Detrixhe v. Sanofi S.A. et al

MOTION TO DISMISS FOR FAILURE TO STATE A CLAIM

D. Kan.July 25, 2016

7674424 v1 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF KANSAS KAREN A. DETRIXHE, Plaintiff, v. SANOFI S.A., AVENTIS PHARMA S.A., and SANOFI-AVENTIS U.S. LLC, Defendants. ) ) ) ) ) ) ) ) ) ) ) Civil Case No. 2:16-cv-02250-CM-KGG SANOFI-AVENTIS U.S. LLC’S MOTION TO DISMISS PLAINTIFF’S COMPLAINT FOR FAILURE TO STATE A CLAIM UPON WHICH RELIEF CAN BE GRANTED AND MEMORANDUM IN SUPPORT Defendant sanofi-aventis U.S. LLC (“sanofi-aventis”) files this Motion to Dismiss Plaintiff’s Complaint and Memorandum in Support, pursuant to Federal Rule of Civil Procedure 12(b)(6) for failure to state a claim upon which relief can be granted. 1 I. INTRODUCTION This product liability action involves an FDA-approved prescription chemotherapy known as “Taxotere ® ” and/or its generic equivalent, “docetaxel” (hereinafter collectively referred to as “Taxotere ® ”). Plaintiff allegedly was prescribed Taxotere ® by her physician to treat her breast cancer. At the time Plaintiff’s physician prescribed Taxotere ® , it was, as it remains today, the front-line therapy for the treatment of breast cancer. Indeed, it is listed on the World Health Organization’s Model List of Essential Medicines. Plaintiff does not allege that Taxotere ® was ineffective in treating her breast cancer, nor does she claim that sanofi-aventis 1 Sanofi-aventis respectfully requests oral argument for its Motion to Dismiss Plaintiff’s Complaint pursuant to Local Rule 7.2. Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 1 of 16 2 failed to disclose the risk of alopecia (hair loss), which is both disclosed within Taxotere ® ’s labeling and a generally known side effect of chemotherapy. Rather, Plaintiff alleges that sanofi- aventis failed to adequately warn her that her alopecia might not be completely reversible. Plaintiff’s Complaint is a classic and disfavored “shotgun pleading” as Plaintiff brings twelve causes of action jointly against defendants sanofi-aventis U.S. LLC, sanofi S.A., and Aventis Pharma S.A. 2 Furthermore, virtually all of Plaintiff’s claims must be dismissed for other reasons. First, Plaintiff’s claims are product liability claims under the Kansas Product Liability Act (“KPLA”). The KPLA subsumes all causes of actions regardless of the underlying theory into three claims: manufacturing defect, design defect, and warning defect claims. Therefore, all of Plaintiff’s claims must arise, if at all, pursuant to the KPLA’s three cognizable claims. Finally, even if some of Plaintiff’s claims remain under the KPLA, several of these KPLA claims still fail because they are preempted by federal law, are not pled with particularity as required by Rule 9(b), and fail to meet the pleading and plausibility requirements of Rule 8(a) as articulated by the U.S. Supreme Court. See Ashcroft v. Iqbal, 129 S. Ct. 1937 (2009); Bell Atlantic v. Twombly, 127 S. Ct. 1955 (2007). For these reasons, and those more fully articulated below, Plaintiff’s Complaint should be dismissed. II. LEGAL STANDARD In order to survive a Rule (12)(b)(6) motion to dismiss, a complaint must set forth facts demonstrating a plausible claim for relief. Twombly, 550 U.S. at 556. In Twombly and Iqbal, the U.S. Supreme Court most recently articulated the pleading standard applicable to a complaint 2 Sanofi S.A. and Aventis Pharma S.A. are foreign entities, located in France who have not been served and, as such, do not join in this motion. Nevertheless, to the extent the Court dismisses any particular cause of action, it should, as a practical matter, do so as to all defendants as the pleading insufficiencies raised in this Motion apply globally to all defendants named. Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 2 of 16 3 filed in federal court. For a plaintiff’s complaint to survive a motion to dismiss, the “[f]actual allegations must be enough to raise a right to relief above the speculative level.” Twombly, 550 U.S. at 555. A proper pleading “requires more than labels and conclusions.” Id. The “threshold requirement of Rule 8(a)(2)” is that the complaint “possess enough heft to show that the pleader is entitled to relief.” Id. at 557 (internal quotation marks omitted). In Iqbal, the Supreme Court established a two-step process based on Rule 8(a) to determine whether a complaint meets the standard to survive a motion to dismiss. Iqbal, 556 U.S. at 678-81. First, the court must identify those allegations that, because they are no more than conclusions, are not entitled to the assumption of truth. Id. at 679. “Threadbare recitals of the elements of a cause of action, supported by mere conclusory statements, do not suffice,” nor do “formulaic recitation[s] of