Date of approval.
Date of revision.
Exemestane Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Exemestane Tablets
Trade name: Sulley
English name: Exemestane Tablets
Hanyu Pinyin: Yiximeitan Pian
Ingredients
The main ingredient of this product is exemestane.
Chemical name: 6-methylene-androsta-1,4-diene-3,17-dione
Chemical structure formula.
Molecular formula: C20H24O2
Molecular weight: 296.41
Properties
This product is white or off-white round film coated tablets, one side has the engraved word “111”, after removing the coating appears white or off-white.
Indications
For the adjuvant treatment of early invasive breast cancer in postmenopausal estrogen receptor positive women after 2-3 years of adjuvant tamoxifen therapy until the completion of a total of 5 years of adjuvant endocrine therapy.
For advanced breast cancer in natural or artificially postmenopausal women whose disease has progressed after tamoxifen treatment. The efficacy of this product in estrogen receptor-negative patients is not clear.
Specification
25mg
Dosage]
Adults and elderly patients.
The recommended dose for the treatment of patients with early and advanced breast cancer is 25 mg, one tablet once daily, with meals.
Patients with early stage breast cancer should continue treatment with exemestane after 2-3 years of tamoxifen therapy in the absence of recurrence or contralateral breast cancer until completion of 5 years of combined sequential adjuvant endocrine therapy (i.e. tamoxifen sequential exemestane).
Patients with advanced breast cancer should continue to take exemestane until tumor progression.
The combination of strong inducers of cytochrome P-450 (CYP) 3A4 will reduce exemestane exposure. The recommended dose of exemestane is 50 mg once daily with a meal when patients receive concomitant CYP 3A4 strong inducers such as rifampin and phenytoin (see [Drug Interactions] and [Pharmacokinetics]).
[Adverse Reactions].
Among patients with early-stage breast cancer treated with tamoxifen sequential adjuvant exemestane, 7.4% withdrew from treatment due to adverse events. The most frequently reported adverse events were mild to moderate hot flashes (22%), arthralgia (18%), fatigue (16%), headache (13.1%), insomnia (12.4%), and increased sweating (11.8%).
Discontinuation due to adverse events was similar in the exemestane and tamoxifen groups (6.3% vs. 5.1%). The incidence of myocardial ischemic events (myocardial infarction, angina pectoris, myocardial ischemia) was 1.6% in the exemestane group and 0.6% in the tamoxifen group. The incidence of heart failure was 0.4% in the exemestane group and 0.3% in the tamoxifen group.
Among all patients with advanced breast cancer, the rate of study withdrawal due to adverse events was 2.8%. The most frequently reported adverse reactions were hot flashes (14%), nausea (12%), fatigue (8%), increased sweating (4%), and increased appetite (3%).
Most of the adverse reactions were due to normal pharmacological reactions (e.g., hot flashes) that occur when estrogen production is blocked.
The reported adverse reactions are listed below according to frequency of occurrence and systemic organ class (see Table 1).
Frequency of occurrence was defined as: very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1,000 to <1/100), and rare (≥1/10,000 to <1/1,000).
Table 1. Adverse reactions by frequency of occurrence and systemic organ
Metabolic and nutritional disorders/common Anorexia Mental abnormalities/very common Depression, insomnia Nervous system abnormalities/very common Headache, dizziness Common Carpal tunnel syndrome Rare Drowsiness Vascular abnormalities/very common Hot flashes Gastrointestinal abnormalities/very common Abdominal pain, nausea Common Vomiting, diarrhea, constipation, dyspepsia Hepatobiliary abnormalities: very common Elevated liver enzymes, elevated blood bilirubin, elevated blood alkaline phosphatase Skin and subcutaneous tissue abnormalities/very common Common Increased sweating Common Hair loss, rash Musculoskeletal abnormalities: Very common
Common Joint and musculoskeletal pain (*)
Fractures, osteoporosis Systemic and local abnormalities: Very common
Common
Rare Pain, fatigue
Peripheral edema
Weakness (*) Includes: arthralgia, and occasional extremity pain, osteoarthritis, back pain, arthritis, myalgia, and joint stiffness
Clinical trial experience
Because clinical trials are conducted under widely varying conditions, the rates of adverse reactions observed in clinical trials of one drug are not directly comparable to those observed in clinical trials of another drug and may not reflect the rates observed in clinical practice.
