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    Thread: Aromasin - Aromasin Side Effects

    1. #1
      mick-G's Avatar
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      Default Aromasin - Aromasin Side Effects



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      Pharmacology: Breast cancer cell growth is often estrogen-dependent and antitumor activity is expected following effective and continuous estrogen suppression in patients with hormone-sensitive breast cancer. Aromatase is the key enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (mainly androstenedione) to estrogens (primarily estrone) by the aromatase enzyme in peripheral tissues. This occurs mainly in the adipose tissue, but also in the liver, muscle, hair follicles, and breast tissue. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for postmenopausal patients with hormone-dependent breast cancer.

      Exemestane is a potent aromatase inactivator, causing estrogen suppression and inhibition of peripheral aromatisation. It is a steroidal irreversible Type I aromatase inhibitor, structurally related to the natural substrate androstenedione. Exemestane is a specific competitive inactivator of human placental aromatase, which has been shown to be more potent than the irreversible aromatase inhibitor formestane or the reversible inhibitor aminoglutethimide in vitro.

      In vivo studies of aromatase inactivation indicate that exemestane, by the oral route, is several times more potent than formestane. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as suicide inhibition£. De novo aromatase enzyme synthesis is required for recovery of enzyme activity. Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women , but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

      Pharmacokinetics: Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Maximum exemestane plasma concentration (C max) was observed within 2 hours of receiving exemestane. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast; however, no further effect on estrogen suppression was observed since maximum activity was already achieved under fasting conditions. Exemestane appears to be more rapidly absorbed in women with breast cancer than in the healthy women. After repeated doses, mean T max was 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. Mean AUC values following repeated doses were approximately 2-fold higher in women with breast cancer (75.4 ng.h/mL) compared with healthy women (41.4 ng.h/mL). However, there was considerable overlap between the range of pharmacokinetic parameters observed in these two populations.

      Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and a 1-acid glycoprotein contribute equally to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

      After reaching maximum plasma concentration, exemestane levels declined polyexponentially with a mean terminal half-life of about 24 hours. Following administration of a single oral dose of radiolabeled exemestane, the elimination of drug-related products was essentially complete within 1 week. Approximately equal proportions of the dose were eliminated in urine and feces. The amount of drug excreted unchanged in urine was less than 1% of the dose, indicating that renal excretion is a limited elimination pathway. Exemestane was extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or demonstrate minimal ability to inhibit aromatase compared with the parent drug. Studies using human liver preparations indicate that cytochrome P450 3A4 (CYP3A4) is the principal isoenzyme involved in the oxidation of exemestane.

      Although women ranging in age up to 99 years were enrolled in the clinical studies, healthy postmenopausal women aged 43 to 68 years were enrolled in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

      The pharmacokinetics of exemestane following administration of a single, 25 mg tablet to fasted healthy males (mean age 32 years; range 19 to 51 years) or to fasted healthy postmenopausal women (mean age 55 years; range 45 to 68 years) have been compared. Mean C max and AUC values in healthy males (12.3±5.8 ng/mL and 28.4±17.3 ng.h/mL, respectively) were similar to those determined in healthy postmenopausal women (11.1±4.4 ng/mL and 29.7±7.8 ng.h/mL, respectively). Thus, the pharmacokinetics of exemestane does not appear to be influenced by gender.

      The influence of race on exemestane pharmacokinetics has not been formally evaluated.

      The pharmacokinetics of exemestane have been investigated in subjects with moderate and severe hepatic insufficiency. Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. However no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25-mg daily dose.

      The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m 2) compared with the AUC in healthy volunteers. However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose.

      Children: The pharmacokinetics of exemestane have not been studied in pediatric patients.


      Indications: Hormonal treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status whose disease has progressed following antiestrogen therapy.

      Contraindications: In patients with a known hypersensitivity to the drug or to any of the excipients.


      Warnings: Pregnancy: Exemestane might cause fetal harm when administered to a pregnant woman. Exemestane caused placental enlargement, dystocia, and prolonged gestation when given to pregnant rats at doses greater than 4 mg/kg/day (24 mg/m 2/day), approximately 1.5 times the recommended human daily dose (16.0 mg/m 2/day) on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women using exemestane. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus or the potential risk for loss of the pregnancy.

      Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. The administration of exemestane to pregnant rats at doses of 50 mg/kg/day during the organogenesis period caused an increase in fetal resorption, but there was no evidence of teratogenicity up to the dose of 810 mg/kg/day (4860 mg/m 2/day).

      Daily doses of exemestane 270 mg/kg/ day (4320 mg/m 2/day), which is greater than 200 times the recommended human daily dose, given to rabbits during organogenesis caused abortions, an increase in resorptions, and a reduction in fetal body weight; there was no increase in the incidence of malformations.

      Children: The safety and effectiveness of exemestane in pediatric patients have not been established.

      Lactation: Although it is not known whether exemestane is excreted in human milk, the drug was shown to be excreted in the milk of lactating rats . Because there is a potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with exemestane.

