AROMASIN(cid:210)(cid:210)
`(exemestane) Tablets
`
`DESCRIPTION
`
`AROMASIN(cid:210) Tablets for oral administration contain 25 mg of exemestane, an irreversible,
`steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-
`1,4-diene-3,17 -dione. Its molecular formula is C20H2402 and its structural formula is as
`follows:
`
`CH 3
`
`O
`
`CH 3 H
`
`H
`
`H
`
`CH 2
`
`O
`
`The active ingredient is a white to slightly yellow crystalline powder with a molecular weight
`of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and
`practically insoluble in water.
`
`Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone,
`polysorbate 80, hydroxypropyl methylcellulose, colloidal silicon dioxide, microcrystalline
`cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000,
`sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`Breast cancer cell growth may be estrogen-dependent. Aromatase(exemestane) is the principal
`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 (androstenedione and testosterone) to estrogens (estrone and
`1
`
`CELGENE 2133
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through
`aromatase inhibition is an effective and selective treatment for some postmenopausal patients
`with hormone-dependent breast cancer.
`
`Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural
`substrate androstenedione. 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.” 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 to healthy postmenopausal women, exemestane is rapidly
`absorbed. After maximum plasma concentration is reached, levels decline polyexponentially
`with a mean terminal half-life of about 24 hours. Exemestane is extensively distributed and is
`cleared from the systemic circulation primarily by metabolism. The pharmacokinetics of
`exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50
`mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged
`drug are similar to levels measured after a single dose.
`
`Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following
`single or repeated doses have been compared with those in healthy, postmenopausal women.
`Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the
`healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in
`the healthy women. After repeated dosing, the average oral clearance in women with advanced
`breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with
`corresponding higher systemic exposure. Mean AUC values following repeated doses in
`women with breast cancer (75.4 ng(cid:215) h/mL) were about twice those in healthy women
`(41.4 ng(cid:215) h/mL).
`
`Absorption: Following oral administration of radiolabeled exemestane, at least 42% of
`radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased
`by approximately 40% after a high-fat breakfast.
`Distribution: 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 both contribute to the binding. The distribution of exemestane and its
`metabolites into blood cells is negligible.
`Metabolism and Excretion: Following administration of radiolabeled exemestane to healthy
`postmenopausal women, the cumulative amounts of radioactivity excreted in urine and
`feces were similar (42 – 3% in urine and 42 – 6% in feces over a 1-week collection
`period). The amount of drug excreted unchanged in urine was less than 1% of the dose.
`
`2
`
`

`

`Exemestane is 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 inhibit aromatase with
`decreased potency compared with the parent drug. One metabolite may have androgenic activity
`(see Pharmacodynamics, Other Endocrine Effects). Studies using human liver preparations
`indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the
`oxidation of exemestane.
`
`Special Populations
`Geriatric: 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.
`Gender: The pharmacokinetics of exemestane following administration of a single, 25-mg
`tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of
`exemestane in fasted healthy postmenopausal women (mean age 55 years).
`Race: The influence of race on exemestane pharmacokinetics has not been evaluated.
`Hepatic Insufficiency: The pharmacokinetics of exemestane have been investigated in subjects
`with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg
`oral dose, the AUC of exemestane was approximately 3 times higher than that observed in
`healthy volunteers. (See Precautions)
`Renal Insufficiency: The AUC of exemestane after a single 25-mg dose was approximately
`3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance
`<35 mL/min/1.73 m2) compared with the AUC in healthy volunteers (see Precautions).
`Pediatric: The pharmacokinetics of exemestane have not been studied in pediatric patients.
`
`Drug-Drug Interactions
`Exemestane is metabolized by cytochrome P-450 3A4 (CYP 3A4) and aldoketoreductases. It
`does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and
`3A4. In a clinical pharmacokinetic study, ketoconazole showed no significant influence on the
`pharmacokinetics of exemestane. Although no other formal drug-drug interaction studies have
`been conducted, significant effects on exemestane clearance by CYP isoenzymes inhibitors
`appear unlikely. However, a possible decrease of exemestane plasma levels by known inducers
`of CYP 3A4 cannot be excluded.
`
`Pharmacodynamics
`Effect on Estrogens: Multiple doses of exemestane ranging from 0.5 to 600 mg/day were
`administered to postmenopausal women with advanced breast cancer. Plasma estrogen
`(estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of
`exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose.
`Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting
`radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a
`
`3
`
`