Blood and Lymphatic System Abnormalities
Rarely, thrombocytopenia or leukopenia has been reported in patients with advanced breast cancer treated with exemestane. Episodic lymphopenia occurs in approximately 20% of patients receiving exemestane, particularly in patients with prior lymphopenia; however, the mean lymphocyte count in these patients did not change significantly over time, and no increase in corresponding viral infections was observed. None of these abnormalities were found in the early breast cancer study.
Adjuvant therapy for early-stage breast cancer
The data described below reflect exposure of 2325 women with early postmenopausal breast cancer to exemestane. 2 rigorous controlled studies evaluated the tolerability of exemestane in women with early postmenopausal breast cancer, the IES Study (Intergroup Exemestane Study) and the 027 Study (a specially designed randomized, placebo-controlled, double-blind, parallel study to evaluate the tolerability of exemestane in women with early postmenopausal breast cancer). The two clinical studies were the IES (Intergroup Exemestane Study) and 027 (a specially designed randomized, placebo-controlled, double-blind, parallel study to evaluate the effects of exemestane treatment on bone metabolism, hormones, lipids and coagulation factors over 2 years).
The severity of signs and symptoms in both studies were graded according to the CTC (Common Toxicity Criteria) criteria. list assessment without evaluation of their severity. These included myocardial infarction, other cardiovascular diseases, obstetric and gynecological diseases, osteoporosis, osteoporotic fractures, other primary neoplasms, and hospitalization.
The median duration of treatment for patients receiving adjuvant therapy in the IES study was 27.4 months in the exemestane group and 27.3 months in the tamoxifen group.027 The median duration of treatment for patients receiving adjuvant therapy in the IES study was 23.9 months in both the exemestane and placebo groups.027 The median duration of observation in the IES study was 34.5 months in the exemestane group and 34.6 months in the tamoxifen group.027 The median duration of observation in the IES study was 34.5 months in the exemestane group and 34.6 months in the tamoxifen group.027 The median duration of observation for both studies was 30 months.
The incidence of treatment discontinuation due to adverse effects was 6.3% in the exemestane group and 5.1% in the tamoxifen group in the IES study.027 The incidence of treatment discontinuation due to adverse effects was 12.3% in the exemestane group and 4.1% in the placebo group in the IES study. In the IES study, the incidence of death from any cause in patients in the exemestane group was 1.3% compared with 1.4% in the tamoxifen group. Deaths due to stroke occurred in 6 patients in the exemestane group and 2 in the tamoxifen group. Deaths due to heart failure occurred in 5 patients in the exemestane group and 2 in the tamoxifen group.
The incidence of cardiac ischemic events (myocardial infarction, angina pectoris and myocardial ischemia) was 1.6% in the exemestane group and 0.6% in the tamoxifen group. The incidence of heart failure was 0.4% in the exemestane group and 0.3% in the tamoxifen group.
The incidence of adverse reactions and diseases of all causes ≥5% after treatment in patients in the IES study during and within 1 month after the end of treatment are shown in Table 2.
Table 2. incidence of all CTC-graded1 adverse reactions and disease in the IES study in women with early postmenopausal breast cancer (incidence ≥5%)
Patient % Body systems and adverse reactions named in MedDRA dictionary Exemestane
25 mg/day
(N = 2252) Tamoxifen
20mg/day2
(N = 2280) Eyes
Visual disturbances3
5.0
3.8 Gastrointestinal
Nausea3
8.5
8.7 Whole body abnormalities
Fatigue3
16.1
14.7 Musculoskeletal
Joint pain
Extremity pain
Back pain
Osteoarthritis
14.6
9.0
8.6
5.9
8.6
6.4
7.2
4.5 Neurological
Headache3
Dizziness3
13.1
9.7
10.8
8.4 Mental illness
Insomnia3
Depression
12.4
6.2
8.9
5.6 Skin and subcutaneous tissue
Increased sweating 3
11.8
10.4 Vascular system
Hot flashes3
Hypertension
21.2
9.8
19.9
8.4 1 Graded by CTC.
