1
`2
`3
`
`4
`5
`
`6
`
`7
`8
`9
`10
`
`11
`12
`13
`14
`15
`16
`17
`18
`19
`
`20
`
`21
`22
`23
`24
`25
`26
`27
`
`Femara ®
`(letrozole tablets)
`2.5 mg Tablets
`Rx only
`
`Prescribing Information
`
` T2000-xx
` xxxxxxxx
`
`DESCRIPTION
`Femara (letrozole tablets) for oral administration contains 2.5 mg of letrozole, a nonsteroidal
`aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-
`1,2,4-Triazol-1-ylmethylene)dibenzonitrile, and its structural formula is
`
`Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in
`dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a
`molecular weight of 285.31, empirical formula C17H11N5, and a melting range of 184°C-
`185°C.
`Femara (letrozole tablets) is available as 2.5 mg tablets for oral administration.
`Inactive Ingredients. Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose,
`lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose,
`polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment
`of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone
`receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen
`levels
`(ovariectomy, adrenalectomy, hypophysectomy) or
`inhibit estrogen effects
`(antiestrogens and progestational agents). These interventions lead to decreased tumor mass
`or delayed progression of tumor growth in some women.
`
`FMI v. Caris MPI
`Exhibit 1160
`IPR2019-00170
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 2
`FEMARA® (letrozole tablets)
`
`In postmenopausal women, estrogens are mainly derived from the action of the aromatase
`enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to
`estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in
`the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase
`enzyme.
`Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits
`the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female
`animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum
`LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy,
`treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively
`inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or
`glucocorticoid synthesis.
`Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the
`cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in
`all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol
`and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid
`synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
`Pharmacokinetics
`Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is
`not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide
`conjugate is excreted renally, representing the major clearance pathway. About 90% of
`radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about
`2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-
`6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from
`the concentrations measured after a single dose, indicating a slight non-linearity in the
`pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels
`are maintained over extended periods, however, and continuous accumulation of letrozole
`does not occur. Letrozole is weakly protein bound and has a large volume of distribution
`(approximately 1.9 L/kg).
`Metabolism and Excretion
`(4,4'-methanol-
`carbinol metabolite
`Metabolism
`to
`a pharmacologically-inactive
`bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the
`major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was
`the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and
`6% was unchanged letrozole.
`In human microsomes with specific CYP isozyme activity, CYP 3A4 metabolized letrozole to
`the carbinol metabolite while CYP 2A6 formed both this metabolite and its ketone analog. In
`human liver microsomes, letrozole strongly inhibited CYP 2A6 and moderately inhibited
`CYP 2C19.
`
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`
`45
`46
`47
`48
`49
`50
`51
`52
`53
`54
`55
`56
`
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`
`

`

`Novartis
`Revised Package Insert
`
`Special Populations
`
`Confidential
`
`Page 3
`FEMARA® (letrozole tablets)
`
`Pediatric, Geriatric and Race:
`In the study populations (adults ranging in age from 35 to >80 years), no change in
`pharmacokinetic parameters was observed with increasing age. Differences in letrozole
`pharmacokinetics between adult and pediatric populations have not been studied. Differences
`in letrozole pharmacokinetics due to race have not been studied.
`
`Renal Insufficiency:
`In a study of volunteers with varying renal function (24-hour creatinine clearance:
`9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg
`of Femara (letrozole tablets) was found. In addition, in a study of 347 patients with advanced
`breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal
`impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma
`letrozole concentration.
`
`Hepatic Insufficiency:
`In a study of subjects with varying degrees of non-metastatic hepatic dysfunction (e.g.,
`cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with
`moderate hepatic impairment were 37% higher than in normal subjects, but still within the
`range seen in subjects without impaired function. Patients with severe hepatic impairment
`(Child-Pugh classification C) have not been studied (see DOSAGE & ADMINISTRATION
`Hepatic Impairment).
`
`Drug/Drug Interactions:
`A pharmacokinetic interaction study with cimetidine showed no clinically significant effect
`on letrozole pharmacokinetics. An interaction study with warfarin showed no clinically
`significant effect of letrozole on warfarin pharmacokinetics.
`There is no clinical experience to date on the use of Femara in combination with other anti-
`cancer agents.