`

`single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to
`3 days after dosing and persisted for 4 to 5 days.
`Effect on Corticosteroids: In multiple-dose trials of doses up to 200 mg daily, exemestane
`selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect
`cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no
`glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane
`treatment.
`Other Endocrine Effects: Exemestane does not bind significantly to steroidal receptors, except
`for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The
`binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100-times
`that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on
`circulating levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, or 17-
`hydroxy-progesterone. Increases in testosterone and androstenedione levels have been
`observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding
`globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight,
`nondose-dependent increases in serum lutenizing hormone (LH) and follicle-stimulating
`hormone (FSH) levels have been observed even at low doses as a consequence of feedback at
`the pituitary level.
`
`CLINICAL STUDIES
`
`Exemestane 25 mg administered once daily was evaluated in a randomized double-blind,
`multicenter, multinational comparative study and in two multicenter single-arm studies of
`postmenopausal women with advanced breast cancer who had disease progression after
`treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have
`received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.
`
`The primary purpose of the three studies was evaluation of objective response rate (complete
`response [CR] and partial response [PR]). Time to tumor progression and overall survival
`were also assessed in the comparative trial. Response rates were assessed based on World
`Health Organization (WHO) criteria, and in the comparative study, were submitted to an
`external review committee that was blinded to patient treatment. In the comparative study, 769
`patients were randomized to receive AROMASIN (exemestane) 25 mg once daily (N = 366) or
`megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics
`are presented in Table1.
`
`4
`
`

`

`Table 1. Demographics and Baseline Characteristics from the Comparative Study of
`Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after
`Tamoxifen Therapy
`AROMASIN
`(N = 366)
`
`Megestrol Acetate
`(N = 403)
`
`Parameter
`
`Median Age (range)
`ECOG Performance Status
` 0
` 1
` 2
`Receptor Status
` ER and/or PgR +
` ER and PgR unknown
` Responders to prior tamoxifen
` NE for response to prior tamoxifen
`Site of Metastasis
` Visceral –
` other sites
` Bone only
` Soft tissue only
` Bone & soft tissue
`Measurable Disease
`Prior Tamoxifen Therapy
` Adjuvant or Neoadjuvant
` Advanced Disease, Outcome
` CR, PR or SD> 6 months
` SD< 6 months, PD or NE
`Prior Chemotherapy
` For advanced disease –
` Adjuvant only
` No chemotherapy
`
` adjuvant
`
`65 (35-89)
`
`167 (46%)
`162 (44%)
`34 (9%)
`
`246 (67%)
`116 (32%)
`68 (19%)
`46 (13%)
`
`207 (57%)
`61 (17%)
`54 (15%)
`43 (12%)
`287 (78%)
`
`145 (40%)
`
`179 (49%)
`42 (12%)
`
`58 (16%)
`104 (28%)
`203 (56%)
`
`65 (30-91)
`
`187 (46%)
`172 (43%)
`42 (10%)
`
`274 (68%)
`128 (32%)
`85 (21%)
`41 (10%)
`
`239 (59%)
`73 (18%)
`51 (13%)
`38 (9%)
`314 (78%)
`
`152 (38%)
`
`210 (52%)
`41 (10%)
`
`67 (17%)
`108 (27%)
`226 (56%)
`
`The efficacy results from the comparative study are shown in Table 2. The objective response
`rates observed in the two treatment arms showed that AROMASIN(exemestane) was not
`different from megestrol acetate. Response rates for exemestane from the two single-arm trials
`were 23.4% and 28.1%.
`
`5
`
`

