CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`20-541/S-006
`
`FINAL PRINTED LABELING ©
`
`(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)(cid:3)(cid:21)(cid:20)(cid:22)(cid:23)
`CELGENE 2134
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:89)(cid:17)(cid:3)(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)
`APOTEX v. CELGENE
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:22)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:21)
`IPR2023-00512
`
`

`

`PROFESSIONAL INFORMATION "2OCHURE
`ARIMIDEX®
`(anastrozole) Tablets
`
`APPROVED
`SEP
`1 2000
`
`Rev H-6 05/00
`
`DESCRIPTION
`
`SIC No. XXXXX-XX
`
`ARIMIDEX® (anastrozole) tablets for oral administration contain | mg of anastrozole, a non-steroidal
`aromataseinhibitor.
`It is chemically described as 1,3-Benzenediacetonitrile, a, a, a", a!-tetramethyl-5-(1H-1,2,4-
`triazol-|-ylmethyl).
`Its molecular formulais C17H)9Ns andits structural formula is:
`
`
`
`Anastrozole is an off-white powder with a molecular weight of293.4. Anastrozole has moderate aqueous
`solubility (0.5 mg/mLat 25°C); solubility is independentofpH in the physiological range. Anastrozole is freely
`soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
`
`lactose, magnesium stearate, hydroxypropylmethyicellulose,
`Eachtablet contains as inactive ingredients:
`polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`In
`Manybreast cancers have estrogen receptors and growth ofthese tumors can be stimulated by estrogen.
`post-menopausal women,
`the principal source of circulating estrogen (primarily estradiol)
`is conversion of
`adrenally-generated androstenedione to estrone by aromatase in peripherel tissues, such as adipose tissue, with
`further conversion of estroneto estradiol.Many breast cancers also contain aromatase; the importance oftumor-
`
`generated estrogensis uncertain.
`
`ARIMIDEXis a trademark, the property ofAstraZeneca Group.
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`ARIMIDEX®
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`Treatmentofbreast cancerhas inc!nded efforts to decrease estrogen levels, by ovariectomy premenopausal]y
`and Ly use of anti-estrogens and Progestational agents both pre- and post-menopausally; and these interventions
`lead tdecreased tumor mass or delayed progression oftumorgrowth in some women.
`
`It significantly lowers serum
`Anastrozole is a potent and Selective non-steroidal aromatase inhibitor.
`estradiol concentrations and has no detectable effect on formation ofadrenal Corticosteriods oraldosterone.
`
`Pharmacokinetics
`
`Inhibition ofaromataseActivity is primarily due to anastrozole, the parent drug. Studies with radiolabeled
`drug have demonstrated that orally administered anastrozole is well absorbed into the Systemiccirculation with 83
`to 85% ofthe radiolabel recovered in urine and feces. Food does not affectthe extent ofabsorption. Elimination of
`anastrozole is primarily via hepatic metabolism (approximately 85%) and to a lesser extent, renal excretion
`(approximately 11%), and anastrozole has a mean terminal elimination half-life of approximately 50 hours in
`postmenopausal women. The major circulating metabolite ofanastrozole, triazole, lacks pharmacologic activity,
`The pharmacokinetic parameters are similar, in patients and in healthy postmenopausal volunteers.
`The
`pharmacokinetics of anastrozole are linear over the dose range of | to 20 mg and do not change with repeated
`dosing. Consistent with the approximately 2-day terminal elimination half-life, plasma concentrations approach
`Steady-state levels at about 7 days of once daily dosing and steady-state levels are approximatelythree- to four-fold
`higher than levels observed aftera single dose ofARIMIDEX. Anastrozole is 40% bound to plasma proteins in the
`therapeutic range.
`
`Metabolism and Excretion: Studies in Postmenopausal women demonstrated that anastrozole is extensively
`metabolized with about 10% ofthe dose excreted in the urine as unchanged drug within 72 hours ofdosing, and the
`remainder (about 60% of‘the dose) is excreted in urine as metabolites. Metabolism ofanastrozole occurs by N-
`dealkylation, hydroxylation and glucuronidation. Three metabolites ofanastrozole have been identified in -human
`plasma and urine. The known metabolites are triazole, a glucuronide conjugate of hydroxy-anastrozole, and a
`glucuronide ofanastrozole itself. Several minor (less than 5% ofthe radioactive dose) metabolites have not been:
`
`identified.