`Pharmacodynamics
`In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg
`Femara suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75%-95%
`from baseline with maximal suppression achieved within two-three days. Suppression is
`dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone
`sulfate that were below the limit of detection in the assays. Estrogen suppression was
`maintained throughout treatment in all patients treated at 0.5 mg or higher.
`Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of
`adrenal steroidogenesis.
` No clinically-relevant changes were found in the plasma
`concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or
`in plasma renin activity among postmenopausal patients treated with a daily dose of Femara
`0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with
`
`67
`
`68
`69
`70
`71
`72
`
`73
`74
`75
`76
`77
`78
`79
`
`80
`81
`82
`83
`84
`85
`86
`
`87
`88
`89
`90
`91
`92
`
`93
`94
`95
`96
`97
`98
`99
`100
`101
`102
`103
`104
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 4
`FEMARA® (letrozole tablets)
`
`daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone
`or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not
`necessary.
`No changes were noted in plasma concentrations of androgens (androstenedione and
`testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of
`Femara or in plasma concentrations of androstenedione among postmenopausal patients
`treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen
`biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH
`and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by
`TSH levels, T3 uptake, and T4 levels.
`Clinical Studies
`First-Line Breast Cancer:
`A randomized, double-blinded, multinational trial compared Femara 2.5 mg with tamoxifen
`20 mg in 907 postmenopausal patients with locally advanced (Stage IIIB or locoregional
`recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer.
`Time to progression (TTP) was the primary endpoint of the trial. Selected baseline
`characteristics for this study are shown in the following table:
`
`Table 1: Selected Study Population Demographics
`Baseline Status Femara tamoxifen
`N=453
`N=454
`
`Stage of disease
` IIIB
`IV
`Receptor Status
`
`ER & PR Positive
`ER or PR Positive
`Both unknown
`ER- or PR - /other unknown
`
`Previous Antiestrogen Therapy
`Adjuvant
`None
`
`Dominant Site of Disease
`Soft Tissue
`Bone
`Visceral
`
`
`
`6%
`93%
`
`38%
`26%
`34%
` <1%
`
`19%
`81%
`
`25%
`32%
`43%
`
`7%
`92%
`
`41%
`26%
`33%
`0
`
`18%
`82%
`
`25%
`29%
`46%
`
` Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 2).
`No differences were seen in duration of tumor response. Results from the prospectively
`
`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`
`115
`116
`117
`118
`119
`120
`121
`
`122
`123
`124
`125
`126
`127
`128
`129
`130
`131
`132
`133
`134
`135
`136
`137
`138
`139
`140
`141
`142
`143
`144
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 5
`FEMARA® (letrozole tablets)
`
`defined secondary endpoint of time to treatment failure and clinical benefit were supportive of
`the results of the primary efficacy endpoint.
`Table 2 summarizes the results of the trial, with a total median follow-up of approximately
`18 months. (All analyses are unadjusted and use 2-sided p-values.)
`
`
`
`Table 2: Results
`ratio (95% CI)
` tamoxifen 20 mg
`Femara 2.5 mg
` N = 453 N = 454 p-value (2-sided)
`
`6.0 months 0.70 (0.60, 0.82)1
`9.4 months
`Median Time to progression
` p= 0.0001
`92 (20%) 1.71 (1.26, 2.32) 2
`Objective Response Rate(CR+PR)
`137 (30%)
`p=0.0006
`2.75 (1.43, 5.29) 2
`p= 0.002
`
`CR
`
`34 (8%)
`
`13 (3%)
`
`1Hazard ratio
`2odds ratio
`
`Figure 1 shows the Kaplan-Meier curves for TTP.
`
`Table 3 shows results in the subgroup and women who had received prior antiestrogen
`adjuvant therapy and Table 4 shows results by disease site.
