`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`
`NDA 21-923
`
`
`Bayer Pharmaceuticals Corporation
`Attention: Aileen Ryan, M.Sc.
`Director, Global Regulatory Affairs Therapeutic Area Oncology
`400 Morgan Lane
`West Haven, CT 06516
`
`
`Dear Ms. Ryan:
`
`Please refer to your new drug application (NDA) dated July 6, 2005, received July 8, 2005,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Nexavar
`(sorafenib) 200 mg tablets.
`
`We acknowledge receipt of your submissions dated April 28, June 1 and 17, August 8, 19, 23, and
`25, September 13, 16, and 23, October 7, 13, 18, 24, and 31, November 4 (2 submissions) and 8,
`and December 2, 5, 6, 15 and 19, 2005.
`
`This new drug application provides for the use of Nexavar (sorafenib) tablets 200 mg for the
`treatment of patients with advanced renal cell carcinoma.
`
`We have completed our review of this application, as amended. It is approved, effective on the date
`of this letter, for use as recommended in the agreed-upon labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package
`insert, text for the patient package insert, immediate container and carton labels). Marketing the
`product with FPL that is not identical to the approved labeling text may render the product
`misbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled
`Providing Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20
`paper copies of the FPL as soon as it is available but no more than 30 days after it is printed.
`Individually mount 15 of the copies on heavy-weight paper or similar material. For administrative
`purposes, designate this submission “FPL for approved NDA 21-923.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 001
`
`

`

`NDA 21-923
`Page 2
`
`We remind you of your post-marketing study commitments as agreed upon on December 19, 2005.
`These commitments, along with any completion dates agreed upon, are listed below.
`
`
`
`
`Clinical
`
`
`
`
`
`
`
`
`
`Regarding Study 11213, “A phase 3 randomized study of BAY43-9006 in patients with
`unresectable and/or metastatic renal cell cancer”:
`
`1. Provide the results of the second interim analysis of overall survival (cutoff date of
`November 30, 2005).
`
` Protocol Submission: October 16, 2003 (IND 60,453, serial number 317)
` Study start: November 15, 2003
` Report submission on second interim analysis: February 2006
`
`
`2. Provide the complete study report and datasets with the definitive statistical analysis of
`overall survival (after approximately 540 events).
`
` Protocol Submission: October 16, 2003 (IND 60,453, serial number 317)
` Study start: November 15, 2003
` Final report submission: March 2007
`
`Clinical Pharmacology and Biopharmaceutics
`
`3. Provide a full report for the dose-ranging Phase 1 study in Japan (Study 11497) and
`additional data in Asian patients from ongoing studies. The evaluation and submission
`of data from this Phase 1 study and other ongoing studies will be completed by
`December 2006. If the FDA concludes that further trials are warranted, you will conduct
`modeling and simulation analyses to devise a dosing regimen designed to achieve
`similar exposures between Asians and Caucasians. After agreement with the FDA on
`the proposed dosing regimen and study design, you will perform a clinical
`pharmacokinetic study to confirm that the proposed regimen achieves similar exposures
`between these two populations.
`
`The modeling and simulation analysis to determine a dosing regimen will be completed
`in March 2007. If a PK study to evaluate an alternative dosing regimen in Asian patients
`is warranted, the study will be reported by June 2008.
`
`Protocol submission: March 2007
`Study start: July 2007
`Final report submission: June 2008
`
`
`
`
`
`
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 002
`
`

