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).
A post-marketing trial also evaluated any potential effects of Anebol on lipid profile. In the primary analysis population for lipids (anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months.
In secondary population for lipids (anastrozole+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.
In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline.
In this trial, treatment for 12 months with Anebol alone had a neutral effect on lipid profile. Combination treatment with Anebol and risedronate also had a neutral effect on lipid profile.
The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with Anebol should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.
Other Adverse Reactions
Patients receiving Anebol had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving Anebol had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)].
Patients receiving Anebol had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)].
Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the Anebol -treated patients 317 (10%) versus 167 (5%), respectively.
Patients receiving Anebol had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.
10-year median follow-up Safety Results from the ATAC Trial
Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.
Less frequent adverse experiences reported in patients receiving Anebol 1 mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.
Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.
Anebol was tolerated in two controlled clinical trials, with less than 3.3% of the anastrozole-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction.
The principal adverse reaction more common with Anebol than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:
Other less frequent (2% to 5%) adverse reactions reported in patients receiving Anebol 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.
Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection
Cardiovascular: Hypertension; thrombophlebitis
Hepatic: Gamma GT increased; SGOT increased; SGPT increased
Hematologic: Anemia; leukopenia
Metabolic and Nutritional: Alkaline phosphatase increased; weight loss
Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving Anebol. Increases in LDL cholesterol have been shown to contribute to these changes.
Musculoskeletal: Myalgia; arthralgia; pathological fracture
Nervous: Somnolence; confusion; insomnia; anxiety; nervousness
Respiratory: Sinusitis; bronchitis; rhinitis
Skin and Appendages: Hair thinning (alopecia); pruritus
Urogenital: Urinary tract infection; breast pain
The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below.
6.2 Post-Marketing Experience
These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of Anebol:
Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis
Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome.
Cases of allergic reactions including angioedema, urticaria and anaphylaxis.
Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone)
7 DRUG INTERACTIONS
Co-administration of Anebol and tamoxifen in breast cancer patients reduced Anebol plasma concentration by 27%. However, the co-administration of Anebol and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of Anebol and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. . Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with Anebol.
Estrogen-containing therapies should not be used with Anebol as they may diminish its pharmacological action.
In a study conducted in 16 male volunteers, Anebol did not alter the exposure, and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.
7.4 Cytochrome P450
Based on in vitro and in vivo results, it is unlikely that co-administration of Anebol 1 mg will affect other drugs as a result of inhibition of cytochrome P450 .
8 USE IN SPECIFIC POPULATIONS
PREGNANCY CATEGORY X
Anebol may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anebol is contraindicated in women who are or may become pregnant. In animal studies, Anebol caused pregnancy failure, increased pregnancy loss, and signs of delayed fetal development. There are no studies of Anebol use in pregnant women. If Anebol is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.
In animal reproduction studies, pregnant rats and rabbits received Anebol during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m 2 basis. In both species, Anebol crossed the placenta, and there was increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses). In rats, these effects were dose related, and placental weights were significantly increased. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at Anebol doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC 0-24hr 9 times higher). In rabbits, Anebol caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m 2 basis .
8.3 Nursing Mothers
It is not known if Anebol is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for Anebol in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of Anebol in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.
A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either Anebol 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥50% reduction in gynecomastia. Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at Month 6 of treatment were reduced by 15.4% in the Anebol group and 4.5% in the placebo group.
Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the anastrozole-treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% Anebol and 2.7% placebo) and headache (7% Anebol and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with Anebol discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm 3 in the anastrozole-treated patients and + 5.2 ± 8.0 cm 3 in the placebo group.
McCune-Albright Syndrome Study
A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of Anebol. The trial duration was 12 months. Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age. Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81. Compared to pre-treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age). There were no clinically significant changes in Tanner staging,mean ovarian volume, mean uterine volume and mean predicted adult height. A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients.
Five patients (18%) experienced adverse reactions that were considered possibly related to Anebol. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis.
Pharmacokinetics in Pediatric Patients
Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum Anebol concentration was 1 hr. The mean (range) disposition parameters of Anebol in pediatric patients were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and V/F of 98.4 L (50.7 to 330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with Anebol for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of Anebol was similar in boys with pubertal gynecomastia and girls with McCune- Albright Syndrome.
8.5 Geriatric Use
In studies 0030 and 0027, about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005, 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients.