the elements of [the] cause[s] of action” with no facts to support the claims. Id. at 678 (citing Twombly, 550 U.S. at 555). “While legal conclusions can provide the framework of a complaint, they must be supported by factual allegations.” Id. at 679. Complaints comprised of “‘naked assertion[s]’ devoid of ‘further factual enhancement”’ are plainly insufficient. Id. (quoting Twombly, 550 U.S. at 557). Second, the court should assume the truth of well-pled factual allegations, if the complaint contains any, and determine whether they plausibly give rise to an entitlement to relief. Id. at 681. “[W]here the well-pleaded facts do not permit the court to infer more than the mere possibility of misconduct, the complaint has alleged-but has not ‘show[n]’-‘that the pleader is entitled to relief,”’ and it, therefore, should be dismissed. Id. at 679 (quoting FED. R. CIV. P. 8(a)(2)). The Rule 8 pleading standard requires “more than an unadorned, the-defendant- unlawfully-harmed-me accusation.” Id. at 678 (citing Twombly, 550 U.S. at 555). Courts must Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 3 of 16 4 dismiss complaints that assert only “a sheer possibility that a defendant has acted unlawfully.” Id. (citing Twombly, 550 U.S. at 556). In applying the Twombly/Iqbal standard, the Tenth Circuit has held that plausibility refers “to the scope of the allegations in a complaint: if they are so general that they encompass a wide swath of conduct, much of it innocent, then the plaintiffs have not nudged their claims across the line from conceivable to plausible.” Khalik v. United Air Lines, 671 F.3d 1188, 1191 (10th Cir. 2012) (quoting Robbins v. Oklahoma, 519 F.3d 1242, 1247 (10th Cir. 2008)). In addition to satisfying the pleading requirements enunciated in Twombly, Iqbal, and their progeny, fraud and misrepresentation claims are subject to the heightened pleading requirements set forth in Federal Rule of Civil Procedure 9(b). III. ARGUMENT A. Plaintiff’s Complaint is an Example of “Shotgun Pleading” that Violates Rule 8 Pleading Standards. In addition to pleading at least twelve separate causes of action-virtually every claim imaginable-collectively against three defendants, Plaintiff’s Complaint engages in several types of shotgun pleading in violation of the Federal Rules of Civil Procedure. First, Plaintiff’s Complaint impermissibly incorporates long narrative introductory sections into each cause of action by reference, making it virtually impossible for sanofi-aventis to identify what facts are part of which cause of action. The Tenth Circuit has disparaged complaints that force District Courts and defendants to “search through the several paragraphs of the plaintiffs’ ‘Introductory Allegations’ and attempt to match the factual assertions with the elements of [a cause of action] to determine if the complaint states a claim for relief.” Glenn v. First Nat'l Bank in Grand Junction, 868 F.2d 368, 371 (10th Cir. 1989) (affirming the District Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 4 of 16 5 Court’s description of this method of pleading as “shotgun” pleading and statement that “[the Court] was not going to do Appellants’ work for them . . . ”). The Tenth Circuit has also held that collective allegations against all “Defendants” without identifying which alleged bad acts are attributed to which defendants are in contravention of Federal pleading standards. Hart v. Salois, 605 F. App’x 694, 701 (10th Cir. 2015). Multiple and collective allegations against all defendants and a corresponding failure to identify each individual defendant’s culpable actions classically describe a “shotgun” pleading and exacerbates the deficiency of such pleadings. Id. Here, almost half of Plaintiff’s Complaint is devoted to an extended narrative describing supposed misconduct. Plaintiff follows this narrative with a smattering of twelve causes of action, formulaically outlining the elements of each claim with little of the factual support required by Federal pleading standards. See, e.g., Compl. ¶¶1-119 (describing the background of the collective defendants’ supposed bad acts); Id. at ¶172 (blandly alleging that “Defendants knew of the use for which TAXOTERE® was intended and impliedly warranted the product to be of merchantable quality and safe and fit for such use” without describing how Taxotere ® was supposedly unfit or identifying facts to point to sanofi-aventis’s supposed knowledge of Plaintiff’s particular purposes for Taxotere ® ). Second, Plaintiff compounds this problem by alleging all twelve causes of action against all three defendants, collectively. Plaintiff alleges that every defendant communally did or did not do certain things, but fails to specify what conduct she alleges each defendant did or did not do vis-à-vis the other defendants in this lawsuit. The 10 th Circuit has rejected this type of combined assertion of claims against “Defendants.” In Fox v. California Franchise Tax Board, plaintiff’s allegations were “pointed at all the defendant[s] universally.” 