`

`NDA 21-923
`Page 3
`
`
`4. Complete the ongoing study of the effect of sorafenib on paclitaxel (a CYP 2C8
`substrate) pharmacokinetics: Study 100375.
`
`
`
`Protocol submission: November 29, 2001 (IND 60,453, serial number 038)
`Study start: July 15, 2002
`Final report submission: June 2006
`
`
`5. Complete the ongoing investigation of biomarkers to identify patients who respond to
`sorafenib. This request will be fulfilled based on data from studies 100391 and 11213.
`
`Study 100391
` Protocol Submission: April 12, 2002 (IND 60,453, serial number 67)
` Study start: September 25, 2002
` Final report submission: September 2006
`
`Study 11213
` Protocol Submission: October 16, 2003 (IND 60,453, serial number 317)
` Study start: November 15, 2003
` Final report submission: September 2006
`
`
`6. Complete the ongoing study examining rifampin’s effects on sorafenib
`pharmacokinetics.
`
`
`
`Protocol submission: October 3, 2005 (IND 60,453, serial number 1109)
`Study start: October 27, 2005
`Final report submission: June 2006
`
`
`7. Complete the ongoing study examining sorafenib pharmacokinetics in patients with
`renal impairment.
`
`
`
`
`
`Protocol submission: April 4, 2005 (IND 60,453, serial number 798)
`Study start: June 3, 2005
`Final report submission: September 2006
`
`
`The FDA acknowledges your commitment to make appropriate changes as recommended by the
`USAN Council if the Council does not accept your proposed nonproprietary name.
`
`In addition, although not considered post-marketing commitments, we have the following
`suggestions and comments.
`
`
`1. Hemorrhage has been reported in association with sorafenib. Consider performing a
`study of platelet function ----------- or similar assay) in patients before and during
`(b)(4)
`sorafenib therapy,
`
`
`2. Hypophosphatemia occurs commonly during treatment with sorafenib and is an unusual
`adverse event of anti-neoplastic therapy. Consider further study to elucidate the
`mechanism of sorafenib-associated hypophosphatemia.
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 003
`
`

`

`NDA 21-923
`Page 4
`
`
`3. Thyroid changes and hypothyroidism were observed in nonclinical sorafenib studies.
`Although only two sorafenib-treated patients were diagnosed with clinical
`hypothyroidism in the phase 3 study, this adverse event was not prospectively assessed.
`We recommend close monitoring of post-marketing adverse event reports for
`hypothyroidism. Further study to assess changes in thyroid function may be warranted
`based on post-marketing reports.
`
`
`
`4. Sorafenib may act as a VEGF-R inhibitor. Another approved VEGF inhibitor has been
`associated with thrombosis, hemorrhage, and delayed surgical wound healing. We
`recommend careful post-marketing monitoring of these adverse events.
`
`
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We
`are waiving the pediatric study requirement for this application.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use
`for this product. Submit all proposed materials in draft or mock-up form, not final print. Send one
`copy to the Division of Drug Oncology Products and two copies of both the promotional materials
`and the package insert directly to:
`
`
`
`
`
`
`We have not completed validation of the regulatory methods. However, we expect your continued
`cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Patty Garvey, Regulatory Project Manager, at (301) 796-1356.
`
`
`Division of Drug Marketing, Advertising, and Communications
`Food and Drug Administration
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`
`
`
`
`
`
`Enclosure
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 004
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Richard Pazdur
`12/20/2005 12:14:48 PM
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 005
`
`

`

`NEXAVAR®
`
`(sorafenib)
`tablets 200 mg
`
`DESCRIPTION
`
`NEXAVAR, a multikinase inhibitor targeting several serine/threonine and receptor tyrosine
`kinases, is the tosylate salt of sorafenib.
`Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]
`ureido}phenoxy)-N2-methylpyridine-2-carboxamide
`4-methylbenzenesulfonate
`and
`its
`structural formula is:
`
`O
`
`CH3
`
`O
`
`NH
`
`NH
`
`F
`
`F
`
`F
`
`Cl
`
`
`Sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula of
`C21H16ClF3N4O3 x C7H8O3S and a molecular weight of 637.0 g/mole. Sorafenib tosylate is
`practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400.
`Each red, round NEXAVAR film-coated tablet contains sorafenib tosylate (274 mg)
`equivalent to 200 mg of sorafenib and the following inactive ingredients:
`croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate,
`magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib
`inhibited tumor growth of the murine renal cell carcinoma, RENCA, and several other human
`tumor xenografts in athymic mice. A reduction in tumor angiogenesis was seen in some
`tumor xenograft models. Sorafenib was shown to interact with multiple intracellular (CRAF,
`BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, VEGFR- 2, VEGFR- 3, and
`PDGFR- ß). Several of these kinases are thought to be involved in angiogenesis.
`
`CH3
`
`NH
`
`O
`
`N
`
`O
`
`OH
`
`S O
`
`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
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 006
`
`