`

`Table 2. Efficacy Results from the Comparative Study of Postmenopausal Women with
`Advanced Breast Cancer Whose Disease Had Progressed after TamoxifenTherapy
`AROMASIN
`Megestrol
`(N=366)
`acetate (N=403)
`15.0
`12.4
`
`Response Characteristics
`Objective Response Rate = CR + PR (%)
`Difference in Response Rate (AR-MA)
`95% C. I.
`
`CR (%)
`PR (%)
` SD ‡
` 24 Weeks (%)
`Median Duration of Response (weeks)
`Median TTP (weeks)
`Hazard Ratio (AR-MA)
`
`2.6
`7.5, -2.3
`
`0.84
`
`1.2
`11.2
`21.1
`71.0
`16.6
`
`2.2
`12.8
`21.3
`76.1
`20.3
`
`Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change),
`TTP = time to tumor progression, , C.I. = confidence interval. MA = megestrol acetate, AR =
`AROMASIN
`
`There were too few deaths occurring across treatment groups to draw conclusions on overall
`survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative
`study is shown in Figure 1.
`
`6
`
`

`

`Figure 1. Time to Tumor Progression in the Comparative Study of
`Postmenopausal Women With Advanced Breast Cancer Whose Disease
`Had Progressed After TamoxifenTherapy
`
`INDICATIONS AND USAGE
`
`AROMASIN(exemestane) Tablets are indicated for the treatment of advanced breast cancer in
`postmenopausal women whose disease has progressed following tamoxifen therapy.
`
`7
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`

`

`CONTRAINDICATIONS
`
`AROMASIN(exemestane) Tablets are contraindicated in patients with a known hypersensitivity
`to the drug or to any of the excipients.
`
`WARNINGS
`
`AROMASIN(exemestane) Tablets may cause fetal harm when administered to a pregnant
`woman. Radioactivity related to 14C-exemestane crossed the placenta of rats following oral
`administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was
`approximately equivalent in maternal and fetal blood. When rats were administered exemestane
`from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days
`of lactation, an increase in placental weight was seen at 4 mg/kg/d (approximately 1.5 times the
`recommended human daily dose on a mg/m2 basis). Prolonged gestation and abnormal or
`difficult labor was observed at doses equal to or greater than 20 mg/kg/d. Increased resorption,
`reduced number of live fetuses, decreased fetal weight, and retarded ossification were also
`observed at these doses. No malformations were noted when exemestane was administered to
`pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320
`times the recommended human dose on a mg/m2 basis). Daily doses of exemestane, given to
`rabbits during organogenesis caused a decrease in placental weight at 90 mg/kg/day
`(approximately 70 times the recommended human daily dose on a mg/m2 basis). Abortions, an
`increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There
`was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day
`(approximately 210 times the recommended human dose on a mg/m2 basis).
`
`There are no studies in pregnant women using AROMASIN. AROMASIN is indicated for
`postmenopausal women. If there is exposure to AROMASIN during pregnancy, the patient
`should be apprised of the potential hazard to the fetus and potential risk for loss of the
`pregnancy.
`
`PRECAUTIONS
`
`General. AROMASIN(exemestane) Tablets should not be administered to premenopausal
`women. AROMASIN should not be coadministered with estrogen-containing agents as these
`could interfere with its pharmacologic action.
`
`Hepatic Insufficiency. The pharmacokinetics of exemestane have been investigated in subjects
`with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg
`oral dose, the AUC of exemestane was approximately 3 times higher than that observed in
`healthy volunteers. The safety of chronic dosing in patients with moderate or severe hepatic
`impairment has not been studied. Based on experience with exemestane at repeated doses up to
`
`8
`
`