443 F. App’x 354, 362 Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 5 of 16 6 (10th Cir. 2011). The court held that it was the plaintiff’s burden “to provide fair notice of the grounds for the claims made against each of the defendants.” Id. (citing Robbins, 519 F.3d 1250). The court reasoned that when a complaint “use[s] ... the collective term ‘Defendants’ ... with no distinction as to what acts are attributable to whom, it is impossible for any of these individuals to ascertain what particular [] acts they are alleged to have committed.” Id. The rationale adopted by the Fox court applies equally in this case. Because Plaintiff’s shotgun pleading does not give sanofi-aventis fair notice of the claims against it as required by Rule 8, the Court should dismiss her Complaint. B. Plaintiff’s Claims are Subsumed by the Kansas Product Liability Act and All Claims (Other Than Plaintiff’s KCPA Claim) Must Be Dismissed. Plaintiff’s claims are product liability claims and, therefore, must be brought under the KPLA. The KPLA was passed by the Kansas Legislature for the purpose of strengthening the position of product sellers and manufactures. Miller v. Lee Apparel Co., 881 P.2d 576, 585 (Kan. 1994). “The legislature, in the KPLA, [] declared the public policy of the state.” Id. This “policy is to limit the rights of plaintiffs to recover in product liability suits generally.” Id. The KPLA applies to claims for personal injury caused by a product regardless of the underlying substantive theory. K.S.A. §§ 60-3301 to 60-3307; Savina v. Sterling Drug, Inc., 795 P.2d 915, 931 (Kan. 1990). And it “consolidates all product liability actions, regardless of theory, into one basis for liability.” David v. Hett, 270 P.3d 1102, 1106 (Kan. 2011). The provisions of the KPLA “apply to actions based on strict liability in tort as well as negligence, breach of express or implied warranty, and breach of or failure to discharge a duty to warn or instruct.” Savina, 795 P.2d at 931. Under the Act, a product liability claim can be “brought for harm caused by the manufacture, production, making, construction, fabrication, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, storage or labeling Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 6 of 16 7 of the relevant product.” K.S.A. § 60-3302(c). Therefore, if a product liability claim is to be brought at all, it must be brought under the KPLA. At its core, Plaintiff’s Complaint seeks redress for personal injuries allegedly caused by Taxotere ® ’s design and warnings. See, e.g., Compl. ¶¶94-97. Plaintiff’s claims are, therefore, product liability claims under the KPLA and if they are to be brought at all they must be brought under the Act. As such, Plaintiff’s negligence (Count 1), warranty (Counts 4-5), misrepresentation (Counts 8-9), non-KCPA fraud claims (Counts 6-7, 10), and intentional infliction of emotional distress claims (Count 12) should be dismissed. Mattos v. Eli Lilly & Co., No. 12-1014-JWL, 2012 WL 1893551, at *2 (D. Kan. May 23, 2012) (dismissing and consolidating claims under the KPLA); see also Cooper v. Zimmer Holdings, Inc., 320 F.Supp.2d 1154, 1163 (D. Kan. 2004) (stating reasons why KCPA claims should not merge into KPLA claims). C. Plaintiff’s Design Defect Claims are Preempted by Federal Law (Counts One and Two). Among other theories, Counts One and Two of Plaintiff’s Complaint appear to allege negligent design and strict liability design defect theories, respectively. Compl. ¶121 (“Defendants had a duty to exercise reasonable care in the designing…of TAXOTERE®.”); Id. at ¶137 (“the foreseeable risks exceeded the benefits associated with the design or formulation of TAXOTERE®”). These state law design defect claims conflict with federal law as it pertains to FDA-approved prescription medications and, therefore, they should be dismissed. Under federal law, “[o]nce a drug-whether generic or brand name-is approved, the manufacturer is prohibited from making any major changes to the ‘qualitative or quantitative formulation of the drug product, including active ingredients, or in the specifications provided in the approved application.’” Mutual Pharm. Co. v. Bartlett, 133 S. Ct. 2466, 2470 (2013) Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 7 of 16 8 (quoting 21 C.F.R. § 314.70(b)(2)(i)). In contrast, to state a design defect claim under Kansas law, a plaintiff must show that the defendant’s product was defective and unreasonably dangerous, and