      Precautions: General: Exemestane should not be administered to women with premenopausal endocrine status. Exemestane should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

      Laboratory Tests: Approximately 20% of patients receiving exemestane in clinical studies, particularly those with pre-existing lymphocytopenia, experienced a moderate transient decrease in lymphocytes. However, mean lymphocyte values in these patients did not change significantly over time. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevation of the serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase >5 times the upper value of the normal range have been rarely reported. These changes were mostly attributable to the underlying presence of liver and/or bone metastases. In the Phase III study, elevation of the gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with exemestane and in 1.8% of patients treated with megestrol acetate.

      Drug Interactions : Exemestane is metabolized by cytochrome P450 (CYP) 3A4 and aldoketoreductases, and does not inhibit any of the major CYP isoenzymes, including CYP1A2, 2C9, 2D6, 2E1, and 3A. In a clinical pharmacokinetic study, the specific inhibition of CYP3A4 by ketoconazole administration showed no significant influence on the pharmacokinetics of exemestane. Although no formal drug-drug interaction studies have been conducted, significant pharmacokinetic interactions mediated by CYP isoenzymes appear unlikely. However, a possible decrease of exemestane plasma levels by known inducers of CYP3A4 cannot be excluded.

      Laboratory Test Interactions : No clinically relevant changes in the results of clinical laboratory tests have been observed.

      Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with exemestane. Exemestane was not mutagenic in bacteria (Ames test) or genotoxic in V79 Chinese hamster cells, rat hepatocytes, or the mouse micronucleus assay. Exemestane was clastogenic in human lymphocytes in vitro at a concentration of 12.5 µg/mL, approximately 700 times the maximum plasma concentration in humans after a single, 25-mg dose of exemestane. No fertility studies in male rats were performed. Exemestane showed no effects on female fertility parameters (e.g., ovarian function, mating behavior, conception rate) in rats given doses up to 4 mg/kg/day (24 mg/m 2/day).

      Geriatrics: Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

      Renal Dysfunction: The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m 2) compared with the AUC in healthy volunteers. However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose.

      Hepatic Dysfunction: Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. However, no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25 mg daily dose.

      Potential Effect on Antithrombin III: To date, there is no indication that exemestane affects antithrombin III. Some steroidal compounds are known to affect antithrombin III, increasing the risk of thromboembolic events. Preclinical data evaluating exemestane's potential to affect antithrombin III is not available; however, studies in humans are ongoing.

      Adverse Effects: A total of 1058 patients were treated with Aromasin (exemestane) Tablets 25 mg once daily in the clinical trials program. Exemestane was generally well tolerated and adverse events were usually mild to moderate. Only 1 death was potentially related to treatment with exemestane; an 80-year-old women with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 2.8% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations due to adverse events were uncommon (0.3%).

      In the Phase III study, 358 patients were treated with exemestane and 400 patients were treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (1.7 vs 5%). Adverse events in the Phase III study that were considered drug related or of indeterminate cause included hot flashes (12.6%), nausea (9.2%), fatigue (7.5%), increased sweating (4.5%), and increased appetite (2.8%). The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17.1 vs 7.6%, p=0.001). Table I shows the adverse events of all National Cancer Institute (NCI) Common Toxicity grades regardless of causality reported in 5% or greater of patients in the Phase III study treated either with exemestane or megestrol acetate.

      In the overall clinical trials program (N=1058), adverse events reported in 5% or greater of patients treated with exemestane 25 mg once daily included pain at tumor site (8%), asthenia (5.8%) and fever (5%). Less frequent adverse events (2 to 5%) reported in all patients receiving exemestane 25 mg once daily were arthralgia, peripheral edema, back pain, dyspepsia, paresthesia, bronchitis, rash, chest pain, edema, hypertension, upper respiratory tract infection, pruritus, urinary tract infection, pathological fracture, alopecia, leg edema, sinusitis, skeletal pain, infection, pharyngitis, rhinitis, hypoesthesia, confusion, and lymphedema.

      Overdose: Symptoms and Treatment: Clinical trials have been conducted with exemestane given up to 800 mg as a single dose to healthy female volunteers and up to 600 mg daily for 12 weeks to postmenopausal women with advanced breast cancer. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

      A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leukocytosis (WBC: 25 000/mm 3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given.

      In rats and dogs, mortality was observed after single oral doses of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m 2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m 2 basis), respectively.


      Dosage: The recommended dose is 25 mg once daily. Take with food. Treatment should continue until tumor progression is evident. No dose adjustments are required for patients with hepatic or renal insufficiency.

      Information for the Patient: See Blue Section--Information for the Patient Aromasin.

      Supplied: Each round, biconvex, off-white to slightly gray tablet, printed on one side with the number 7663£ in black, contains: exemestane 25 mg. Nonmedicinal ingredients: carnauba wax, cetyl esters wax, colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium carbonate, magnesium stearate, mannitol, methyl-p-hydroxybenzoate, microcrystalline cellulose, polyethyleneglycol, polysorbate 80, polyvinyl alcohol, shellac, simethicone, sodium starch glycolate, sucrose, talc and titanium dioxide. HDPE bottles with a child-resistant screw cap of 30. Store between 15 and 30°C.

    2. #2
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      a-bomb83 is offline Elite FG Resident
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      Default Re: Aromasin - Aromasin Side Effects

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      very, very good info.
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