2 75 patients received tamoxifen at a dose of 30 mg/day.
3 Events were actively collected.
In the IES study, the exemestane group had a higher incidence of adverse events in the musculoskeletal and neurological systems compared with the tamoxifen group, including the following events with an incidence of less than 5% [osteoporosis (4.6% vs 2.8%), osteochondrosis and trigger finger (0.3% vs 0), sensory abnormalities (2.6% vs 0.9%), carpal tunnel syndrome (2.4% vs 0.2%) and neurological disorders (0.6% vs 0.1%)]. Diarrhea occurred more frequently in the exemestane group (4.2% vs 2.2%). Clinical fractures occurred in 94 patients (4.2%) in the exemestane group and 71 patients (3.1%) in the tamoxifen group. After a median treatment duration of approximately 30 months and a median follow-up of approximately 52 months, the incidence of gastric ulcers was slightly higher in the exemestane group than in the tamoxifen group (0.7% vs <0.1%). The majority of patients in the exemestane group who developed gastric ulcers had received concurrent NSAID therapy and/or had a prior history of gastric ulcers during the study period.
Adverse reactions with a higher incidence associated with tamoxifen were muscle cramps (3.1% vs 1.5%), thromboembolism (2.0% vs 0.9%), endometrial hyperplasia (1.7% vs 0.6%), and uterine polyps (2.4% vs 0.4%).
In the IES study, the incidence of ischemic cardiovascular events was 4.5% vs 4.2% in the exemestane and tamoxifen groups, respectively. No significant differences were found between the two groups for any of the individual cardiovascular events, including hypertension (9.9% vs 8.4%), myocardial infarction (0.6% vs 0.2%), and heart failure (1.1% vs 0.7%).
In the IES study, exemestane was associated with a higher incidence of hypercholesterolemia compared with triamcinolone, with an incidence of 3.7% and 2.1% in the exemestane and triamcinolone groups, respectively.
The common adverse reactions in the 027 study are shown in Table 3.
Table 3. incidence of all CTC-graded* adverse reactions following treatment in patients in study 027 (incidence ≥ 5%)
Adverse reactions Exemestane
N = 73
(incidence %) Placebo
N = 73
(incidence %) Hot flashes 32.924.7 Arthralgia 28.828.8 Increased sweating 17.820.6 Hair loss 15.14.1 Hypertension 15.16.9 Insomnia 13.715.1 Nausea 12.316.4 Fatigue 11.019.2 Abdominal pain 11.013.7 Depression 9.66.9 Diarrhea 9.61.4 Dizziness 9.69.6 Dermatitis 8.21.4 Headache 6.94.1 Myalgia 5.54.1 Edema 5.56.9* Most events were CTC grade 1-2
In study 027, exemestane was associated with a mean 7-9% reduction in plasma HDL-cholesterol compared with a 1% increase in the placebo group. ApoA1 was reduced by 5-6% in the exemestane group but by 0-2% in the placebo group. The results of the analysis of other lipid markers (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein B, and lipoprotein-a) were similar in both groups. The clinical significance of these results is unclear.
Treatment of advanced breast cancer
A total of 1058 patients were treated with exemestane 25 mg/day in the clinical study. Only one patient’s death may have been related to treatment with exemestane. An 80-year-old female patient with coronary artery disease developed myocardial infarction accompanied by multiple organ failure at week 9 after treatment with exemestane. In the above clinical study, only 3% of patients discontinued treatment due to adverse effects, mainly in the first 10 weeks of treatment, and discontinuation of treatment due to adverse effects afterwards was rare (0.3%).
In a controlled study, 358 patients treated with exemestane and 400 patients treated with megestrol acetate were evaluated for adverse reactions. The incidence of discontinuation of treatment due to adverse reactions was lower in patients receiving exemestane than in the medroxyprogesterone acetate group, at 2% and 5%, respectively. The incidence of drug-related or unidentified adverse reactions in the exemestane and megestrol acetate groups were: hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%), respectively. The percentage of patients who gained weight (>10% of baseline weight) was significantly higher in the megestrol acetate group than in the exemestane group, 17% and 8%, respectively. Table 4 shows all CTC grades for patients treated with exemestane or megestrol acetate in the study, regardless of causality, and with an incidence of ≥5% adverse reactions.