`

`26
`27
`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
`
`Pharmacokinetics
`After administration of NEXAVAR tablets, the mean relative bioavailability is 38-49% when
`compared to an oral solution. The mean elimination half-life of sorafenib is approximately
`25-48 hours. Multiple dosing of NEXAVAR for 7 days resulted in a 2.5- to 7-fold
`accumulation compared to single dose administration. Steady-state plasma sorafenib
`concentrations are achieved within 7 days, with a peak-to-trough ratio of mean concentrations
`of less than 2.
`
`Absorption and Distribution
`Following oral administration, sorafenib reaches peak plasma levels in approximately
`3 hours. When given with a moderate-fat meal, bioavailability was similar to that in the
`fasted state. With a high-fat meal, sorafenib bioavailability was reduced by 29% compared to
`administration in the fasted state. It is recommended that NEXAVAR be administered
`without food (at least 1 hour before or 2 hours after eating) (see DOSAGE AND
`ADMINISTRATION section).
`Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered
`orally twice daily.
`In vitro binding of sorafenib to human plasma proteins is 99.5%.
`
`Metabolism and Elimination
`Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated
`by CYP3A4, as well as glucuronidation mediated by UGT1A9.
`Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady-
`state. Eight metabolites of sorafenib have been identified, of which five have been detected in
`plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows
`in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16%
`of circulating analytes at steady-state.
`Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96%
`of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of
`the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting
`for 51% of the dose, was found in feces but not in urine.
`
`Special Populations
`Analyses of demographic data suggest that no dose adjustments are necessary for age or
`gender.
`
`Race
`
`Limited pharmacokinetic data on sorafenib 400 mg twice daily in a study in Japanese patients
`(n=6) showed a 45% lower systemic exposure (mean steady-state AUC) as compared to
`pooled Phase 1 pharmacokinetic data in Caucasian patients (n=25). The clinical significance
`of this finding is not known (see PRECAUTIONS – General - Race).
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 007
`
`

`

`63
`
`
`
`64
`65
`
`66
`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
`
`Pediatric
`There are no pharmacokinetic data in pediatric patients.
`
`Hepatic Impairment
`Sorafenib is cleared primarily by the liver.
`In patients with mild (Child-Pugh A, n=14) or moderate (Child-Pugh B, n=8) hepatic
`impairment, exposure values were within the range observed in patients without hepatic
`impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe
`(Child-Pugh C) hepatic impairment (See PRECAUTIONS – Patients with Hepatic
`Impairment section).
`
`Renal Impairment
`In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy
`subjects, 19% of the administered dose of sorafenib was excreted in urine.
`In four Phase 1 clinical trials, sorafenib was evaluated in patients with normal renal function
`(n=71) and in patients with mild renal impairment (CrCl >50–80 mL/min, n=24) or moderate
`renal impairment (CrCl 30–50 mL/min, n=4). No relationship was observed between renal
`function and steady-state sorafenib AUC at doses of 400 mg twice daily.
` The
`pharmacokinetics of sorafenib have not been studied in patients with severe renal impairment
`(CrCl <30 ml/min) or in patients undergoing dialysis (see PRECAUTIONS – Patients with
`Renal Impairment section).
`
`Drug-Drug Interactions
`CYP3A4 inhibitors: In vitro data indicate that sorafenib is metabolized by CYP3A4 and
`UGT1A9 pathways. Ketoconazole (400 mg), a potent inhibitor of CYP3A4, administered
`once daily for 7 days did not alter the mean AUC of a single oral 50 mg dose of sorafenib in
`healthy volunteers. Therefore, sorafenib metabolism is unlikely to be altered by CYP3A4
`inhibitors.
`CYP isoform-selective substrates: Studies with human liver microsomes demonstrated that
`sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4 as indicated by Ki
`values of 17 µM, 22 µM, and 29 µM, respectively. Administration of NEXAVAR 400 mg
`twice daily for 28 days did not alter the exposure of concomitantly administered midazolam
`(CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19
`substrate). This indicates that sorafenib is unlikely to alter the metabolism of substrates of
`these enzymes in vivo.
`CYP2C9 substrates: Studies with human liver microsomes demonstrated that sorafenib is a
`competitive inhibitor of CYP2C9 with a Ki value of 7-8 µM. The possible effect of sorafenib
`on the metabolism of the CYP2C9 substrate warfarin was assessed indirectly by measuring
`PT-INR. The mean changes from baseline in PT-INR were not higher in NEXAVAR
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 008
`
`