under the applicable “consumer expectation test,” the product must have been dangerous to an extent beyond that contemplated by the ordinary consumer. See Jenkins v. Amchem Prods., Inc., 256 Kan. 602, 630 (1994). Under the Supreme Court’s interpretation of federal law, these requirements conflict. In three decisions, the Supreme Court laid out the standard for addressing preemption of state law claims involving prescription medications. Mutual Pharm. Co. v. Bartlett, 133 S. Ct. 2466 (2013); PLIVA, Inc. v. Mensing, 131 S. Ct. 2567 (2011); Wyeth v. Levine, 555 U.S. 555 (2009). The overarching principle is that if a manufacturer of prescription drugs is required to seek FDA approval before conforming its activities to meet state law requirements, then state law is preempted. Even though Kansas has adopted the consumer expectations test, and evidence of a safer alternative design is not required in all cases, Kansas law would still conflicts with federal law. Jenkins, 886 P.2d at 890. The FDA’s approval of a medication is a finding by the agency that the benefits of the medication outweigh the risks. Monroe v. Novartis Pharm. Corp., 29 F. Supp. 3d 1115, 1124 (S.D. Ohio 2014). A contrary finding by a Kansas court would directly conflict the FDA’s determination. Or, to put it another way, the only way for a defendant to avoid further liability in Kansas would be to stop selling the medication in Kansas. The Supreme Court has determined that any state court finding that a company must stop selling a medication in order to conform to state law requirements conflicts with and is preempted by federal law (i.e., the FDA’s approval of the medication). See Bartlett, 133 S. Ct. at 2470. Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 8 of 16 9 As the Supreme Court noted in Bartlett, “[i]n the drug context… reducing [a drug’s] ‘risk of danger’ would require redesigning the drug: A drug’s usefulness and its risk of danger are both direct results of its chemical design and, most saliently, its active ingredients.” Bartlett, 133 S. Ct. at 2475. If sanofi-aventis were to “to change the composition of its [drug]”-as would be required to avoid liability under Kansas law-“the altered chemical would be a new drug that would require its own [New Drug Application] NDA [and prior approval by FDA] to be marketed in interstate commerce.” Id. at 2475 (citing 21 C.F.R. § 310.3(h)); see also Yates v. Ortho-McNeil-Janssen Pharm., Inc., 808 F.3d 281, 296 (6th Cir. 2015) (holding that state-law design defect claims against manufactures of FDA-approved drugs are preempted because manufacturers cannot alter the design of medications without prior FDA approval). Several courts have recognized that, although the Supreme Court’s holding in Bartlett specifically addressed preemption of generic medications, the rationale applies with equal force to name-brand drugs because neither a name-brand manufacturer nor a generic manufacturer can alter the chemical composition of an approved drug product without approval of the FDA. Yates, 808 F.3d at 298 (“Therefore, to the extent Yates argues that defendants should have altered the formulation of ORTHO EVRA® after the FDA had approved the patch, we find this claim clearly preempted.”); Booker v. Johnson & Johnson, No. 3:12 OE 40000, 2014 WL 5113305 (N.D. Ohio Oct. 10, 2014); Amos v. Biogen IDEC Inc., No. 13-CV-6375T, 2014 WL 2882104, at *3 (W.D.N.Y. June 25, 2014) (relying on Bartlett to dismiss with prejudice and as a matter of law the plaintiffs’ design defect claims against name-brand manufacturer even though the plaintiffs agreed the claim was preempted and sought dismissal without prejudice); Rheinfrank v. Abbott Labs., Inc., No. 1:13-cv-144, 2015 WL 5836973, at *5 (S.D. Ohio Oct. 2, 2015) (finding that design defect claims against both generic and name-brand medications are preempted by Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 9 of 16 10 federal law because an “alternative design would require changing the composition of an FDA- approved drug, which is prohibited by federal law.”) Because compliance with both state and federal law is impossible here, Plaintiff’s state law claims premised on any “design” of Taxotere ® that is different than its current FDA- approved design are preempted, and, therefore, Plaintiff’s design defect claim must be dismissed. D. Plaintiff’s Manufacturing Defect Claim Must Be Dismissed because It Is Conclusory and Lacks Any Supporting Factual Allegations (Count Two). Count Two of Plaintiff’s Complaint appears to plead a manufacturing defect claim. See Compl. ¶¶133-155. This claim must be dismissed because Plaintiff’s allegations are conclusory and therefore fail to meet federal pleading standards. The issue in manufacturing defect cases