`
`Because renal elimination is not a significant pathwayofelimination, total body clearance ofanastrozole is
`unchanged even in severe (creatinine cléarance less than 30 mL/min/1.73m’) renal impairment, dosing adjustment
`in
`patients with renal dysfuncticn is not necessary (see Special Populations
`and DOSAGE AND -
`ADMINISTRATION sections). Dosage adjustmentis also unnecessary in patients with stable hepatic cirrhosis (see
`Special Populations and DOSAGE AND ADMINISTRATION sections).
`
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`-‘pecial Populations:
`Geriatric: Anastrozole 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.
`
`Race:_Estradiol and estrone sulfate levels were similar between Japanese and Caucasian post-menopausal
`women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean Steady state minimum plasma
`concentrationsin Caucasian and Japanese post-menopausal women were 25.7 and 30.4 ng/mLrespectively.
`
`investigated in subjects with renal
`Renal Iasufficiency: Anastrozole pharmacokinetics have been
`insufficiency.
`Anastrozole renal clearance decreased Proportionally with creatinine clearance and was
`approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m?)
`compared to controls. Since only about 10% of anastrozole is excreted unchanged in the urine, the reduction in
`renal clearance did notinfluence the
`total body clearance. (see DOSAGEAND ADMINISTRATION).
`
`Hepatic Insufficiency: Hepatic metabolism accounts for approximately 85% of anastrozole elimination.
`Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse.
`The apparent oral clearance (CL/F) ofanastrozole was approximately 30% lower in subjects with stable hepatic
`curthosis than in control subjects with normal liver function. However, plasma anastrozole concentrations in the
`Subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinica]
`trials (see DOSAGE AND ADMINISTRATION),so that no dosage adjustment is needed.
`
`Drug-Drug Interactions: Anastrozoleinhibited 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 C,,. values
`observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactionscatalyzed by cytochrome
`P450 2A6 or 2D6 in vitro, Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to
`subjects had no effect on theclearanceofantipyrineorurinary recoveryofantipyrinemetabolites. Basedon these in .
`vitro and in vivo resuits,it is unlikely that co-administration of ARIMIDEX I mg with other drugs will result in
`clinically significant inhibition ofcytochrome P450 mediated metabolism.
`
`In a study conducted in 16 male volunteers, anastrozoledid notalter the pharmacokinetics as measured by C,,, and
`AUC,and anticoagulant activity as measured by prothrombin time, activated partial thromboplastin time, and
`thrombin time of both R- and S-warfarin.
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`Pharmacodynamics
`
`Effect on Estradiol: Mean serum concentrations of estradiol were evalua‘ed in multiple daily dosing trials
`with 0.5, 1, 3, 5, and 10 mg of ARIMIDEXin postmenopausal women with advanced breast cancer. Clinically
`Significant suppression ofserum estradiol was seen with all doses. Doses of1 mgand higherresulted in suppression
`of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily
`dose, ARIMIDEX I 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 ARIMIDEX 1 mg.
`
`Effect on Corticosteroids: In multiple daily dosing trials with 3, 5, and 10 mg,the selectivity ofanastrozole
`was assessed by examining effects on corticosteriod synthesis. Forall doses, anastrozole did not affect cortisol or
`aldosterone secretion at baseline.or in response to ACTH. No glucocorticoid or mineralccorticoid replacement
`therapy is necessary with anastrozole.
`
`Other Endocrine Effects: In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone
`(TSH) was measured; there was No increase in TSH during the administration of ARIMIDEX. ARIMIDEX does
`not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating
`levels of progesterone, androgens, and estrogens.
`
`Clinical Studies - First Line Therapyin Postmenopausal Womenwith Advanced Breast Cancer: Two
`double-blind well-controlled clinical studies of similar design (0030, a North American study and 0027, a
`predominately European study) were conducted to assess the efficacy of ARIMIDEX compared with tamoxifen as
`first-line therapy for hormone receptor
`positive or hormonereceptor unknownlocally advanced or metastatic breast
`¢ancer_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 randomizedto receive I_me of ARIMIDEX once daily or 20
`me oftamoxifen once daily. The primary end points for both trials were time to tumor progression, objective tumor
`response rate, andsafety.