Table 4. Incidence (%) of all CTC-graded* adverse reactions with an incidence of ≥5% in controlled studies of advanced breast cancer
Body systems and adverse reactions named after MedDRA dictionary Exemestane
25 mg QD
(N = 358) Megestrol acetate
40mg QID
(N = 400) Autonomic
Increased sweating
6
9 General
Fatigue
Hot flashes
Aches and pains
Flu-like symptoms
Edema (generalized edema, peripheral edema, and leg edema)
22
13
13
6
7
29
6
13
5
6 Cardiovascular system
Hypertension
5
6 Nervous system
Depression
Insomnia
Anxiety
Dizziness
Headache
13
11
10
8
8
9
9
11
6
7 Gastrointestinal
Nausea
Vomiting
abdominal pain
Anorexia
Constipation
Diarrhea
Increased appetite
18
7
6
6
5
4
3
12
4
11
5
8
5
6 Respiratory system
Difficulty in breathing
Coughing
10
6
15
7* Classified by CTC
In that controlled study, the less frequent adverse reactions of any cause (incidence 2%-5%) in patients treated with exemestane 25 mg/day were fever, generalized weakness, abnormal sensation, pathological fracture, bronchitis, sinusitis, rash, pruritus, urinary tract infection, and lymphedema.
Other adverse reactions with an incidence of ≥5% from any cause observed in patients treated with exemestane 25 mg/day in all clinical studies (N=1058) (except control studies) were localized tumor pain (8%), malaise (6%), and fever (5%). Adverse reactions with an incidence of 2%-5% from any cause in patients in the above clinical studies were chest pain, dullness of sensation, confusion, dyspepsia, arthralgia, back pain, bone pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia.
Laboratory abnormalities: The incidence of hematologic toxicity (≥ CTC grade 1) was lower in the exemestane group than in the tamoxifen group in patients with early-stage breast cancer. The incidence of CTC grade 3 or 4 adverse reactions was low in both groups (approximately 0.1%). In clinical studies in advanced breast cancer, CTC grade 3 or 4 lymphopenia occurred in approximately 20% of patients treated with exemestane, of whom 89% had mild lymphopenia prior to treatment and 40% recovered or decreased in severity after treatment. No significant increase in viral infections and opportunistic infections were observed. Plasma AST, ALT, alkaline phosphatase, and gamma-glutamyl transferase levels greater than 5 times the upper limit of the normal range (e.g., ≥CTC grade 3) were reported rarely in patients with advanced breast cancer on treatment, but were mostly seen in patients with underlying liver and/or bone metastases. The incidence of elevated CTC grade 3 or 4 γ-glutamyl transferase levels in controlled studies of patients with advanced breast cancer without liver metastases was 2.7% in the exemestane group and 1.8% in the megestrol acetate group.
In patients with early-stage breast cancer, elevated levels of bilirubin, alkaline phosphatase, and creatinine were more likely to occur in the exemestane group than in the tamoxifen or placebo groups. The incidence of treatment-related elevations in bilirubin levels (any CTC grade) in the IES study was 5.3% in the exemestane group and 0.8% in the tamoxifen group, and 6.9% in the exemestane group and none in the placebo group in Study 027. The incidence of elevated bilirubin levels in CTC grade 3 or 4 was 0.9% in the exemestane group and 0.1% in the tamoxifen group. The incidence of elevated alkaline phosphatase levels in any CTC class was 15.0% in the exemestane group and 2.6% in the tamoxifen group in the IES study and 13.7% in the exemestane group and 6.9% in the placebo group in the 027 study. The incidence of elevated creatinine levels was 5.8% in the exemestane group and 4.3% in the tamoxifen group in the IES study; 5.5% in the exemestane group and none in the placebo group in the 027 study.
A decrease in BMD associated with treatment duration was observed in the exemestane group. Changes in BMD from baseline to 24 months of treatment are shown in Table 5. concomitant use of bisphosphonates, vitamin D supplementation, and calcium were not allowed in the trial.