`
`(Note to Novartis: label this figure similarly to the figure following Table 6)
`
`Figure 1
`
`Time to progression (TTP)
`
` 3
`
` 6
`
` 9
`
`12
`Months
` letrozole
` tamoxifen
`
`15
`
`18
`
`21
`
`24
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`Start
`
`Progression free
`
`145
`146
`147
`148
`149
`150
`151
`152
`153
`154
`155
`156
`157
`158
`159
`160
`161
`162
`163
`164
`165
`166
`167
`
`168
`169
`170
`
`171
`172
`173
`174
`175
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 6
`FEMARA® (letrozole tablets)
`
`Table 3:
`Efficacy in patients who received prior antiestrogen adjuvant therapy
`
`Femara 2.5 mg
`N = 84
`
`tamoxifen 20 mg
`N = 83
`
`p-value (2-sided)
`
`Median Time To Progression 8.8 months
`
`5.9 months
`
`Objective Response Rate
`(CR + PR)
`1Hazard ratio
`2odds ratio
`
`29% 8%
`
`0.041
`
`0.0022
`
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`187
`188
`189
`190
`191
`192
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 7
`FEMARA® (letrozole tablets)
`
`Table 4:
`Efficacy by Disease Site
`
`Femara 2.5 mg
`N = 453
`
`tamoxifen 20 mg p-value (2-sided)
`N = 454
`
`N = 113
`12.9 months
`48%
`
`N = 130
`9.7 months
`22%
`
`N = 208
`8.2 months
`26%
`
`N = 116
`6.4 months
`35%
`
`6.2 months
`14%
`
`4.7 months
`16%
`
`0.051
`0.042
`
`0.011
`0.082
`
`0.0011
`0.022
`
`Dominant Disease Site
`Soft Tissue:
`TTP
` Median
`Objective Response Rate
`
`Bone:
`N = 146
`TTP
` Median
`Objective Response Rate
`
`Visceral:
`N = 194
`TTP
` Median
`Objective Response Rate
`
`1Hazard ratio
`2odds ratio
`
`Second-Line Breast Cancer:
`Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative
`phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown
`advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients
`had received other hormonal therapies and also may have received cytotoxic therapy. Eight
`(20%) of forty patients treated with Femara 2.5 mg daily in phase I/II trials achieved an
`objective tumor response (complete or partial response).
`Two large randomized controlled multinational (predominantly European) trials were
`conducted in patients with advanced breast cancer who had progressed despite antiestrogen
`therapy. Patients were randomized to Femara 0.5 mg daily, Femara 2.5 mg daily, or a
`comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg bid
`with corticosteroid supplementation in the other study). In each study over 60% of the
`patients had received therapeutic antiestrogens, and about one-fifth of these patients had had
`an objective response. The megestrol acetate controlled study was double-blind; the other
`study was open label. Selected baseline characteristics for each study are shown in the
`following table:
`
`Table 5: Selected Study Population Demographics
`Parameter megestrol acetate study aminoglutethimide study
`No. of Participants
`552
`557
`
`193
`194
`195
`196
`197
`198
`199
`200
`201
`202
`203
`204
`205
`206
`207
`208
`209
`210
`211
`212
`213
`214
`215
`216
`
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`
`234
`235
`236
`237
`
`

`

`Novartis
`Revised Package Insert
`
`Receptor Status
`
`ER/PR Positive
`ER/PR Unknown
`
`Previous Therapy
`Adjuvant Only
`Therapeutic +/- Adj.
`
`Sites of Disease
`Soft Tissue
`Bone
`Visceral
`
`Confidential
`
`Page 8
`FEMARA® (letrozole tablets)
`
`57%
`43%
`
`33%
`66%
`
`56%
`50%
`40%
`
`56%
`44%
`
`38%
`62%
`
`50%
`55%
`44%
`
`Confirmed objective tumor response (complete response plus partial response) was the
`primary endpoint of the trials. Responses were measured according to the Union
`Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review.
`All responses were confirmed by a second evaluation 4-12 weeks after the documentation of
`the initial response.
`The following table shows the results for the first trial, with a minimum follow-up of
`15 months, that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg
`daily. (All analyses are unadjusted.)