`
`Demographics and otherbaseline characteristics, including patients who had measurable and no measurable
`patients who were
`piven
`revious adjuvant therapy,
`the site of metastatic disease and ethnic origin were
`disease,
`
`
`
`simiar for the two treatment groups for both trials. The following table summarizes the hormone receptorstatus at
`entryfor all randomized patients in trials 0030 and 0027,
`
`_
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`Receptorstatus
`
`Table t
`Number(%) ofsubjects
`Trial 0030
`Trial 0027
`ARIMIDEX
`Tamoxifen
`ARIMIDEX Tamoxifen
`! mg
`20 mg
`Img
`20 mg
`(n=171)
`(n=182)
`(n=340)
`(n=328)
`151 (88.3)
`162 (89.0)
`154 (45.3)
`144 (43.9)
`19 (11.1)
`20 (11.0)
`185 (54.4)
`183 (55.8)
`
`ER+ and/or PR+
`ER unknown, PR unknown
`ER = Estrogen receptor
`PR = Progesterone Teceptor
`trial 0030 showed ARIMIDEX wasat least as effective as tamoxifen for objective
`For the primary
`endpoints.
`fumor response rate. ARIMIDEX had a Statistically
`significant advantage over tamoxifen
`(p=0.006)
`for time to
`tumor progression (see Table 2 and Fi ure 1). Trial 0027 showed ARIMIDEX was at least as effective as tamoxifen
`for objective tumor response rate and time to tumor progression (See Table 2 and Figure 2).
`
`Table 2 below summarizes the results oftrial 0030 andtrial 0027 forthe primary efficacy endpoints.
`
`End point
`
`Timeto progression (TTP)
`Median TTP (months)
`Number(%)ofsubjects
`whoprogressed
`Hazard ratio (LCL)!
`2-sided 95% Cl
`p-value?
`Best objective responserate
`Number(%) of subjects
`with CR + PR
`Odds Ratio (LCL)?
`
`CR = Complete Response
`PR = Partial Response
`Cl = ConfidenceInterval
`LCL = Lower Confidence Limit
`! Tamoxifen:ARIMIDEX
`2Two-Sided Log Rank
`3ARIMIDEX: Tamoxifen
`
`Table 2
`Trial 0027
`Trial 0030
`ARIMIDEX Tamoxifen
`| mg
`20 mg
`(n=171)
`(n=182)
`U1
`5.6
`114 (67%)
`138 (76%)
`1.42 (1.15)
`(1.11, 1.82)
`0.006
`
`ARIMIDEX Tamoxifen
`Img
`20 mg
`(n=340)
`(n=328)
`8.2
`8.3
`249 (73%) 247 (75%)
`1.01 (0.87)
`(0.85, 1.20)
`0.920
`
`36 (21.1%)
`1.30 (0.83)
`
`31 (17.0%)
`
`112 (32.9%)
`1.01 (0.77)
`
`107 (32.6%)
`
`.
`
`vee
`
`ceeeeeteee
`
`en bee be eee ee ee
`
`
`
`Figure ! - Kaplan-Meier cobabili
`treat) in Trial 0030
`
`
`
`of time to disease
`
`
`progression for all randomized patients (intent-to-
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`PROPORTIONNOTPROGRESSING
`
`
`
`i ili -to-treat)Figure 2 Ka in Trial
`
`
`
`
`
`
`
`FROPORTIONNOTPROGRESSING o uw
`
`6
`
`6
`
`10
`
`
`12 4 «606
`hte
`ee
`22
`24
`26
`26
`30
`32
`34
`3¢
`36
`«640
`42
`TIME TO PROGRESSION CHONTHS )
`
`RANDOMISED TREATMENT
`ANASTROZOLE
`— —- TANOKIFEN
`40
`38
`36
`34
`32
`06
`14
`2
`4
`6
`@
`to
`t2
`10
`20
`22
`24
`26
`26
`30
`6
`;
`MONTHS
`a
`2
`3
`s
`s
`668 S@2 440 359 322 249 108 1S@ (IT 6 6S Ss 4s
`35
`24
`Ie
`AT RISK :
`Results from the secondary endpoints oftime to treatment failure, duration of tumor response, and duration
`of clinical benefit were supportive of the results of the
`prim
`Ppo'
`pnmary efficacy endpoints. “There were too few deaths
`occurring across treatment groups ofboth trials to draw conclusions on overall survival differences.