`

`200 mg daily that demonstrated a moderate increase in non-life threatening adverse events,
`dosage adjustment does not appear to be necessary.
`
`Renal Insufficiency. The AUC of exemestane after a single 25-mg dose was approximately
`3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance
`<35 mL/min/1.73 m2) compared with the AUC in healthy volunteers. The safety of chronic
`dosing in patients with moderate or severe renal impairment has not been studied. Based on
`experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate
`increase in non-life threatening adverse events, dosage adjustment does not appear to be
`necessary.
`
`Laboratory Tests. Approximately 20% of patients receiving exemestane in clinical studies,
`experienced Common Toxicity Criteria (CTC) grade 3 or 4 lymphocytopenia. Of these patients,
`89% had a pre-exisiting lower grade lymphopenia. Forty percent of patients either recovered or
`improved to a lesser severity while on treatment. Patients did not have a significant increase in
`viral infections, and no opportunistic infections were observed. Elevations of serum levels of
`AST, ALT, alkaline phosphatase and gamma glutamyl transferase > 5 times the upper value of
`the normal range (i.e., ‡
` CTC grade 3) have been rarely reported but appear mostly attributable
`to the underlying presence of liver and/or bone metastases. In the comparative study, CTC
`grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver
`metastasis was reported in 2.7% of patients treated with AROMASIN(exemestane) and in 1.8%
`of patients treated with megestrol acetate.
`
`Drug Interactions. Exemestane is extensively metabolized by CYP3A4, but coadministration
`of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane
`pharmacokinetics. Significant pharmacokinetic interactions mediated by inhibition of CYP
`isoenzymes therefore appear unlikely; however, a possible decrease of exemestane plasma
`levels by known inducers of CYP 3A4 cannot be excluded (see CLINICAL
`PHARMACOLOGY, Pharmacokinetics).
`
`Drug/ Laboratory Tests 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
`mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human
`lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus
`assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat
`hepatocytes.
`
`Untreated female rats showed reduced fertility when mated to males treated with 500 mg/kg/day
`exemestane (approximately 200 times the recommended human dose on a mg/m2 basis) for 63
`days prior to and during cohabitation. Exemestane given to female rats 14 days prior to mating
`
`9
`
`

`

`and through day 15 or 20 of gestation increased the placental weights at 4 mg/kg/day
`(approximately 1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on
`female fertility parameters (e.g., ovarian function, mating behavior, conception rate) in rats
`given doses up to 20 mg/kg/day (approximately 8 times the human dose on a mg/m2 basis), but
`mean litter size was decreased at this dose. In general toxicology studies, changes in the ovary,
`including hyperplasia, an increase in ovarian cysts and a decrease in corpora lutea were
`observed with variable frequency in mice, rats and dogs at doses that ranged from 3-20 times
`the human dose on a mg/m2 basis.
`
`Pregnancy. Pregnancy Category D. See WARNINGS.
`
`Nursing Mothers. AROMASIN(exemestane) is only indicated in postmenopausal women.
`However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral
`administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites
`were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral
`dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted in human milk.
`Because many drugs are excreted in human milk, caution should be exercised if a nursing woman
`is inadvertently exposed to AROMASIN (see WARNINGS).
`
`Pediatric Use. The safety and effectiveness of AROMASIN(exemestane) in pediatric patients
`have not been established.
`
`Geriatric Use. The use of AROMASIN(exemestane) in geriatric patients does not require
`special precautions.
`
`ADVERSE REACTIONS
`
`A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials
`program. Exemestane was generally well tolerated, and adverse events were usually mild to
`moderate. Only one death was considered possibly 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 3% of the
`patients discontinued treatment with exemestane because of adverse events, mainly within the
`first 10 weeks of treatment; late discontinuations because of adverse events were uncommon
`(0.3%).
`
`In the comparative study, adverse reactions were assessed for 358 patients treated with
`AROMASIN(exemestane) and 400 patients treated with megestrol acetate. Fewer patients
`receiving AROMASIN discontinued treatment because of adverse events than those treated with
`megestrol acetate (2% versus 5%). Adverse events that were considered drug related or of
`indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs.
`10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%). The proportion of
`
`10
`
`