`

`100
`101
`102
`103
`104
`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
`
`patients compared to placebo patients, suggesting that sorafenib did not inhibit warfarin
`metabolism in vivo (see PRECAUTIONS – Warfarin Co-administration section).
`CYP3A4 inducers: There is no clinical information on the effect of CYP3A4 inducers on the
`pharmacokinetics of sorafenib. Substances that are inducers of CYP3A4 activity (e.g.
`rifampin, St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) are
`expected to increase metabolism of sorafenib and thus decrease sorafenib concentrations.
`Combination with other antineoplastic agents: In clinical studies, NEXAVAR has been
`administered with a variety of other antineoplastic agents at their commonly used dosing
`regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no
`effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with
`NEXAVAR resulted in a 21% increase in the AUC of doxorubicin. When administered with
`irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway,
`there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of
`irinotecan. The clinical significance of these findings is unknown (see PRECAUTIONS –
`Drug Interactions sections).
`
`In vitro studies
`
`In vitro studies of enzyme inhibition: Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with
`Ki values of 6 and 1-2 µM, respectively. Systemic exposure to substrates of CYP2B6 and
`CYP2C8 is expected to increase when co-administered with NEXAVAR.
`Sorafenib inhibits glucuronidation by the UGT1A1 (Ki value: 1 µM) and UGT1A9 pathways
`(Ki value: 2 µM). Systemic exposure to substrates of UGT1A1 and UGT1A9 may increase
`when co-administered with NEXAVAR.
`In vitro studies of CYP enzyme induction: CYP1A2 and CYP3A4 activities were not altered
`after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is
`unlikely to be an inducer of CYP1A2 or CYP3A4.
`
`CLINICAL STUDIES
`
`The safety and efficacy of NEXAVAR in the treatment of advanced renal cell carcinoma
`(RCC) were studied in the following 2 randomized controlled clinical trials.
`Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-
`controlled trial in patients with advanced renal cell carcinoma who had received one prior
`systemic therapy. Primary study endpoints included overall survival and progression-free
`survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included
`769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk
`category1 (low or intermediate) and country and randomized to NEXAVAR 400 mg twice
`daily (N=384) or to placebo (N=385).
`Table 1 summarizes the demographic and disease characteristics of the study population
`analyzed. Baseline demographics and disease characteristics were well balanced for both
`treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6
`and 1.9 years for the NEXAVAR and placebo groups, respectively.
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 009
`
`