`,
`
`.
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`Clinical Studies - Second Line Therapy in Postmenopausal Women with Advanced Breast Cancer whooeeeeipyinLostmenopausalWomenwithAdvancedBreastCancerwho
`
`
`
`
`had Disease Progression following Tamoxifen Therapy:
`Anastrozole was studied in two well-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. Someofthe 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 ifthey had had a positive response to tamoxifen. Eligible
`patients with measurable and non-measurable disease were randomized to receive either a single daily dose of| mg
`or 10mg of ARIMIDEX or megestrol acetate 40 mg four times a day. The studies were double-blinded with
`_ Fespect to ARIMIDEX. 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 Intemationale Contre le Cancer (UICC)criteria. Therate ofprolonged (more than 24 weeks)
`Stable disease, the rate ofprogression, and surviyal were also calculated.
`
`Both trials included over 375 patients; demographics and other baseline characteristics were similar for the
`three treatment groupsin eachtrial. 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; $7% in Trial 0005),
`18% ofthese patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have
`responded.
`In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative.
`In Trial 0005, 58% ofpatients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0604,
`62% ofpatients had measurable disease compared to 79% in Trial 0005. Thesites ofmetastatic disease were similar
`among treatment groupsfor each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone
`metastases; and 40% hadvisceral (15% liver) metastases.
`
`As shownin the table below, similar results were observed amongtreatment groups and between the two
`trials. Noneofthe within trialdifferences were statistically significant.
`
`Add:Table3
`
`ARIMIDEX ARIMIDEX
`Meeestro}
`.
`Acetate
`
`160 mg
`(n=128)
`32.9
`26.7
`
`Trial 0004
`
`CN. America)
`Median Follow-up (months)*
`Median Timeto Death (mionths)
`
`I meg
`(n=128)
`31.3
`29.6
`
`10 me
`(n=130)
`30.9
`25.7
`
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`2 Year Survival Probability (%)
`Median Timeto Progression (months)
`Objective Response
`(all patients) (%)
`Stable Disease for >24 weeks (%)
`Progression (%)
`
`Trial 0005
`
`(n=135)
`
`(Europe, Australia, S. Africa)
`Median Follow-up (months)*
`Median Timeto Death (months)
`2 Year Survival Probability (%)
`Median Timeto Progression (months)
`Objective Response
`(all patients) (%)
`Stable Disease for >24 weeks (%)
`Progression (%)
`*Surviving Patients
`
`62.0
`5.7
`12.5
`35.2
`86.7
`
`(n=118)
`31.0
`24.3
`50.5
`44
`12.6
`24.4
`91.9
`
`58.0
`$.3
`10.0
`29.2
`85.4
`
`(n=125)
`30.9
`24.8
`50.9
`5.3
`15.3
`25.4
`89.8
`
`53.1
`5.1
`10.2
`32.8
`90.6
`
`31.5
`19.8
`39.1
`3.9
`144
`23.2
`“92.0
`
`More than 1/3 ofthe patients in each treatment group in both studies hadeither an objective response or
`Stabilization of their disease for greater than 24 weeks. Amongthe 263 patients who received ARIMIDEX | mg,
`there were 1! complete responders and 22 partial responders. In patients who had an objective response, more than
`80% werestill responding at 6 months from randomization and more than 45% were still responding at 12 months
`
`from randomization.
`
`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 ARIMIDEX 1 mg and megestrol acetate. Thereis, in
`this data, no indication that ARIMIDEX 10 mgis superior to ARIMIDEX I mg.