`
`Table 6: Megestrol Acetate Study Results
`Femara 0.5 mg Femara 2.5 mg Megestrol Acetate
` N = 188 N = 174 N = 190
`
`Objective Response (CR + PR)
`
`22 (11.7%)
`
`41 (23.6%)
`
`31 (16.3%)
`
`Median Duration of Response
`
`552 days
`
`(Not reached)
`
`561 days
`
`Median Time to Progression
`
`154 days
`
`170 days
`
`Median Survival
`
`633 days
`
`730 days
`
`168 days
`
`659 days
`
`Odds Ratio for Response
`
`Femara 2.5 : Femara 0.5 = 2.33
`(95% CI: 1.32, 4.17); p=0.004*
`
`Femara 2.5: Megestrol = 1.58
`(95% CI: 0.94, 2.66); p = 0.08*
`
`Relative Risk of Progression
`
`Femara 2.5: Femara 0.5 = 0.81
`(95% CI: 0.63, 1.03); p = 0.09*
`_____________________________________
`*two-sided p-value
`
`Femara 2.5: Megestrol = 0.77
`(95% CI: 0.60, 0.98), p = 0.03*
`
`238
`239
`240
`241
`242
`243
`244
`245
`246
`247
`248
`249
`250
`251
`252
`253
`254
`255
`256
`257
`258
`
`259
`260
`261
`262
`263
`264
`265
`266
`267
`268
`269
`270
`271
`272
`273
`274
`275
`276
`277
`278
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 9
`FEMARA® (letrozole tablets)
`
`The Kaplan-Meier Curve for progression for the megestrol acetate study is shown below in
`figure 2.
`
`Figure 2
`
`The results for the study comparing Femara to aminoglutethimide, with a minimum follow-up
`of nine months, are shown in the following table. (Unadjusted analyses are used).
`
`Table 7: Aminoglutethimide Study Results
`Femara 0.5
`Femara 2.5 Aminoglutethimide
`N = 193
`N = 185
`N = 179
`
`Objective Response (CR + PR)
`
`34 (17.6%)
`
`34 (18.4%)
`
`22 (12.3%)
`
`Median Duration of Response
`
`619 days
`
`706 days
`
`450 days
`
`Median Time to Progression
`
`103 days
`
`123 days
`
`112 days
`
`Median Survival
`
`636 days
`
`792 days
`
`592 days
`
`Odds Ratio for Response
`
`Relative Risk of Progression
`
`Femara 2.5 : Femara 0.5
`=1.05
`(95% CI: 0.62, 1.79); p=0.85*
`
`Femara 2.5: Aminoglutethimide
`=1.61
`(95% CI: 0.90, 2.87); p = 0.11*
`
`Femara 2.5: Femara 0.5
`=0.86
`(95% CI: 0.68, 1.11); p = 0.25*
`
`Femara 2.5: Aminoglutethimide
`=0.74
`(95% CI: 0.57, 0.94), p = 0.02*
`
`279
`280
`281
`282
`
`283
`284
`285
`
`286
`287
`288
`289
`290
`291
`292
`293
`294
`295
`296
`297
`298
`299
`300
`301
`302
`303
`304
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 10
`FEMARA® (letrozole tablets)
`
`__________________________________________
`*two-sided p-value
`
`The Kaplan-Meier Curve for progression for the aminoglutethimide study is shown below in
`figure 3.
`
`Figure 3
`
`INDICATIONS AND USAGE
`Femara (letrozole tablets) is indicated for first-line treatment of postmenopausal women with
`hormone receptor positive or hormone receptor unknown locally advanced or metastatic
`breast cancer. Femara is also indicated for the treatment of advanced breast cancer in
`postmenopausal women with disease progression following antiestrogen therapy.
`
`CONTRAINDICATIONS
`Femara is contraindicated in patients with known hypersensitivity to Femara or any of its
`excipients.
`
`305
`306
`307
`308
`309
`310
`311
`
`312
`313
`
`314
`315
`316
`317
`318
`
`319
`320
`321
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 11
`FEMARA® (letrozole tablets)
`
`WARNINGS
`Pregnancy
`Letrozole may cause fetal harm when administered to pregnant women. Studies in rats at
`doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended
`human dose on a mg/m2 basis) administered during the period of organogenesis, have shown
`that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased
`resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal
`anomalies including absence and shortening of renal papilla, dilation of ureter, edema and
`incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A
`0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2
`basis) caused fetal domed head and cervical/centrum vertebral fusion.
`Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when
`administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum
`recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included
`incomplete ossification of the skull, sternebrae, and fore- and hindlegs.