is whether the product as produced conformed to the manufacturer’s specifications. Jenkins v. Amchem Prods., Inc., 886 P.2d 869, 887 (Kan. 1994) (holding that a cause of action for a manufacturing defect cannot survive when a plaintiff makes no claim that the units of products he used were somehow different than other units of the same product). In other words, in order to establish a manufacturing defect claim a plaintiff must plead that the product the plaintiff received somehow deviated from the manufacturer’s specifications and this deviation caused the alleged injury. McCroy ex rel. McCroy v. Coastal Mart, Inc., 207 F. Supp. 2d 1265, 1271 (D. Kan. 2002) (finding no manufacturing defect when product performed as the manufacturer intended). Plaintiff pleads no facts to demonstrate how the Taxotere ® Plaintiff allegedly received differed from manufacturing specifications. In fact, Plaintiff does not plead what the specifications for Taxotere ® were. Instead, Plaintiff only pleads, in a conclusory fashion, that Taxotere ® was “in an unsafe, defective, and inherently dangerous condition,” Compl. ¶136, and suffered from a manufacturing defect. Id. at ¶145. As such, Plaintiff’s manufacturing defect Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 10 of 16 11 claim is conclusory and lacks any of the factual support necessary to meet federal pleading standards. See Funk v. Stryker Corp., 631 F.3d 777, 782 (5th Cir. 2011) (dismissing Plaintiff’s complaint as “impermissibly conclusory and vague; it does not specify the manufacturing defect; nor does it specify a causal connection between the failure of the specific manufacturing process and the specific defect in the process that caused the personal injury.”). For this reason, Plaintiff’s manufacturing defect claim must be dismissed. E. Plaintiff’s Failure to Warn Claim Must Be Dismissed Because, Under the Learned Intermediary Doctrine, a Manufacturer of a Prescription Medication Has a Duty to Warn Only the Prescribing Physician Not the Patient About the Risks of the Medication (Count Three). Plaintiff’s third count alleges a strict liability failure to warn claim. Compl. ¶¶156-160. A product may be unreasonably dangerous due to a manufacturing defect, a design defect, or a failure to warn. Savina v. Sterling Drug, Inc., 795 P.2d 915, 923 (Kan. 1990). Under Kansas law, “[a] product may be perfectly manufactured and meet every requirement for its designed utility and still be rendered unreasonably dangerous through failure to warn of its dangerous characteristics.” Samarah v. Danek Med., Inc., 70 F. Supp. 2d 1196, 1204 (D. Kan. 1999) (citations omitted). In the prescription drug context, a manufacturer’s duty to warn is only owed to a prescribing physician. Nichols v. Central Merch., Inc., 817 P.2d 1131, 1133 (Kan. 1991). According to the Kansas Supreme Court, the “rule is based upon the theory that the physician acts as a learned intermediary between the drug manufacturer and the patient.” Humes v. Clinton, 792 P.2d 1032, 1039 (Kan. 1990). Because “prescription drugs are available only to a physician, it is the physician's duty to inform himself or herself of the characteristics of the drugs prescribed and to exercise his or her judgment of which drug to administer in light of the drug's propensities and the patient's susceptibilities.” Id. This is known as the learned intermediary doctrine. See Miller v. Pfizer Inc. (Roerig Div.), 196 F. Supp. 2d 1095, 1121 (D. Kan. 2002). Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 11 of 16 12 Sanofi-aventis’s duty was to warn Plaintiff’s prescribing physician only, and not Plaintiff. Despite this well established doctrine, Plaintiff repeatedly alleges that sanofi-aventis should be held liable for failing to adequately warn Plaintiff and all users of Taxotere ® . See Compl. ¶158 (“Defendants failed to provide adequate warnings to physicians and users, including Plaintiff’s physicians and Plaintiff….”). This is contrary to Kansas law and sanofi-aventis cannot be held liable for failing to warn to Plaintiff directly. Therefore, to the extent Plaintiff alleges that sanofi-aventis can be held liable for failing to warn her directly of the risks of Taxotere ® , her claim is not cognizable and should be dismissed. F. Plaintiff Has Failed to Plead Her Fraud-Based Kansas Consumer Protection Act Claim with Sufficient Particularity (Count Eleven). Plaintiff asserts a fraud-based Kansas Consumer Protection Act claim, which must comply with the heightened pleading standard set forth in Rule 9(b). Gonzalez v. Pepsico, Inc., 489 F. Supp. 2d 1233, 1247 (D. Kan. 2007) (“Allegations of unfair trade practices under the KCPA must be pleaded with particularity in accordance with Rule 9(b).”). As the 10 th Circuit has