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`Add:
`
`Table4Trials 0004 & 0005 ARIMIDEX Img ARIMIDEX 10 mg Megestrol Acetate
`
`
`(Pooled Data)
`N=263
`N=248
`160 mg
`Median Timeto
`26.7
`25.5
`22.5
`Death (months)
`2 Year Survival
`56.1
`54.6
`46.3
`Probability (%)
`Median Timeto
`4.8
`5.3
`4.6
`Progression
`(months)
`Objective Response
`(all patients) (%)
`
`N=253
`
`12.3
`
`12.5
`
`,
`
`12.5
`
`Objective response rates and median times to progression and death for ARIMIDEX | mg were similar to
`megestrol acetate for women overor under 65. There were too few non-white patients studied to draw conclusions
`about racial differences in response.
`
`INDICATIONS AND USAGE
`ARIMIDEX is indicated for the first-line treatment of postmenopausal women with hormone receptor
`Positive or hormone receptor unknown locally advanced or metastatic breast cancer.
`
`ARIMIDEXis indicated for the treatment ofadvanced breast cancer in postmenopausal womenwith disease
`Progression following tamoxifen therapy.
`
`Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely
`
`responded to ARIMIDEX.
`
`CONTRAINDICATIONS
`
`None known.
`
`WARNINGS
`
`ARIMIDEX can cause fetal harm when administered to a pregnant woman. Anastrozole has been found to
`cross the placenta following oral administration-of-0.4-mg/kg inrats and rabbits(about 3/4 and 1.5times the
`recommended human dose, respectively, on a mg/m’ basis). Studies in both rats and rabbits at doses equal to or
`greater than 0.1 and 0.02 mg/kg/day, respectively (about 3/4 and 1/3, respectively, the recommended human dose
`on a me/n.* basis), administered during the period of organogenesis showed that anastrozole increased pregnancy ©
`loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers oflive fetuses);
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`effects were dose related in rats. Placental Weights weresignificantly increased in rats at doses of ~.2 mg/kg/day or
`
`more.
`
`Evidence offetotoxicity, including delayed fetal development(i.¢., incomplete ossification and depressed
`fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole
`Comex and AUC, nw that were 19 times and 9 times higher than the respective values found in healthy post-
`menopausal humansatthe recommended dose). There was no evidence ofteratogenicity in rats administered doses
`up to 1.0 mg/kg/day.
`In rabbits, anastrozole caused pregnancy failureat doses equal to or greater than 1.0
`mg/kg/day (about 16 times the recommended human dose on a mg/m? 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?
`
`basis).
`
`There are no adequate andwell-controlled Studies in pregnant women using ARIMIDEX. IfARIMIDEXis
`used during pregnancy,orifthe patient becomespregnantwhile receiving this drug, the patient should be apprised
`ofthe potential! hazard to the fetus or potential risk for loss ofthe pregnancy.
`
`PRECAUTIONS
`
`General: Before starting treatment with ARIMIDEX, pregnancy must be excluded (see WARNINGS).
`
`ARIMIDEXshould be administered under the supervision ofa qualified physician experienced in the use of
`anticanceragents.
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`Three-foid elevations of mean serun. $mma glutamyltransferase (GT) levels have
`Laboratory Tests:
`been ¢ bserved among patients with liver metastases receiving ARIMIDEX or megestrolacetate. These changes
`werelikely related to the progression ofliver metastases in these patients, although other contributing factors could
`
`not be ruled out.
`
`(See CLINICAL PHARMACOLOGY) Anastrozole inhibited in vitro metabolic
`Drug Interactions:
`reactions catalyzed by cytochromes P450 1A2, 2C8/9, and 3A4 but only at relatively high concentrations.
`Anastrozole did not inhibit P450 2A6or the polymorphic P4S0 2D6 in human liver microsomes. Anastrozole did
`not alter the pharmacokinetics ofantipyrine. Although there have been no formal interaction studies other than with
`antipyrine, based on these in vivo and in vitro studies, it is unlikely that co-administration of a I mg dose of
`ARIMIDEX with other drugs will result in clinically significant drug inhibition of cytochrome P450-mediated
`metabolism ofthe other drugs.
`:
`-
`
`An_interaction study with warfarin showed no clinically significant effect of anastrozole on_warfarin
`pharmacokinetics or anticoagulant activity.
`
`Drug/Laboratory Test Interactions: No clinically significant changes in the results ofclinical laboratory
`
`tests have been observed.