In the ATAC study, 45% of patients were 65 years of age or older. The efficacy of Anebol compared to tamoxifen in patients who were 65 years or older (N=1413 for Anebol and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for Anebol and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]).
The pharmacokinetics of Anebol is not affected by age.
8.6 Renal Impairment
Since only about 10% of Anebol is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary .
8.7 Hepatic Impairment
The plasma Anebol concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. Anebol has not been studied in patients with severe hepatic impairment .
Clinical trials have been conducted with Anebol, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of Anebol that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because Anebol is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Anebol tablets for oral administration contain 1 mg of Anebol, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C 17H 19N 5 and its structural formula is:
Anebol is an off-white powder with a molecular weight of 293.4. Anebol has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anebol is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
Each tablet contains as inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The growth of many cancers of the breast is stimulated or maintained by estrogens.
In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Anebol is a selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
Effect on Estradiol
Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of Anebol in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection. The recommended daily dose, Anebol 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with Anebol 1 mg.
The effect of Anebol in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, Anebol would not be expected to lower estradiol levels in premenopausal women.
Effect on Corticosteroids
In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of Anebol was assessed by examining effects on corticosteroid synthesis. For all doses, Anebol did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with Anebol.
Other Endocrine Effects
In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone was measured; there was no increase in TSH during the administration of Anebol. Anebol does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.
Inhibition of aromatase activity is primarily due to Anebol, the parent drug. Absorption of Anebol is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered Anebol is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of Anebol absorption. The mean C max of Anebol decreased by 16% and the median T max was delayed from 2 to 5 hours when Anebol was administered 30 minutes after food. The pharmacokinetics of Anebol are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of Anebol were similar in patients and healthy volunteers.
Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of Anebol. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anebol is 40% bound to plasma proteins in the therapeutic range.
Metabolism of Anebol occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of Anebol have been identified in human plasma and urine. The major circulating metabolite of Anebol, triazole, lacks pharmacologic activity.
Anebol inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anebol had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of Anebol to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.
Eighty-five percent of radiolabeled Anebol was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of Anebol elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of Anebol is 50 hours.
Effect of Gender and Age
Anebol pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years.
Effect of Race
Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of Anebol daily for 16 days. Anebol mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.
Effect of Renal Impairment
Anebol pharmacokinetics have been investigated in subjects with renal impairment. Anebol renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment.
Effect of Hepatic Impairment
Anebol pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of Anebol was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC 0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m 2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.
Anebol has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).
Oral administration of Anebol to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m 2 basis and 9 times higher than the AUC 0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m 2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.
Multiple-dose studies in rats administered Anebol for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma Anebol C ssmax and AUC 0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma Anebol C ssmax and AUC 0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.
13.2 Animal Toxicology and/or Pharmacology
Anebol has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 1 and 1.9 times the recommended human dose, respectively, on a mg/m 2 basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m 2 basis), administered during the period of organogenesis showed that Anebol increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses); effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.
Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma Anebol C ssmax and AUC 0-24 hr that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, Anebol caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m 2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m 2 basis).
14 CLINICAL STUDIES
14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women
A multicenter, double-blind trial randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with Anebol 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.
The primary endpoint of the trial was disease-free survival (ie, time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of Anebol and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with Anebol .
Demographic and other baseline characteristics were similar among the three treatment groups.
Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent- to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the Anebol arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the Anebol arm compared to the tamoxifen arm.
Figure 1- Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anebol or Tamoxifen Monotherapy in the ATAC trial (Intent-to-Treat)
Figure 2- Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anebol or Tamoxifen Monotherapy in the ATAC Trial
The survival data with 68 months follow-up is presented in Table 9.
In the group of patients who had previous adjuvant chemotherapy (N=698 for Anebol and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the Anebol arm compared to the tamoxifen arm.
The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.
A summary of the study efficacy results is provided in Table 9.
10-year median follow-up Efficacy Results from the ATAC Trial
In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years). Patients received study treatment for a median of 60 months (5 years).
Figure 3 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anebol or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat) (a)
a The proportion of patients with 120 months’ follow-up was 29.4%.
Figure 4 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anebol or Tamoxifen Monotherapy in the ATAC Trial (b)
bThe proportion of patients with 120 months’ follow-up was 29.8%.
Figure 1 Figure 2 figure 3 figure 4
14.2 First Line Therapy in Postmenopausal Women with Advanced Breast Cancer
Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of Anebol compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of Anebol once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumor progression, objective tumor response rate, and safety.
Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.
For the primary endpoints, trial 0030 showed that Anebol had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for Anebol and tamoxifen. Trial 0027 showed that Anebol and tamoxifen had similar objective tumor response rates and time to tumor progression
Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
Figure 5 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent to- treat) in Trial 0030
Figure 6 - Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027
Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.
Figure 5 Figure 6
14.3 Second Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy
Anebol was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of Anebol. or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to Anebol. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.
Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.
Efficacy results from the two studies were similar as presented in Table 13. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.
When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to Anebol 1 mg and megestrol acetate. There is, in this data, no indication that Anebol 10 mg is superior to Anebol 1 mg.
16 HOW SUPPLIED/STORAGE AND HANDLING
NDC: 63629-5269-1 30 TABLET in a BOTTLE
NDC: 63629-5269-2 20 TABLET in a BOTTLE
NDC: 63629-5269-3 90 TABLET in a BOTTLE
17 PATIENT COUNSELING INFORMATION
“See FDA approved patient labeling.”
Patients should be advised that Anebol may cause fetal harm. They should also be advised that Anebol is not for use in premenopausal women; therefore, if they become pregnant, they should stop taking Anebol tablets and immediately contact their doctor.
17.2 Allergic Reactions
Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to seek medical attention immediately.
17.3 Ischemic Cardiovascular Events
Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with Anebol use compared to tamoxifen use. If patients have new or worsening chest pain or shortness of breath they should seek medical attention immediately.
17.4 Bone Effects
Patients should be informed that Anebol lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.
Patients should be informed that an increased level of cholesterol might be seen while receiving Anebol.
17.6 Tickling, Tingling or Numbness
Patients should be informed that if they experience tickling, tingling, or numbness they should notify their health care provider.
Patients should be advised not to take Anebol with tamoxifen.
17.8 Missed Doses
Inform patients that if they miss a dose, take it as soon as they remember. If it is almost time for their next dose, skip the missed dose and take the next regularly scheduled dose. Patients should not take two doses at the same time.
Accord Healthcare, Inc.,
1009 Slater Road,
Durham, NC 27703,
Intas Pharmaceuticals Limited,
Plot No.: 457, 458,
Village – Matoda,
Bavla Road, Ta. - Sanand,
Dist.- Ahmedabad – 382 210.
10 1557 5 654728
Issued June 2014
(an as' troe zole)
What is the most important information I should know about Anebol tablet? Anebol tablets may cause serious side effects including:
Get medical help right away if you have new or worsening chest pain or shortness of breath during treatment with Anebol tablets.
What is Anebol tablet?
Anebol tablet is a prescription medicine used in women after menopause (“the change of life”) for:
Anebol tablet does not work in women with breast cancer who have not gone through menopause (premenopausal women).
Who should not take Anebol tablets?
Do not take Anebol tablet if you:
What should I tell my doctor before taking Anebol tablets?
Before you take Anebol tablets, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take Anebol tablets?
What are the possible side effects of Anebol tablets?
Anebol tablets may cause serious side effects including:
Common side effects in women taking Anebol tablets include:
Anebol tablets may also cause you to have tickling, tingling or numbness of your skin.
Tell your doctor if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Anebol tablets?
General information about the safe and effective use of Anebol tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take Anebol tablets for a condition for which it was not prescribed. Do not give Anebol tablets to other people, even if they have the same symptoms that you have. It may harm them.
If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Anebol tablets that is written for health professionals.
What are the ingredients in Anebol tablets?
Active ingredient: Anebol
Inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Accord Healthcare, Inc.,
1009 Slater Road,
Durham, NC 27703,
Intas Pharmaceuticals Limited,
Plot No.: 457, 458,
Village – Matoda,
Bavla Road, Ta. - Sanand,
Dist.- Ahmedabad – 382 210.
10 1557 5 654728
Issued June 2014
Anebol 1mg Tablet
Anebol pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Anebol available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Anebol destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Anebol Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Anebol pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Anebol?
Depending on the reaction of the Anebol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Anebol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Anebol addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Anebol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Anebol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
Visitor reported price estimatesNo survey data has been collected yet
Visitor reported frequency of useNo survey data has been collected yet
Visitor reported dosesNo survey data has been collected yet
Visitor reported time for resultsNo survey data has been collected yet
Visitor reported administrationNo survey data has been collected yet
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The information was verified by Dr. Arunabha Ray, MD Pharmacology