`There are no studies in pregnant women. Femara is indicated for post-menopausal women. If
`there is exposure to letrozole during pregnancy, the patient should be apprised of the potential
`hazard to the fetus and potential risk for loss of the pregnancy.
`
`PRECAUTIONS
`Laboratory Tests
`No dose-related effect of Femara on any hematologic or clinical chemistry parameter was
`evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were
`observed in some patients receiving Femara (letrozole tablets) 2.5 mg. This depression was
`transient
`in about half of
`those affected.
` Two patients on Femara developed
`thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to
`laboratory abnormalities, whether related to study treatment or not, was infrequent.
`Increases in SGOT, SGPT, and gamma GT ≥5 times the upper limit of normal (ULN) and of
`bilirubin ≥1.5 times the ULN were most often associated with metastatic disease in the liver.
`About 3% of study participants receiving Femara had abnormalities in liver chemistries not
`associated with documented metastases; these abnormalities may have been related to study
`drug therapy. In the megestrol acetate comparative study about 8% of patients treated with
`megestrol acetate had abnormalities in liver chemistries that were not associated with
`documented
`liver metastases;
`in
`the aminoglutethimide
`study about 10% of
`aminoglutethimide-treated patients had abnormalities in liver chemistries not associated with
`hepatic metastases.
`
`322
`
`323
`324
`325
`326
`327
`328
`329
`330
`331
`332
`333
`334
`335
`336
`337
`338
`339
`
`340
`
`341
`342
`343
`344
`345
`346
`347
`348
`349
`350
`351
`352
`353
`354
`355
`356
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 12
`FEMARA® (letrozole tablets)
`
`Drug Interactions
`Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of
`Femara with these drugs does not result in clinically-significant drug interactions. (See
`CLINICAL PHARMACOLOGY)
`There is no clinical experience to date on the use of Femara in combination with other anti-
`cancer agents.
`Drug/Laboratory Test-Interactions
`None observed.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about one to
`100 times the daily maximum recommended human dose on a mg/m2 basis) administered by
`oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign
`ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma
`showed a significant trend in females when the high dose group was excluded due to low
`survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times
`higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The
`carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the
`daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced
`an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian
`hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At
`10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast
`cancer patients at the recommended dose.
`Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was
`observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster
`ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).
`Studies to investigate the effect of letrozole on fertility have not been conducted; however,
`repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in
`males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively
`(about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis,
`respectively).
`Pregnancy: Pregnancy Category D (See WARNINGS).
`Nursing Mothers
`It is not known if letrozole is excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when letrozole is administered to a nursing woman
`(See WARNINGS AND PRECAUTIONS).
`Pediatric Use
`The safety and effectiveness in pediatric patients have not been established.
`
`357
`358
`359
`360
`361
`362
`
`363
`364
`
`365
`366
`367
`368
`369
`370
`371
`372
`373
`374
`375
`376
`377
`378
`379
`380
`381
`382
`383
`384
`385
`386
`387
`
`388
`389
`390
`391
`
`392
`393
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 13
`FEMARA® (letrozole tablets)
`
`Geriatric Use
`The median age of patients in the trial that compared Femara 2.5 mg daily to tamoxifen 20 mg
`daily as first-line therapy was 65 years. About 1/3 of the patients were ≥ 70 years old. Femara
`time to tumor progression and tumor response rate were better in patients ≥ 70 than in patients
`< 70 years of age.
`The mean age of patients in the two second-line randomized trials, that compared Femara (0.5
`mg and 2.5 mg) to megestrol acetate and to aminoglutethimide, was 64 years. Thirty percent
`of patients were ≥70 years old. The proportion of patients responding to each dose of Femara
`was similar for women ≥70 years old and <70 years old.
`
`ADVERSE REACTIONS
`Femara was generally well tolerated across all studies as first-line and second-line treatment
`for breast cancer and adverse reaction rates were similar in both settings.
`First-line breast cancer:
`A total of 455 patients was treated for a median time of exposure of 11 months. The incidence
`of adverse experiences was similar for Femara and tamoxifen. The most frequently reported
`adverse experiences were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea.
`Discontinuations for adverse experiences other than progression of tumor occurred in 10/455
`(2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen.