`

`139
`
`Characteristics
`
`
`267
`116
`
`276
`11
`
`(70)
`(30)
`
`(72)
`(3)
`
`(52)
`(48)
`
`Table 1: Demographic and Disease Characteristics - Study 1
`NEXAVAR N=384
`Placebo N=385
`N
`(%)
`n
`(%)
`
`(75)
`(25)
`
`Gender
`Male
`Female
`Race
`White
`Black/Asian/
`Hispanic/Other
`Not reported a
`(25)
`97
`
`
`Age group
`(67)
`255
`< 65 years
`(33)
`127
`≥ 65 years
`ECOG performance status at baseline
`0
`184
`(48)
`1
`191
`(50)
`2
`6
`(2)
`Not reported
`3
`(<1)
`MSKCC prognostic risk category1
`194
`Low
`200
`191
`Intermediate
`184
`
`Prior IL-2 and/or interferon
`(81)
`313
`(83)
`Yes
`319
`(19)
`72
`(17)
`No
`65
`a. Race was not collected from the 186 patients enrolled in France due to local
`regulations. In 8 other patients, race was not available at the time of analysis.
`
`
`287
`98
`
`278
`10
`
`97
`
`280
`103
`
`180
`201
`1
`3
`
`(73)
`(2)
`
`(25)
`
`(73)
`(27)
`
`(47)
`(52)
`(<1)
`(<1)
`
`(50)
`(50)
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 0010
`
`

`

`140
`141
`142
`143
`144
`
`145
`
`146
`147
`148
`
`149
`150
`151
`152
`153
`154
`155
`156
`157
`158
`159
`160
`161
`162
`
`Progression-free survival, defined as the time from randomization to progression or death
`from any cause, whichever occurred earlier, was evaluated by blinded independent
`radiological review using RECIST criteria. Figure 1 depicts Kaplan-Meier curves for PFS.
`The PFS analysis was based on a two-sided Log-Rank test stratified by MSKCC prognostic
`1 and country.
`risk category
`
`Figure 1: Kaplan-Meier Curves for Progression-free Survival – Study 1
`
`
`NOTE: HR is from Cox regression model with the following covariates: MSKCC prognostic risk category1 and country.
`P-value is from two-sided Log-Rank test stratified by MSKCC prognostic risk category1 and country.
`
`The median PFS for patients randomized to NEXAVAR was 167 days compared to 84 days
`for patients randomized to placebo. The estimated hazard ratio (risk of progression with
`NEXAVAR compared to placebo) was 0.44 (95% CI: 0.35, 0.55).
`A series of patient subsets were examined in exploratory univariate analyses of PFS. The
`subsets included age above or below 65 years, ECOG PS 0 or 1, MSKCC prognostic risk
`category1, whether the prior therapy was for progressive metastatic disease or for an earlier
`disease setting, and time from diagnosis of less than or greater than 1.5 years. The effect of
`NEXAVAR on PFS was consistent across these subsets, including patients with no prior IL-2
`or interferon therapy (n=137; 65 patients receiving NEXAVAR and 72 placebo), for whom
`the median PFS was 172 days on NEXAVAR compared to 85 days on placebo.
`Tumor response was determined by independent radiological review according to RECIST
`criteria. Overall, of 672 patients who were evaluable for response, 7 (2%) NEXAVAR
`patients and 0 (0%) placebo patients had a confirmed partial response. Thus the gain in PFS
`in NEXAVAR-treated patients primarily reflects the stable disease population.
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 0011
`
`