`
` Carcinogenesis: Neteng-term-animal-studies-have-beer cendusted-te-assess_the-_carcinesenic-—potenti
`ARIMIDEX. A conventional carcinogenesis study in rats at doses of1.0 to 25 mg/kg/day (about8 to 200 times the
`daily maximum recommended human dose on a mg/m? basis) 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 adenomain males at the high dose. A dose related increase was observedin the incidence of
`ovarian anduterine hyperplasia in females. At 25 mg/kg/day, plasma AUC,4, levels in rats were 110 to 125 times
`higher than the level exhibited in post-menopausal volunteers at the recommended dose. A Separate carcinogenicity
`Study in mice atoral doses of 5 to 50 mg/kg/day (about 20 to 200 times thé daily maximum recommended human
`dose on a mg/m’basis) for up to 2 years produced an increase in the incidence ofbenign ovarian stromal, epithelial
`and granulosa cell tumors at all dose levels. A doserelated increase in the incidence ofovarian hyperplasia was also
`observed in female mice. These ovarian changes are consideredtobe rodent-specific effectsofaromatase inhibition~~
`and are of questionable significance to humans. The incidence of lymphosarcoma. was- increased-in- mates -and-
`females at the high dose. At 50 me/kg/day, plasma AUClevels in mice were 35 to 40 times higher than the level
`exhibited in post-menopausal volunteers at the recommended dose. :
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`Mutagenesis: ARIMIDEX has not been shown to be mutagenic in in vitro tests (Ames and E.coli bacterial
`tests, CHO-KI gene mutation assay) or clastogeniceither in vitro (chromosome aberrations in human lymphocytes)
`or in vivo (micronucleus test in Fats).
`
`Impairment of Fertility: Studies to investigate the effect of ARIMIDEX on fertility have not been
`conducted; however, chronic studies indicated hypertrophyofthe ovaries and the presence offollicular cysts in rats
`administered doses equalto or greater than | mg/kg/day (which produced plasma anastrozole C,,,,,, and AUC, bs
`that were 19 and 9 times higher than the respective values found in healthy post-menopausal humans at the
`recommended dose).
`In addition, hyperplastic uteri were observed in chronic studies of female dogs administered
`doses equal to or greater than | mg/kg/day (which produced plasmaanastrozole C..., and AUC,,,,,, that were 22
`times and 16 times higher than the respective values found in post-menopausal humans at the recommended dose).
`It is not known whetherthese effects on the reproductive organsofanimals are associated with impaired fertility in
`
`humans.
`
`Pregnancy: Pregnancy Category D: (See WARNINGS).
`
`It is not known if anastrozole is excreted in human milk. Because many drugs are
`Nursing Mothers:
`excreted in human milk, caution should be exercised when ARIMIDEX is administered to a hursing woman.
`(See
`WARNINGSand PRECAUTIONS.)
`
`Pediatric Use: The safety and efficacy ofARIMIDEXin pediatric patients have not been established.
`
`Geriatric Use: In studies 0027 and 0030 about 50% ofpatients were 65 or older. Patients > 65 years ofage
`had moderately better tumor response and timeto tumorprogression than patients < 65 years of age regardless of
`randomized treatment. In studies 0004 and 0005, fifty percent ofpatients were65 or older. Response rates and time .
`to progression were similar for the over 65 and younger patients.
`
`ADVERSE REACTIONS
`First Line Therapy: ARIMIDEX was generally well tolerated in two well-controlled clinical trials (i.e,
`Trials 0030 and 0027). Adverse events occurrin.
`‘with anincidenceofat-teast5% ineither treatment
`
`
`
`
`proup offrials
`0030 and 0027 during or within 2 weeks of the end of treatmentare shown in Table 5.
`
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`APMt ans wre ag
`gait
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`cs - ve - od
`
`PRON a te es ut
`t.
`aed
`cc
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`hogs
`he
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`a
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`Body system
`Adverse event*
`
`Table 5
`
`Number(%) ofsubjects
`ARIMIDEX
`Tamoxifen
`(n=506)
`(n=S11)
`
`_
`
`Musculoskeletal
`
`Nervous .