held, to sustain a fraud claim, the plaintiff must set forth the “who, what, when, where, and how of the alleged fraud.” U.S. ex rel. Sikkenga, 472 F.3d at 727. Plaintiff has failed to do so. In an effort to thwart expired statutes of limitations, Plaintiff has concocted theories based on supposed fraudulent behavior and representations. At its core, however, Plaintiff’s KCPA claim centers on the assertion that some or all of the defendants fraudulently withheld data regarding permanent alopecia from FDA and, as such, failed to warn consumers like Plaintiff. Compl. ¶¶64-98, 112-119, 262 (“Defendants engaged in unfair, deceptive, false, and/or fraudulent acts. . . [by] [p]ublishing instructions and product material containing inaccurate and incomplete factual information regarding TAXOTERE®”). However, these “fraud on the FDA” claims are preempted. Only the federal government can enforce obligations Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 12 of 16 13 owed by a manufacturer to the FDA and federal law broadly preempts and prohibits private actions to enforce violations of FDA-mandated obligations: [W]e hold that the plaintiffs’ state-law fraud-on-the-FDA claims conflict with, and are therefore impliedly pre-empted by, federal law. The conflict stems from the fact that the federal statutory scheme amply empowers the FDA to punish and deter fraud against the Administration, and that this authority is used by the Administration to achieve a somewhat delicate balance of statutory objectives. The balance sought by the Administration can be skewed by allowing fraud-on- the-FDA claims under state tort law. Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341, 348 (2001). The remainder of Plaintiff’s fraud-based allegations not based on representations to the FDA, stand on conclusory and general allegations of supposedly fraudulent behavior. For example, Plaintiff’s Complaint states that, in marketing an FDA-approved prescription medication, sanofi-aventis misrepresented “the nature, quality, and characteristics of TAXOTERE®.” Compl. ¶262(b). The Complaint goes on to state that sanofi-aventis “[e]ngag[ed] in fraudulent or deceptive conduct that create[d] a likelihood of confusion or misunderstanding.” Id. at ¶262(c). Such general averments, however, fail to satisfy the heightened pleading standard for fraud claims under Rule 9. See Farlow v. Peat, Marwick, Mitchell & Co., 956 F.2d 982, 987 (10th Cir. 1992). For example, Plaintiff’s Complaint does not: (1) identify the speakers who made any statements or participated in any misrepresentation, deceit, concealment, or suppression; (2) state when, where, and to whom such fraudulent statements were made to the many alleged recipients identified; (3) explain how and why sanofi-aventis’s actions were fraudulent; and (4) specify the specific concealments and suppression of information that she contends were “fraudulent.” Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 13 of 16 14 Lawrence Nat’l Bank, 924 F.2d at 180. In other words, Plaintiff fails to identify the requisite “who, what, when, where, and how” of sanofi-aventis’s allegedly fraudulent misconduct. 3 Id. The Tenth Circuit, in Koch v. Koch Industries, Inc., held that broad allegations of alleged misrepresentations were insufficient under Rule 9’s specificity standard. 203 F.3d 1202, 1237 (10th Cir. 2000). There, plaintiff alleged that misrepresentations were made “during 1982 and continuing to the present time” and recited a general statement of defendants’ failure to disclose information. Id. The court held that plaintiff’s allegations were not adequately specific as they failed to “alert the Defendants to a sufficiently precise time frame” and failed “to mention at all the place at which any misrepresentations were made” while failing to “identify the specific Defendant who made these alleged fraudulent misrepresentations or omissions.” Id. Here, Plaintiff’s Complaint is likewise lacking the basic factual support necessary to identify when, by whom, and where any fraudulent acts took place and the substance of such allegedly fraudulent communications. Plaintiff merely alleges sanofi-aventis stated that Taxotere ® demonstrated superior efficacy compared to Taxol ® in a 2008 reprint carrier at an annual American Society of Clinical Oncology meeting. Compl. ¶77. However, Plaintiff does not plead that Plaintiff’s prescribing physician attended this meeting or even viewed this reprint carrier prior to using Taxotere ® for her chemotherapy treatment. Further, Plaintiff fails to allege that her physician relied on this statement in the reprint carrier and that this statement induced her physician to use 3 Parsing through the hundreds of paragraphs in Plaintiff’s Complaint, the