Table 5. Change in BMD (%) from baseline to 24 months of treatment, exemestane group vs. control group1
IES Study 027 Study BMD exemestane
N = 29 Tamoxifen
N = 38 exemestane
N = 59 placebo
N = 65 Lumbar spine (%) -3.14-0.18-3.51-2.35 Femoral neck (%) -4.15-0.33-4.57-2.591 Patients with 24 months of data.
Drug/lab test interactions: no clinically relevant changes were observed in the results of clinical laboratory tests.
Postmarketing Experience
Immune system abnormalities
Rare: Hypersensitivity reactions
Neurological abnormalities
Common: sensory confusion
Abnormalities of the hepatobiliary system
Rare: Hepatitis, bilious hepatitis
Because adverse reactions are spontaneously reported from an uncertain population, it is often impossible to properly assess their frequency or to determine a causal relationship with the drug.
Skin and subcutaneous tissue abnormalities
Common: urticaria, pruritus
Rare: Acute generalized eruptive pustulosis
Contraindicated]
Contraindicated in persons with known hypersensitivity to the active ingredient of the drug or any of the excipients, and in premenopausal and pregnant or lactating women.
Precautions】
Use with caution in athletes.
Exemestane tablets are not indicated in women whose endocrine status is premenopausal. Therefore, if clinically indicated, LH, FSH and estradiol levels should be tested to determine if they are in a postmenopausal state. It should also not be used in combination with estrogen-containing drugs, as such drugs will affect their pharmacological effects.
It should be used with caution in patients with impaired liver or kidney function.
Because exemestane tablets are strong estrogen-lowering agents, reduced bone mineral density and increased fracture rates have been observed following treatment. When exemestane is used as an adjunctive therapy, women with osteoporosis or at risk for osteoporosis should have a formal check of bone mineral density using bone densitometry at the start of treatment. Patients should be monitored for bone mineral density loss and treated as needed.
Because of the extreme prevalence of severe vitamin D deficiency associated in women with early-stage breast cancer, routine evaluation of 25hydroxyvitamin D levels should be considered prior to initiation of aromatase inhibitor therapy. Women with vitamin D deficiency should receive vitamin D supplements.
Medication for premenopausal women
Exemestane is not indicated for the treatment of premenopausal breast cancer patients.
Embryo-fetal toxicity
Based on the results of animal studies and mechanism of action, exemestane may cause fetal harm when administered to pregnant women. In animal reproduction studies, the incidence of miscarriage and embryo-fetal toxicity was increased in pregnant rats and rabbits receiving exemestane. Pregnant women should be informed of the potential risks of exemestane to the fetus. Women of reproductive potential should be advised to use effective contraception during treatment with exemestane and for 1 month after the last dose of the drug.
For Pregnant and Lactating Women
Pregnant women
Risk Summary
Based on the results of animal studies and mechanism of action, the use of exemestane in pregnant women may cause fetal harm (see [Pharmacologic Toxicology]). The limited human data in case reports are insufficient to determine drug-related risks. In animal reproduction studies, the incidence of miscarriage, embryo-fetal toxicity, overdue pregnancy, and abnormal or obstructed labor was increased in pregnant rats and rabbits receiving exemestane (see Data). Pregnant women should be informed of the potential risks of exemestane to the fetus.
For the indication population, the expected background risk of major birth defects and miscarriage is unknown. In the general U.S. population, the predicted background risks of major birth defects and miscarriage in clinically confirmed pregnancies are 2-4% and 15-20%, respectively.
Data
Animal Data
In rat and rabbit reproduction studies, exemestane produced embryo-fetal toxicity and was abortifacient. Exemestane was administered orally to rats at 1 mg/kg and 14C-labeled exemestane was found to be transmissible to the placenta. The concentrations of exemestane and its metabolites in the blood of mother rats and embryos were approximately equal. An increase in placental weight was observed when exemestane was administered orally to rats from 14 days prior to mating until day 15 or 20 of gestation and then reintroduced from day 21 of lactation at a dose of 4 mg/kg/day (approximately 1.5 times the recommended human dose, calculated as mg/m2).