`
`Whole body
`83 (16.4)
`Asthenia
`70 (13.8)
`Pain ©
`60 (11.9)
`- Back pain
`47
`(9.3)
`Headache
`40
`(7.9)
`Abdominalpain
`37
`(7.3)
`Chest pain
`35
`(6.9)
`Flu syndrome
`23
`(4.5)
`Pelvic pain
`Cardiovascular
`128 (25.3)
`Vasodilation
`25°
`(4.9)
`Hypertension
`Digestive
`94
`(18.6)
`Nausea
`47
`(9.3)
`Constipation
`40
`(7.9)
`Diarrhea
`38
`(7.5)
`Vomiting
`26
`(5.1)
`Anorexia
`Metabolic and nutritional
`51
`(10.1)
`Peripheral edema
`54 (10.7)
`Bonepain
`30
`(5.9)
`Dizziness
`30
`(5.9)
`Insomnia
`23
`(4.5)
`Depression
`16
`(3.2)
`Hypertonia
`Respiratory
`55 (10.9)
`Cough increased
`51
`(10.1)
`Dyspnea
`49
`(9.7)
`Pharyngitis
`Skin and appendages
`38
`(7.5)
`Rash
`Urogenital
`9
`(1.8)
`Leukorrhea
`* A patient may have had morethan 1 adverse event.
`Less frequent adverse experiences reported in patients receiving ARIMIDEX | mg in either Trial 0030 or
`
`Trial 0027 were similar to those reported for second-line th fe . .NOtoseJL Cie
`
`
`
`reportedforsecond-linetherapy.
`
`.
`
`81 (15.9)
`73 (14.3)
`68 (13.3)
`40 (7.8)
`38 (7.4)
`37 (7.2)
`30 (5.9)
`30 (5.9)
`106 (20.7)
`36 (7.0)
`106 (20.7)
`66 (12.9)
`33
`(6.5)
`36 (7.0)
`46 (9.0)
`41
`(8.0)
`52 (10.2)
`22 (4.3)
`38 (5.5)
`32
`(6.3)
`26 (5.1)
`52 (10.2)
`47 (9.2)
`68 (13.3)
`34 (7.6)
`3I
`(6.1)
`
`.
`
`,
`
`:
`
`»
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`Based on results from second-line therapy and the established safety profile oftamoxifen, the incidences of
`9 prespecified adverse event categories
`potentially
`causally
`related to one or both ofthe therapies because of their
`pharmacology werestatistically analyzed. No significant differences were seen between treatment groups.
`
`Table 6
`Number (n) and Percentage of Patients
`ARIMIDEX
`NOLVADEX
`1 mg
`20 mg
`(n = 506)
`(n= 511)
`n
`n
`(%)
`(%)
`Adverse Event Group*
`23
`(4.5)
`32
`(6.3)
`Depression
`15
`(3.0)
`18
`(3.5)
`TumorFlare
`18
`(3.5)
`33
`(6.5)
`Thromboembolic Disease"
`5
`15
`Venous®
`13
`19
`Coronary and Cerebral‘
`(33.6)
`170
`196
`Gastrointestinal Disturbance
`(26.5)
`134
`118
`Hot Flushes
`(1.7)
`9
`3
`Vaginal Dryness
`(1.2)
`6
`15
`Lethargy
`(1.0)
`5
`1]
`Vaginal Bleeding
`(2.2)
`Il
`8
`Weight Gain
`*A patient may have had more than | adverse event
`"Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis
`‘Includes myocardial infarction, myocardial ischemia, anginapectoris, cerebrovascular accident, cerebral ischemia
`and cerebral infarct
`
`(38.4)
`(23.1)
`(0.6)
`(2.9)
`(2.2)
`(1.6)
`
`<
`
`Despite the lack ofestrogenic activity for Arimidex,there was no increase in myocardial infarction or fracture when
`
`compared with tamoxifen.
`
`Second Line Therapy: ARIMIDEX was generally well tolerated in two well-controlled clinicaltrials (i.c.,
`Trials 0004 and 0005), with less than 3.3% ofthe ARIMIDEX-treated patients and 4.0% ofthe megestrol acetate-
`treated patients withdrawing dueto an adverse event.
`
`The principal adverse event more common with ARIMIDEX than megestrol! acetate was diarrhea. Adverse
`events reported in greater than 5% ofthe patients in any ofthe treatment groups in these two well-controlled clinical
`trials, regardless of Causality, are presented below:
`
`"Add: Table70
`Number(n) and Percentage ofPatients with Adverse Event!