only specific affirmative misrepresentation Plaintiff alleges is that a single reprint carrier that was allegedly used at a meeting of the American Society of Clinical Oncology in June 2008. Yet nowhere does Plaintiff identify the physician that prescribed her Taxotere ® or allege that the physician attended this meeting, saw this reprint carrier, or relied on this reprint carrier. In accordance with the learned intermediary doctrine, Plaintiff must plead that Plaintiff’s physician relied on an alleged misrepresentation from sanofi-aventis, which induced Plaintiff’s physician to prescribe Taxotere ® . See Samarah v. Danek Med., Inc., 70 F. Supp. 2d 1196, 1209 (D. Kan. 1999); Miller v. Pfizer Inc. (Roerig Division), 196 F. Supp. 2d 1095, 1123 (D. Kan. 2002) (relying on Samarah in granting summary judgment in favor of the Defendant). Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 14 of 16 15 Taxotere ® for her treatment. As such, Plaintiff’s fraud-based claims in Counts Six through Eleven should be dismissed. IV. CONCLUSION For the reasons set forth above, sanofi-aventis U.S. LLC respectfully requests that the Court grant their motion to dismiss and dismiss Plaintiff’s causes of action against sanofi-aventis U.S. LLC with prejudice. Dated: July 25, 2016 Respectfully submitted, /s/ Madison Hatten Madison Hatten #78629 Shook Hardy & Bacon L.L.P. 2555 Grand Boulevard Kansas City, Missouri 64108 816.474.6550 mhatten@shb.com Attorney for sanofi-aventis U.S. LLC Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 15 of 16 16 CERTIFICATE OF SERVICE I hereby certify that on July 25, 2016, a true and correct copy of the foregoing document was served upon the following via the Court’s electronic notification system and/or electronic mail: David D. Burkhead The Law Office of David Burkhead P.O. Box 23243 Overland Park, KS 66283 david@burkheadlaw.com Attorney for Plaintiff /s/ Madison Hatten Attorney for sanofi-aventis U.S. LLC Case 2:16-cv-02250-CM-KGG Document 7 Filed 07/25/16 Page 16 of 16 ! " # " $ % & ! $ ! ' ( ) * + # ' , ) $ - $ $ % % # . / 0 0 12 . ! 3 + ! 4 + - + 4 , 4 + - 3 5 6 6 7 8 9 9 : ; 6 < = ; > ? > @ A > @ 7 B ; C D E > B @ 7 B ; = B C : 9 6 E 6 ? 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J % " & R K ' V ) # " % ( ' N $ N )I I I I I I I I I I I I I I I I I I I I I I I I I I I I 3 3 - I I I I I I I I I I I I I I I I I I I I I I I I I I I TAXOTERE is a microtubule inhibitor indicated for: ' ) : single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC (1.1) I ' ) : single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC (1.2) " ' ) : with prednisone in androgen independent (hormone refractory) metastatic prostate cancer (1.3) ' ) : with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction (1.4) U P ' ) : with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN (1.5) I I I I I I I I I I I I I I I I I I I I I I 3 3 3 I I I I I I I I I I I I I I I I I I I I I I I Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hr every 3 weeks. PVC equipment is not recommended. BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent (2.1) BC adjuvant: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (2.1) NSCLC: after platinum therapy failure: 75 mg/m2 single agent (2.2) NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2 (2.2) HRPC: 75 mg/m2 with 5 mg prednisone twice a day continuously (2.3) GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day 1 only) followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1-5), starting at end of cisplatin infusion (2.4) SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1-5), starting at end of cisplatin infusion; for 4 cycles (2.5) SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1000 mg/m2 per day as a 24-hr IV (days 1-4); for 3 cycles (2.5) % . Premedicate with oral corticosteroids (2.6) Adjust dose W X needed (2.7) I I I I I I I I I I I I I I I I I I I I I 3 3 I I I I I I I I I I I I I I I I I I I I I I Two vial TAXOTERE: 80 mg/2 mL and Diluent for Taxotere 80 mg, 20 mg/0.5 mL and Diluent for Taxotere 20 mg (3)I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 3 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Hypersensitivity to docetaxel or polysorbate 80 (4) Neutrophil counts of <1500 cells/mm3 (4) I I I I I I I I I I I I I I I I I I I I I I I 2 3 - I I I I I I I I I I I I I I I I I I I I I I I I Acute myeloid leukemia: In patients who received TAXOTERE, doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) Neurologic reactions: Reactions includingY paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving TAXOTERE (5.10, 8.1) I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 3 , I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Most common adverse reactions across all TAXOTERE indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) % - 3 3 , + I # - $ $ / I R K K I 1 Z Z I / 1 / K 3 / I R K K I 3 I / K R R H H H [ 7 G D [ A B \ ] C 6 G H D E = ^I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 3 - I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. (7) / _ - 3 I % % # % & # . 