`
`Adverse events, regardless of relationship to study drug, that were reported in at least 5% of
`the patients treated with Femara 2.5 mg or tamoxifen 20 mg in the first-line treatment study
`are shown in the following table 8:
`
`394
`395
`396
`397
`398
`399
`400
`401
`402
`
`403
`404
`405
`406
`407
`408
`409
`410
`411
`412
`413
`414
`415
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 14
`FEMARA® (letrozole tablets)
`
`Table 8:
` Adverse
`Experience
`
`Percentage (%) of Patients with Adverse Events
`
`tamoxifen
`20 mg
`(n=455)
`%
`
`Femara
`2.5 mg
`(n=455)
`%
`
`Body as a Whole
`11
`11
`Fatigue
`8
`8
`Chest pain
`Weight decreased 6 4
` Pain-not otherwise specified 5 6
`
`
` Weakness 5 3
`
`Cardiovascular
`Hot flushes 18 15
`Edema-lower limb
`5
`5
`Hypertension
`5
`4
`Digestive System
`Nausea
`Constipation
`Diarrhea
`Vomiting
`Appetite decreased
`Pain-abdominal
`Infections/Infestations
`Influenza
`Musculoskeletal System
`Pain-bone
`Pain-back
`Arthralgia
`Pain-limb
`Nervous System
`Headache
`Insomnia
`Reproductive
`
` Breast Pain 5 6
`Respiratory System
`Dyspnea
`Coughing
`Skin and Appendages
`
` Alopecia/hair thinning 5 4
`Surgical/Medical Procedures
`
` Post-mastectomy lymphoedema 7 6
`
`15
`9
`7
`7
`4
`4
`
`5
`
`20
`17
`14
`8
`
`8
`6
`
`14
`11
`
`16
`9
`4
`7
`6
`5
`
`4
`
`18
`17
`13
`7
`
`7
`4
`
`15
`10
`
`416
`417
`418
`419
`420
`421
`422
`423
`424
`425
`426
`427
`428
`429
`430
`431
`432
`433
`434
`435
`436
`437
`438
`439
`440
`441
`442
`443
`444
`445
`446
`447
`448
`449
`450
`451
`452
`453
`454
`455
`456
`457
`458
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 15
`FEMARA® (letrozole tablets)
`
`Other less frequent (<2%) adverse experiences considered consequential for both treatment
`groups , included peripheral thromboembolic events, cardiovascular events, and
`cerebrovascular events. Peripheral thromboembolic events included venous thrombosis,
`thrombophlebitis, portal vein thrombosis and pulmonary embolism. Cardiovascular events
`included angina, myocardial infarction, myocardial ischemia, and coronary heart disease.
`Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic
`strokes and development of hemiparesis.
`
`Second-line breast cancer:
`Femara (letrozole tablets) was generally well tolerated in two controlled clinical trials.
`Study discontinuations in the megestrol acetate comparison study for adverse events other
`than progression of tumor occurred in 5/188 (2.7%) of patients on Femara 0.5 mg, in 4/174
`(2.3%) of the patients on Femara 2.5 mg, and in 15/190 (7.9%) of patients on megestrol
`acetate. There were fewer thromboembolic events at both Femara doses than on the
`megestrol acetate arm (2 of 362 patients or 0.6% vs. 9 of 190 patients or 4.7%). There was
`also less vaginal bleeding (1 of 362 patients or 0.3% vs. 6 of 190 patients or 3.2%) on
`letrozole than on megestrol acetate.
` In the aminoglutethimide comparison study,
`discontinuations for reasons other than progression occurred in 6/193 (3.1%) of patients on
`0.5 mg Femara, 7/185 (3.8%) of patients on 2.5 mg Femara, and 7/178 (3.9%) of patients on
`aminoglutethimide.
`Comparisons of the incidence of adverse events revealed no significant differences between
`the high and low dose Femara groups in either study. Most of the adverse events observed in
`all treatment groups were mild to moderate in severity and it was generally not possible to
`distinguish adverse reactions due to treatment from the consequences of the patient’s
`metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness.