`

`patients experiencing an excessive weight gain (>10% of their baseline weight) was
`significantly higher with megestrol acetate than with AROMASIN (17% versus 8%). Table 3
`shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater
`of patients in the study treated either with AROMASIN or megestrol acetate.
`
`Table 3. Incidence (%) of Adverse Events of all Grades* and Causes
`Occurring in ‡‡5% of Patients
`In Each Treatment Arm in the Comparative Study
`AROMASIN
`Megestrol
`25 mg
`Acetate
`once daily
`40 mg QID
`(N=358)
`(N=400)
`
`Event
`
`Autonomic Nervous
`Increased sweating
`Body as a Whole
`Fatigue
`Hot flashes
`Pain
`Influenza-like symptoms
`Edema (includes edema, peripheral
` edema, leg edema)
`Cardiovascular
`Hypertension
`Nervous
`Depression
`Insomnia
`Anxiety
`Dizziness
`Headache
`Gastrointestinal
`Nausea
`Vomiting
`Abdominal pain
`Anorexia
`Constipation
`Diarrhea
`Increased appetite
`Respiratory
`Dyspnea
`Coughing
`* Graded according to Common Toxicity Criteria
`
`6
`
`22
`13
`13
`6
`
`7
`
`5
`
`13
`11
`10
`8
`8
`
`18
`7
`6
`6
`5
`4
`3
`
`10
`6
`
`9
`
`29
`6
`13
`5
`
`6
`
`6
`
`9
`9
`11
`6
`7
`
`12
`4
`11
`5
`8
`5
`6
`
`15
`7
`
`Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study
`for patients receiving AROMASIN(exemestane) 25 mg once daily were fever, generalized
`weakness, paresthesia, pathological fracture; bronchitis, sinusitis, rash, itching, urinary tract
`infection, and lymphedema.
`
`11
`
`

`

`Additional adverse events of any cause observed in the overall clinical trials program (N =
`1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the
`comparative study included pain at tumor sites (8%), asthenia (6%) and fever (5%). Adverse
`events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the
`overall clinical trials program but not in the comparative study included chest pain,
`hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper
`respiratory tract infection, pharyngitis, rhinitis, and alopecia.
`
`OVERDOSAGE
`
`Clinical trials have been conducted with exemestane given as a single dose to healthy female
`volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with
`advanced breast cancer at doses as high as 600 mg. 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
`leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after
`the incident and were normal. No treatment was given.
`
`In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the
`lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats
`and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about
`2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about
`4000 times the recommended human dose on a mg/m2 basis), respectively.
`
`Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in
`mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m2
`basis), respectively.
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dose of AROMASIN(exemestane) Tablets is 25 mg once daily after a meal.
`Treatment with AROMASIN should continue until tumor progression is evident.
`
`12
`
`

`

`The safety of chronic dosing in patients with moderate or severe hepatic or renal impairment has
`not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily
`that demonstrated a moderate increase in non-life threatening adverse events, dosage adjustment
`does not appear to be necessary (see CLINICAL PHARMACOLOGY, Special Populations and
`PRECAUTIONS).
`
`HOW SUPPLIED
`
`AROMASIN(exemestane) Tablets are round, biconvex, and off-white to slightly gray. Each
`tablet contains 25 mg of exemestane. The tablets are printed on one side with the number “7663”
`in black. AROMASIN is packaged in either HDPE bottles with a child-resistant screw cap,
`supplied in packs of 30 tablets, or in Aluminium-PVDC/PVC-PVDC opaque white blisters,
`supplied in packs of 30 tablets.
`
`30-tablet HDPE bottle
`30-tablet blister pack
`
`NDC 009-7663-04
`NDC 009-7663-01
`
`Store at 25(cid:176) C (77(cid:176) F); excursions permitted to 15(cid:176) -30(cid:176) C (59(cid:176) -86(cid:176) F) [see USP Controlled
`Room Temperature].
`Rx only
`
`Manufactured for: PHARMACIA & UPJOHN Company
`Kalamazoo, Michigan 49001, USA
`
`By: Pharmacia & Upjohn S.p.A.
`Ascoli Piceno, Italy
`
`October 20, 1999
`
`[1020pi-M.doc]
`
`13
`
`