At doses equal to or greater than 20 mg/kg/day (approximately 7.5 times the recommended daily human dose in mg/m2), increased embryo uptake, decreased number of viable litters, decreased litter weight, delayed ossification, overdue pregnancies, and abnormal or difficult deliveries were observed. Daily doses of exemestane given to rabbits at 90 mg/kg/day (approximately 70 times the recommended human dose in mg/m2) during the fetal organogenesis phase resulted in decreased placental weight and maternal toxicity, abortion, increased embryo uptake and decreased fetal weight were observed at 270 mg/kg/day. No fetal malformations were observed in pregnant rats or rabbits at doses up to 810 and 270 mg/kg/day (approximately 320 and 210 times the recommended human dose, respectively, based on mg/m2) during the fetal organogenesis phase.
Lactating women
Risk Summary
No data are available on the presence or absence of exemestane in breast milk and its effect on breastfed infants or lactation. Concentrations of exemestane in rat milk were similar to maternal blood concentrations (see data). Because the administration of exemestane may cause serious adverse effects in breastfed infants, breastfeeding women are advised not to breastfeed during treatment with exemestane and for 1 month after the last dose of the drug.
Data
Radiolabeled exemestane associated radiotracers appeared in the milk of rats within 15 minutes after oral administration of radiolabeled exemestane. The concentrations of exemestane and its metabolites in rat milk and plasma were approximately equal 24 hours after a single oral dose of 1 mg/kg of 14C-labeled exemestane.
Females and males with reproductive capacity
Pregnancy test
A pregnancy test is recommended for females of reproductive potential within seven days prior to initiation of exemestane.
Contraception
Females
Exemestane may cause fetal harm in pregnant women. Women of childbearing potential should be advised to use effective contraception during treatment with exemestane and for 1 month after the last dose of the drug.
Infertility
Based on animal studies, exemestane treatment has been found to impair fertility in both men and women (see [Pharmacologic Toxicology]).
Pediatric Use]
The efficacy and safety of exemestane has not been evaluated in pediatric patients. It is not recommended for use in children.
Geriatric Use
There are no special precautions for the use of exemestane in elderly patients. See [Dosage and Administration].
Effects on driving and mechanical handling].
Drowsiness, drowsiness, weakness and dizziness have been reported after the use of exemestane. Patients using exemestane should be warned that if these symptoms occur, their physical and/or mental state to operate machinery or drive may be affected.
[Drug Interactions].
Although the clinical significance of this interaction has not been evaluated, combination with drugs known to have an induction effect on CYP3A4, such as: rifampin, anticonvulsants [phenytoin, carbamazepine, phenobarbital, etc.] and certain herbal preparations containing extracts of St John’s Wort, can significantly reduce exposure to exemestane and may decrease exemestane’s the efficacy of exemestane. Therefore, dose adjustment is recommended for patients receiving concomitant strong inducers of cytochrome P-450 (CYP) 3A4 (see [Dosage] and [Pharmacokinetics]).
Exemestane should be used with caution in combination with drugs that are metabolized by CYP3A4 and have a narrow therapeutic window. There is no clinical experience with the combination of exemestane with other anticancer drugs.
Exemestane should not be used in combination with other estrogen-containing drugs, as this will reduce its pharmacological effects.
[Drug overdose].
In clinical studies of exemestane, single doses of up to 800 mg in healthy female volunteers and up to 600 mg daily for 12 weeks in postmenopausal women with advanced breast cancer have been well tolerated. The single dose of exemestane that resulted in life-threatening symptoms is not known. In experiments in rats and dogs, animal mortality was observed at single oral doses equivalent to 2000 and 4000 times the recommended human dose (on a mg/m2 basis), respectively. There is no specific antidote for drug overdose and symptomatic treatment should be given. Routine supportive therapy, including close monitoring of vital signs and clinical observation of the patient, should be used.
A boy (age unknown) accidentally took one tablet (25 mg) of exemestane. The initial physical examination was normal, but routine blood tests 1 hour later suggested leukocytosis (leukocytes 25,000/mm3, neutrophils 90%). 4 days later routine blood tests were normal and no treatment was given.