`

`163
`164
`165
`166
`
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`
`184
`
`185
`
`186
`
`187
`188
`
`At the time of a planned interim survival analysis, based on 220 deaths, overall survival was
`longer for NEXAVAR than placebo with a hazard ratio (NEXAVAR over placebo) of 0.72.
`This analysis did not meet the prespecified criteria for statistical significance. Additional
`analyses are planned as the survival data mature.
`
`Study 2 was a Phase 2 randomized discontinuation trial in patients with metastatic
`malignancies, including RCC. The primary endpoint was the percentage of randomized
`patients remaining progression-free at 24 weeks. All patients received NEXAVAR for the
`first 12 weeks. Radiologic assessment was repeated at week 12. Patients with <25% change
`in bi-dimensional tumor measurements from baseline were randomized to NEXAVAR or
`placebo for a further 12 weeks. Patients who were randomized to placebo were permitted to
`cross over to open-label NEXAVAR upon progression. Patients with tumor shrinkage ≥25%
`continued NEXAVAR, whereas patients with tumor growth ≥25% discontinued treatment.
`Two hundred and two patients with advanced RCC were enrolled into Study 2, including
`patients who had received no prior therapy and patients with tumor histology other than clear
`cell carcinoma. After the initial 12 weeks of NEXAVAR therapy, 79 RCC patients continued
`on open-label NEXAVAR, and 65 patients were randomized to NEXAVAR or placebo.
`After an additional 12 weeks, at week 24, for the 65 randomized patients, the progression-free
`rate was significantly higher in patients randomized to NEXAVAR (16/32, 50%) than in
`patients randomized to placebo (6/33, 18%) (p=0.0077). Progression-free survival was
`significantly longer in the NEXAVAR group (163 days) than in the placebo group (41 days)
`(p=0.0001, HR=0.29).
`
`INDICATIONS AND USAGE
`
`NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma.
`
`CONTRAINDICATIONS
`
`NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or
`any other component of NEXAVAR.
`
`189
`
`WARNINGS
`
`190
`191
`192
`193
`194
`195
`196
`197
`198
`
`Pregnancy Category D
`In rats and rabbits, sorafenib has been shown to be teratogenic and to induce embryo-fetal
`toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and
`retarded fetal weight). The effects occurred at doses considerably below the recommended
`human dose of 400 mg twice daily (approximately 500 mg/m2/day on a body surface area
`basis). Adverse intrauterine development effects were seen at doses ≥ 1.2 mg/m2/day in rats
`and 3.6 mg/m2/day in rabbits (approximately 0.008 times the AUC seen in cancer patients at
`the recommended human dose). A NOAEL (no observed adverse effect level) was not
`defined for either species, since lower doses were not tested.
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 0012
`
`

`

`199
`200
`201
`202
`203
`204
`
`205
`206
`207
`208
`209
`
`Based on the proposed mechanism of multikinase inhibition and multiple adverse effects seen
`in animals at exposure levels significantly below the clinical dose, sorafenib should be
`assumed to cause fetal harm when administered to a pregnant woman. If this drug is used
`during pregnancy, or if the patient becomes pregnant while taking this drug, the patient
`should be apprised of the potential hazard to the fetus (see PRECAUTIONS – Information
`for Patients section).
`
`There are no adequate and well-controlled studies in pregnant women using NEXAVAR.
`Women of childbearing potential should be advised to avoid becoming pregnant while on
`NEXAVAR. NEXAVAR should be used during pregnancy only if the potential benefits
`justify the potential risks to the fetus (see PRECAUTIONS – Information for Patients
`section).
`
`210
`
`PRECAUTIONS
`
`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
`238
`
`General
`Dermatologic Toxicities: Hand-foot skin reaction and rash represent the most common
`adverse events attributed to NEXAVAR. Analysis of cumulative event rates from Study 1
`suggest that rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally
`appear during the first six weeks of treatment with NEXAVAR. Management of
`dermatologic toxicities may include topical therapies for symptomatic relief, temporary
`treatment interruption and/or dose modification of NEXAVAR, or in severe or persistent
`cases, permanent discontinuation of NEXAVAR. Permanent discontinuation of therapy due
`to hand-foot skin reaction occurred in 3 of 451 NEXAVAR patients.
`Hypertension: In Study 1, treatment-emergent hypertension was reported in approximately
`16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo group.
`Hypertension was usually mild to moderate, occurred early in the course of treatment, and
`was managed with standard antihypertensive therapy. Blood pressure should be monitored
`weekly during the first 6 weeks of NEXAVAR therapy and thereafter monitored and treated,
`if required, in accordance with standard medical practice. In cases of severe or persistent
`hypertension, despite institution of antihypertensive therapy, temporary or permanent
`discontinuation of NEXAVAR should be considered. Permanent discontinuation due to
`hypertension occurred in 1 of 451 NEXAVAR patients.
`Hemorrhage:
` An
`increased risk of bleeding may occur following NEXAVAR
`administration. In Study 1, bleeding regardless of causality was reported in 15.3% of patients
`in the NEXAVAR group and 8.2% of patients in the placebo group. The incidence of
`CTCAE Grade 3 and 4 bleeding events was 2% and 0%, respectively, in NEXAVAR
`patients, and 1.3% and 0.2%, respectively, in placebo patients. There was one fatal
`hemorrhage in each treatment group in Study 1. If any bleeding event necessitates medical
`intervention, permanent discontinuation of NEXAVAR should be considered.
`Cardiac Ischemia and/or Infarction: In Study 1, the incidence of treatment-emergent cardiac
`ischemia/infarction events was higher in the NEXAVAR group (2.9%) compared with the
`placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 0013
`
`