`7
`
`ARIMIDEX
`
`ARIMIDEX
`
`_ Megestrol
`Acetate
`
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`I mg
`10 mg
`-160 mg
`(n = 262)
`(n = 246)
`(n= 253)
`n
`n
`a
`%
`%
`%
`Adverse Event
`42
`(16.0)
`33
`(13.4)
`47
`(18.6)
`Asthenia
`41
`(15.6)
`48
`(19.5)
`28
`(11D)
`Nausea
`34
`(13.0)
`44
`(17.9)
`24
`(9.5)
`Headache
`32
`(12.2)
`29
`(10.6)
`21
`(8.3)
`Hot Flushes
`28
`(10.7)
`38
`(15.4)
`29°
`(11.5)
`Pain
`
`
`Back Pain 28=(10.7) 26 (10.6) 19 (7.5)
`
`
`
`Dyspnea
`24
`(9.2)
`27
`(11.0)
`53
`(20.9)
`Vomiting
`24
`(9.2)
`26
`(10.6)
`16
`(6.3)
`Cough Increased
`22
`(8.4)
`18
`(7.3)
`19
`(7.5)
`Diarrhea
`22
`(8.4)
`18
`(7.3)
`7
`(2.8)
`Constipation
`18
`(6.9)
`18
`(7.3)
`21°
`(8.3)
`Abdominal Pain
`18
`(6.9)
`14
`(5.7)
`18
`(7.1)
`Anorexia
`18
`(6.9)
`19
`(7.7)
`Th
`(4.3)
`Bone Pain
`17
`(6.5)
`26
`(11.8)
`19
`(7.5)
`Pharyngitis
`16
`(6.1)
`23
`(9.3)
`1S
`(5.9)
`Dizziness
`16
`(6.1)
`12)
`(4.9)
`15
`(5.9)
`Rash
`1S
`(5.7)
`15
`(6.1)
`19
`(7.5)
`Dry Mouth
`15
`(5.7)
`YW
`(4.5)
`13
`(5.1)
`Peripheral Edema
`14
`(5.3)
`21
`(8.5)
`28
`(11.1)
`Pelvic Pain
`‘14°
`(5.3)
`17
`(6.9)
`13
`(5.1)
`Depression
`14
`(5.3)
`6
`(2.4)
`3
`(2.0)
`Chest Pain
`13
`(5.0)
`18
`(7.3)
`13
`(5.1)
`Paresthesia
`12
`(4.6)
`AS
`(6.1)
`9
`(3.6)
`Vaginal Hemorrhage
`6
`(2.3)
`4
`(1.6)
`3)
`(5.1)
`Weight Gain
`4
`(1.5)
`9
`(3.7)
`30
`(11.9)
`Sweating
`4
`(1.5)
`3
`(1.2)
`16
`(6.3)
`Increased Appetite
`0
`(0)
`I
`(0.4)
`3 (5.1)
`"A patient may have more than one adverse event.
`Otherless frequent (2% to 5%)adverse experiences reported in patients receiving ARIMIDEX | ing 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 ofassessed causality.
`
`Body as a Whole: Flu syndrome;fever; neck pain; malaise; accidental injury; infection
`
`Cardiovascular: Hypertension; thrombophlebitis
`
`Hepatic: Gamma GTincreased: SGOTincreased: SGPTincreased
`
`Hematologic: Anemia; leukopenia
`
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`Metabolic and Nutritional: Alkaline phosphatase increased: weight| ss
`
`levels increased by 0.5 mmol/L among patients receiving ARIMIDEX.
`Mean serum total cholesterol
`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; pruritus
`
`Urogenital: Urinary tract infection; breast pain
`
`Vaginalbleeding has been reported infrequently, mainly in patients during the first few weeks after changing
`from existing hormonal therapy to treatment with ARIMIDEX.
`If bleeding persists, further evaluation should be
`
`considered.
`
`Duringclinical trials and bostmarketing experience joint pain/stiffness has been reported in association with
`the use of ARIMIDEX.
`.
`——a
`
`The incidences of the following adverse