Pharmacology and Toxicology
1. Pharmacological effects
Exemestane is an irreversible steroidal aromatase inhibitor with a structure similar to that of the natural androstenedione substrate. 5mg of exemestane can significantly reduce serum estrogen levels in postmenopausal women, and doses of 10-25mg can reduce estrogen levels to a maximum extent (> 90%). Postmenopausal breast cancer patients treated with 25 mg of exemestane daily showed a 98% reduction in overall aromatization.
Exemestane does not have progestin and estrogen-like effects and has a slight androgen-like effect, which may be related to the structure of the 17-hydroxy derivative, and this androgen-like effect is mainly seen at high doses. In studies with repeated daily administration of exemestane, with or without ACTH stimulation, no effect of exemestane on adrenal cortisone and aldosterone biosynthesis was seen, demonstrating the selective action of exemestane on steroid metabolizing enzymes.
Therefore, patients on exemestane do not require replacement therapy with glucocorticoids or salt corticosteroids. A slight non-dose dependent increase in serum LH and FSH levels is seen with low dose application of exemestane, an effect that is expected to be related to its pharmacological properties and may result from a feedback of pituitary levels due to a decrease in estrogen levels. Decreased estrogen levels in the body stimulate the pituitary gland to secrete gonadotropins, as is the case in postmenopausal women.
2. Toxicological studies
Toxicological studies: The toxicological effects of repeated dosing in rats and dogs are usually due to the pharmacological activity of exemestane, such as effects on the reproductive system and accessory organs. Other toxicological effects (hepatic, renal or central nervous system) occur only at doses significantly above the maximum human exposure and are generally not considered clinically significant.
Mutagenicity: Exemestane was not mutagenic in vitro in bacteria (Ames assay) and mammalian cells (V79 Chinese hamster lung cells). Exemestane was mutagenic in human lymphocytes in vitro in the absence of metabolic activation, but not in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unconventional DNA synthesis in rat hepatocytes in in vitro experiments.
Reproductive toxicity: Exemestane at levels similar to human systemic exposure (application of 25 mg/day of exemestane) causes embryotoxicity in rats or rabbits. No evidence of teratogenicity.
Carcinogenicity: No treatment-related tumorigenesis was observed in the 2-year carcinogenicity study in female rats. In the male rat study, the experiment was terminated at week 92 due to early death caused by chronic kidney disease. In a 2-year carcinogenicity study in mice, medium and high doses of exemestane (150 and 450 mg/kg/day) were found to increase liver tumor incidence in both sexes. This finding is thought to be related to the induction of hepatic microsomal enzymes, which have been found only in mice and not in clinical studies. High doses of exemestane (450 mg/ kg/day) in mice also induced renal tubular adenomas in male mice, an alteration that was species- and sex-specific and occurred at doses 63 times higher than the human therapeutic dose in mice. Clinically, no such effects have been observed in relation to exemestane treatment.
Pharmacokinetics]
After oral administration of exemestane to healthy postmenopausal women, the plasma concentration of exemestane decreases in a multi-exponential manner with a mean terminal half-life of approximately 24 hours. The pharmacokinetics of exemestane showed a dose-effect relationship after single (10 mg to 200 mg) or multiple (0.5 mg to 50 mg) oral doses. After multiple administrations of exemestane 25 mg/day, plasma concentrations were similar to levels following a single dose.
Pharmacokinetic parameters were compared between postmenopausal patients with advanced breast cancer and healthy postmenopausal women after single or multiple dosing. Following multiple dosing, breast cancer patients had a mean oral clearance 45% lower than healthy postmenopausal women, along with relatively high systemic exposure. After multiple dosing, the mean area under the curve (AUC) was approximately twice as high in breast cancer patients (75.4 ng∙hr/mL) as in healthy women (41.4 ng∙hr/mL).
Absorption: Following oral administration, exemestane was more rapidly absorbed in women with breast cancer than in healthy women, with mean time to peak of 1.2 and 2.9 hours, respectively. Approximately 42% of radiolabeled exemestane was absorbed by the gastrointestinal tract. A high-fat breakfast increased the AUC and peak concentration (Cmax) of exemestane by 59% and 39%, respectively, compared to the fasted state.