`

`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
`
`infarction were excluded from this study. Temporary or permanent discontinuation of
`NEXAVAR should be considered in patients who develop cardiac ischemia and/or infarction.
`Race: Limited pharmacokinetic data on sorafenib 400 mg twice daily in a study in Japanese
`patients (n=6) showed a 45% lower systemic exposure (mean steady-state AUC) as compared
`to pooled Phase 1 pharmacokinetic data in Caucasian patients (n=25). The clinical
`significance of this finding is not known.
`Warfarin Co-administration: Infrequent bleeding events or el evations in the International
`Normalized Ratio (INR) have been reported in some patients taking warfarin while on
`NEXAVAR therapy. Patients taking concomitant warfarin should be monitored regularly for
`changes in prothrombin time, INR or clinical bleeding episodes.
`Wound Healing Complications: No formal studies of the effect of NEXAVAR on wound
` Temporary interruption of NEXAVAR therapy is
`healing have been conducted.
`recommended in patients undergoing major surgical procedures. There is limited clinical
`experience regarding the timing of reinitiation of NEXAVAR therapy following major
`surgical intervention. Therefore, the decision to resume NEXAVAR therapy following a
`major surgical intervention should be based on clinical judgment of adequate wound healing.
`Drug Interactions
`
`Caution is recommended when administering NEXAVAR with compounds that are
`metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan) (see
`CLINICAL PHARMACOLOGY – Drug-Drug Interactions section).
`Concomitant treatment with NEXAVAR resulted in a 21% increase in the AUC of
`doxorubicin. Caution is recommended when administering doxorubicin with NEXAVAR.
`Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 µM,
`respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to
`increase when co-administered with NEXAVAR.
` Caution is recommended when
`administering substrates of CYP2B6 and CYP2C8 with NEXAVAR.
`Patients with Hepatic Impairment
`In vitro and in vivo data indicate that sorafenib is primarily metabolized by the liver.
`Systemic exposure and safety data were comparable in patients with Child-Pugh A and B
`hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic
`impairment. No dose adjustment is necessary when administering NEXAVAR to patients
`with Child-Pugh A and B hepatic impairment (see CLINICAL PHARMACOLOGY –
`Hepatic Impairment section).
`
`Patients with Renal Impairment
`
`NEXAVAR has not been studied in patients with severe renal impairment
`(CrCl <30 mL/min) or in patients undergoing dialysis.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenicity studies have not been performed with sorafenib.
`
`West-Ward Exhibit 1102
`NEXAVAR Approval
`Page 0014
`
`

`

`277
`278
`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
`305
`306
`307
`308
`309
`310
`311
`
`312
`313
`314
`315
`
`Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese Hamster
`Ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro
`Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. One
`intermediate in the manufacturing process, which is also present in the final drug substance
`(<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) when
`tested independently.
`No specific studies with sorafenib have