`Adverse events, regardless of relationship to study drug, that were reported in at least 5% of
`the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or
`aminoglutethimide in the two controlled trials are shown in the following table 9:
`
`459
`460
`461
`462
`463
`464
`465
`466
`467
`468
`469
`470
`471
`472
`473
`474
`475
`476
`477
`478
`479
`480
`481
`482
`483
`484
`485
`486
`487
`488
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 16
`FEMARA® (letrozole tablets)
`
`489
`490
`491
`492
`493
`494
`495
`496
`497
`498
`499
`500
`501
`502
`503
`504
`505
`506
`507
`508
`509
`510
`511
`512
`513
`514
`515
`516
`517
`518
`519
`520
`521
`522
`523
`524
`525
`526
`527
`528
`529
`530
`531
`532
`533
`
` Adverse
`Experience
`
`Body as a Whole
`Fatigue
`Chest pain
`Peripheral edema1
`Asthenia
`Weight increase
`Cardiovascular
`Hypertension
`Digestive System
`Nausea
`Vomiting
`Constipation
`Diarrhea
`Pain-abdominal
`Anorexia
`Dyspepsia
`Infections/Infestations
`Viral infection
`Lab Abnormality
`Hypercholesterolemia
`Musculoskeletal System
`Musculoskeletal2
`Arthralgia
`Nervous System
`Headache
`Somnolence
`Dizziness
`Respiratory System
`Dyspnea
`Coughing
`Skin and Appendages
`Hot flushes
`Rash3
`Pruritus
`
`Table 9: Percentage (%) of Patients with Adverse Events
`Pooled
`Pooled
` Megestrol
`Femara
`Femara
`Acetate
`2.5 mg
`0.5 mg
`160 mg
`(n=359)
`(n=380)
`(n=189)
`%
`%
`%
`
`Aminoglutethimide
`500 mg
`(n=178)
`%
`
`8
`6
`5
`4
`2
`
`5
`
`13
`7
`6
`6
`6
`5
`3
`
`6
`
`3
`
`21
`8
`
`9
`3
`3
`
`7
`6
`
`6
`5
`1
`
`6
`3
`5
`5
`2
`
`7
`
`15
`7
`7
`5
`5
`3
`4
`
`5
`
`3
`
`22
`8
`
`12
`2
`5
`
`9
`5
`
`5
`4
`2
`
`11
`7
`8
`4
`9
`
`5
`
`9
`5
`9
`3
`9
`5
`6
`
`6
`
`0
`
`30
`8
`
`9
`2
`7
`
`16
`7
`
`4
`3
`5
`
`3
`3
`3
`5
`3
`
`6
`
`14
`9
`7
`4
`8
`5
`5
`
`3
`
`6
`
`14
`3
`
`7
`9
`3
`
`5
`5
`
`3
`12
`3
`
`1
`2
`3
`
`Includes peripheral edema, leg edema, dependent edema, edema
`Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain
`Includes rash, erythematous rash, maculopapular rash, psoriaform rash, vesicular rash
`
`

`

`Novartis
`Revised Package Insert
`
`Confidential
`
`Page 17
`FEMARA® (letrozole tablets)
`
`Other less frequent (<5%) adverse experiences considered consequential and reported in at
`least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety,
`pleural effusion, alopecia, increased sweating and vertigo.
`
`OVERDOSAGE
`Isolated cases of Femara (letrozole tablets) overdose have been reported. In these instances,
`the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse events
`were reported in these cases, because of the limited data available, no firm recommendations
`for treatment can be made. However, emesis could be induced if the patient is alert. In
`general, supportive care and frequent monitoring of vital signs are also appropriate. In single
`dose studies the highest dose used was 30 mg, which was well tolerated; in multiple dose
`trials, the largest dose of 10 mg was well tolerated.
`Lethality was observed in mice and rats following single oral doses that were equal to or
`greater than 2000 mg/kg (about 4000 to 8000 times the daily maximum recommended human
`dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea.
`Lethality was observed in cats following single IV doses that were equal to or greater than
`10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis);
`death was preceded by depressed blood pressure and arrhythmias.
`
`DOSAGE & ADMINISTRATION
`Adult and Elderly Patients
`The recommended dose of Femara (letrozole tablets) is one 2.5 mg tablet administered once a
`day, without regard to meals. Treatment with Femara should continue until tumor progression
`is evident. No dose adjustment is required for elderly patients. Patients treated with Femara
`do not require gluco