Distribution: Exemestane is widely distributed in tissues. 90% is bound to plasma proteins and the plasma binding rate is non-concentration dependent. Both albumin and α1-acidic glycoprotein are involved in binding. The amount of exemestane and its metabolites distributed in blood cells is negligible.
Metabolism: Exemestane is metabolized in large amounts, with the amount of prodrug in plasma being less than 10% of the total administered dose. The first step in the metabolism of exemestane is the oxidation of the 6-position methylene group and the reduction of the 17-keto group, followed by the formation of many secondary metabolites. The individual metabolites account for only small amounts of drug-related substances. The metabolites are inactive or have a reduced inhibitory effect on aromatase compared to the prodrug. One metabolite may have androgenic activity (see [Pharmacokinetics]). Human liver ex vivo studies have shown that cytochrome P-450 (CYP) 3A4 is the main isoenzyme involved in the oxidation of exemestane. Exemestane is also metabolized by aldo-keto reductase.
Excretion: After administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative excretion of radioactivity in urine and feces was similar (42 ± 3% in urine samples and 42 ± 6% in feces over one week). Urinary excretion of the prodrug was less than 1% of the administered dose.
Specific populations
Elderly: Pharmacokinetic studies in healthy postmenopausal women aged 43 to 68 years did not reveal age-related changes in the pharmacokinetics of exemestane in this age group.
Gender: The pharmacokinetics of exemestane following a single dose of 25 mg under fasted conditions were similar in healthy men (mean age 32 years) and healthy postmenopausal women (mean age 55 years).
Ethnicity: The effect of ethnicity on the pharmacokinetics of exemestane has not been evaluated.
Hepatic impairment: Exemestane pharmacokinetics were studied in subjects with moderate or severe hepatic impairment (Childs-Pugh class B or C). The AUC (area under the blood concentration-time curve) of exemestane was approximately three times higher than the AUC in healthy volunteers after a single 25 mg dose administered orally. However, non-life-threatening adverse effects were moderately increased with increasing the dose of exemestane to 200 mg per day, and no dose adjustment was required based on the above experience.
Renal Impairment: AUC was approximately 3-fold higher in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2) than in healthy volunteers following single-dose oral administration of exemestane 25 mg. However, non-life-threatening adverse effects were moderately increased with increasing the dose of exemestane to 200 mg per day, and no dose adjustment was required based on the above experience.
Children: Pharmacokinetic studies in pediatric patients have not been performed.
Drug Interactions
Exemestane does not inhibit any of the major CYP isozymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4.
In a pharmacokinetic interaction study in 10 healthy postmenopausal volunteers, preadministration of a strong inducer of CYP 3A4, rifampicin 600 mg/day for 14 days, followed by a single dose of exemestane 25 mg, resulted in a 41% and 54% reduction in mean plasma Cmax and AUC 0-∞, respectively (see [DOSAGE AND ADMINISTRATION and [Drug Interactions]).
In a clinical pharmacokinetic study, co-administration of ketoconazole, a strong inhibitor of CYP 3A4, had no significant effect on the pharmacokinetics of exemestane. Although no other formal drug interaction studies have been conducted using inhibitors, it is unlikely that CYP isoenzyme inhibitors would have a significant effect on the clearance of exemestane.
Storage
Seal and store below 30°C.
Package
Aluminum-plastic package, 14 tablets/plate, 1 plate/box.
Expiration date
12 months
Execution Standard
Approval number】
State Drug Certificate H20020002
Drug marketing license holder
Unit name: Qilu Pharmaceutical Co.
Registered Address: No. 317 Xinluo Street, High-tech Zone, Jinan City
Zip code: 250101
Contact: 400-127-7799
Fax: 0531-83126288, 83126545
Web address: http://www.qilu-pharma.com
Manufacturer
Company name: Qilu Pharmaceutical Co.
Production Address: No. 8888, Tourism Road, High-tech Zone, Jinan City
Postal Code: 250102
Telephone number: 400-127-7799
Fax: 0531-83126288, 83126545
Web address: http://www.qilu-pharma.com