1 / Q K / Z 1` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 1 of 63 - . l 1 3 , 6.1 Clinical Trial Experience 2 6.2 Post Marketing Experiences / 3 3 - _ 3 - 1.1 Breast Cancer R - - 1.2 Non-Small Cell Lung Cancer 1.3 Prostate Cancer 8.1 Pregnancy 8.3 Nursing Mothers 1.4 Gastric Adenocarcinoma 8.4 Pediatric Use 1.5 Head and Neck Cancer 8.5 Geriatric Use Q 3 3 3 8.6 Hepatic Impairment 2.1 Breast Cancer / K , 3 2.2 Non-Small Cell Lung Cancer / / 3 2.3 Prostate Cancer / Q 4 2.4 Gastric Adenocarcinoma 12.1 Mechanism of Action 2.5 Head and Neck Cancer 12.3 Human Pharmacokinetics 2.6 Premedication Regimen 2.7 Dosage Adjustments During Treatment / Z ! 4 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 2.8 Administration Precautions 2.9 Preparation and Administration / V - 3 14.1 Locally Advanced or Metastatic Breast Cancer 2.10 Stability 14.2 Adjuvant Treatment of Breast Cancer Z 3 3 14.3 Non-Small Cell Lung Cancer (NSCLC) V 3 14.4 Hormone Refractory Prostate Cancer N 2 3 - 14.5 Gastric Adenocarcinoma 5.1 Toxic Deaths 14.6 Head and Neck Cancer 5.2 Hepatic Impairment / N 5.3 Hematologic Effects / 1 2 - 3 L 3 3 5.4 Hypersensitivity Reactions 16.1 How Supplied 5.5 Fluid Retention 16.2 Storage 5.6 Acute Myeloid Leukemia 16.3 Handling and Disposal 5.7 Cutaneous Reaction 5.8 Neurologic Reactions / _ - 5.9 Asthenia 5.10 Use in Pregnancy *Sections or subsections omitted from the full prescribing information are not listed m n o o p q r s t q u v u w x u w m y q z { | u y w } ~ € ‚ € ƒ ‚ „ † ‡ ˆ † ‰ † Š ‡ ‹ ˆ † ƒ ‰ „ ‡ † ˆ ‹ € † Œ ˆ „ ‚ € ˆ † ƒ Ž € † ~ } ‘ } ’ “ ’ † ~ ‡ ˆ ” Œ € € ‚ ‡ ˆ ƒ € ” ˆ † € † Ž € † ~ ˆ • „ ‡ ‰ ˆ ‹ ‹ € – ‡ — ‚ † € „ ˜ € ” ˆ † € † ‡ ‚ € – € ™ ~ € ™ ~ ‡ ƒ „ ˜ ˆ ƒ€ ” ˆ † € † Ž € † ~ „ Š ‰ ˆ ‹ ‹ ‚ ‹ ‹ ‹ — ™ ‚ ˆ ‡ ‚ € „ ‰ ˆ ˆ ƒ ˆ ~ € † „ ‡ Œ „ ” ‡ € „ ‡ † ‡ ˆ † ‰ † Ž € † ~” ‹ ˆ † € — ‰ Š • ˆ ƒ ‚ ~ ‰ „ † ~ ‡ ˆ ” Œ Ž ~ „ ‡ ‚ € – } ‘ } ’ “ ’ ˆ ˆ € ™ ‹ ˆ ™ † ˆ † ˆ ƒ „ „ š › ›‰ ™ œ ‰ Q ž Ÿ Ÿ ¡ ¢ £ ¤ £ ¥ ž ¡ £ ¦ § ¢ Ÿ ¨ ¡ © ª ¤ « £ ž ¬ - ® ¯ ° ± ®} ‘ } ’ “ ’ ~ „ — ‹ ƒ „ † • ™ € – † „ ” ˆ † € † Ž € † ~ • € ‹ € ‡ — • € ² — ” ” ‡ ‹ € ‰ € † „ „ ‡ ‰ ˆ ‹ ³ ´ µ ¶ · ˜„ ‡ † „ ” ˆ † € † Ž € † ~ ¸ } ˆ ƒ œ „ ‡ µ } ² š ¹ º » ´ µ ¶ ‚ „ ‚ „ ‰ € † ˆ † Ž € † ~ ˆ ‹ ¼ ˆ ‹ € ” ~ „ ” ~ ˆ † ˆ ² ½ ¹ º » ´ µ ¶ ¹ ¾ ˆ † € † Ž € † ~ ‹ – ˆ † € „ „ • € ‹ € ‡ — • € „ ‡ ˆ • „ ‡ ‰ ˆ ‹ € † € „ † ‡ ˆ ˆ ‰ € ˆ ‚ „ ‚ — ‡ ‡ † Ž € † ~ ˆ ‹ ¼ ˆ ‹ € ” ~ „ ” ~ ˆ † ˆ ˆ ‡ ˆ † € ‚ ‡ ˆ ƒ ‡ € ¼ „ ‡ † ~ ƒ – ‹ „ ” ‰ † „ ™ ‡ ˆ ƒ ¿ — † ‡ „ ” € ˆ ˜ • ‡ € ‹ — † ‡ „ ” € ˆ ˜ € ‚ † € „ ˜ – ‡ † ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ ˜ – ‡ † „ ‰ ˆ † € † € ˜ – ‡ ¼ € † „ » € ‚ € † Œ ˜ ˆ ƒ † „ » € ‚ ƒ ˆ † ~ ¹ ¾ ˆ † € † Ž € † ~ € „ ‹ ˆ † ƒ ‹ – ˆ † € „ „ † ‡ ˆ ˆ ‰ € ˆ ² š ¹ º» ´ µ ¶ ˆ ‹ „ ~ ˆ ƒ ˆ ~ € ™ ~ ‡ ‡ ˆ † „ • ‡ € ‹ — † ‡ „ ” € ˆ ™ ‡ ˆ ƒ ¿ • — † ƒ € ƒ „ † ~ ˆ – ˆ € ‚ ‡ ˆ ƒ€ ‚ € ƒ ‚ „ † „ » € ‚ ƒ ˆ † ~ ¹ À € ‹ € ‡ — • € ˜ ¸ } „ ‡ µ } ˜ ˆ ƒ ˆ ‹ ¼ ˆ ‹ € ” ~ „ ” ~ ˆ † ˆ – ˆ ‹ — ~ „ — ‹ ƒ • „ • † ˆ € ƒ ” ‡ € „ ‡ † „ ˆ ‚ ~ ‚ Œ ‚ ‹ „ } ‘ } ’ “ ’ † ~ ‡ ˆ ” Œ ž Ÿ Ÿ ¡ ¢ £ ¤ £ ¥ ž ¡ £ ¦ § ¢ Ÿ ¨ ¡ © ª ¤ « £ ž ¬ - ® Á ° ± ¹} ‘ } ’ “ ’ † ~ ‡ ˆ ” Œ ~ „ — ‹ ƒ „ † • ™ € – † „ ” ˆ † € † Ž € † ~ — † ‡ „ ” ~ € ‹ ‚ „ — † „ Â š º › ›‚ ‹ ‹ œ ‰ ‰ Z ¹ Ã „ ‡ ƒ ‡ † „ ‰ „ € † „ ‡ † ~ „ ‚ ‚ — ‡ ‡ ‚ „ — † ‡ „ ” € ˆ ˜ Ž ~ € ‚ ~ ‰ ˆ Œ • – ‡ ˆ ƒ‡ — ‹ † € € ‚ † € „ ˜ ‡ Ä — † • ‹ „ „ ƒ ‚ ‹ ‹ ‚ „ — † ~ „ — ‹ ƒ • ” ‡ „ ‡ ‰ ƒ „ ˆ ‹ ‹ ” ˆ † € † ‡ ‚ € – € ™} ‘ } ’ “ ’ ž Ÿ Ÿ ¡ ¢ £ ¤ £ ¥ ž ¡ £ ¦ § ¢ Ÿ ¨ ¡ © ª ¤ « £ ž ¬ - ® Å ° ± ¹ 2 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 2 of 63 ¸ – ‡ ~ Œ ” ‡ € † € – € † Œ ‡ ˆ ‚ † € „ ‚ ~ ˆ ‡ ˆ ‚ † ‡ € Æ ƒ • Œ ™ ‡ ˆ ‹ € Æ ƒ ‡ ˆ ~ œ ‡ Œ † ~ ‰ ˆ ˜ ~ Œ ” „ † € „ ˆ ƒ œ „ ‡ • ‡ „ ‚ ~ „ ” ˆ ‰ ˜ „ ‡ – ‡ Œ ‡ ˆ ‡ ‹ Œ ˆ † ˆ ‹ ˆ ˆ ” ~ Œ ‹ ˆ » € ˜ ~ ˆ – • ‡ ” „ ‡ † ƒ € ” ˆ † € † Ž ~ „‡ ‚ € – ƒ ˆ Ç Š ƒ ˆ Œ ƒ » ˆ ‰ † ~ ˆ „ ” ‡ ‰ ƒ € ‚ ˆ † € „ ¹ È Œ ” ‡ € † € – € † Œ ‡ ˆ ‚ † € „ ‡ Ä — € ‡ € ‰ ‰ ƒ € ˆ † ƒ € ‚ „ † € — ˆ † € „ „ † ~ } ‘ } ’ “ ’ € — € „ ˆ ƒ ˆ ƒ ‰ € € † ‡ ˆ † € „ „ ˆ ” ” ‡ „ ” ‡ € ˆ † † ~ ‡ ˆ ” Œ ž Ÿ Ÿ ¡ ¢ £ ¤ £ ¥ ž ¡ £ ¦ § ¢ Ÿ ¨ ¡ © ª ¤ « £ ž ¬ - ® É ° ± ¹ } ‘ } ’ “ ’ ‰ — † „ † • ™ € – † „ ” ˆ † € † Ž ~ „ ~ ˆ – ˆ ~ € † „ ‡ Œ „ – ‡ ~ Œ ” ‡ € † € – € † Œ ‡ ˆ ‚ † € „ † „ } ‘ } ’ “ ’ „ ‡ † „ „ † ~ ‡ ƒ ‡ — ™ „ ‡ ‰ — ‹ ˆ † ƒ Ž € † ~ ” „ ‹ Œ „ ‡ • ˆ † Ê › ž Ÿ Ÿ Ë « £ ª ¢ ¡ ¤ £ ¦ ¤ ¨ ¡ ª ¤ « £ ž ¬ É ° ± ®¸ – ‡ ‹ — € ƒ ‡ † † € „ „ ‚ ‚ — ‡ ‡ ƒ € Ì ¹ º Í ³ Ì œ Î ½ · „ ” ˆ † € † ƒ ” € † — „ ˆ Ç Š ƒ ˆ Œƒ » ˆ ‰ † ~ ˆ „ ” ‡ ‰ ƒ € ‚ ˆ † € „ ‡ ™ € ‰ ¹ Ã † Ž ˆ ‚ ~ ˆ ‡ ˆ ‚ † ‡ € Æ ƒ • Œ „ „ ‡ ‰ „ ‡ „ † ~ „ ‹ ‹ „ Ž € ™ – † Ï ” „ „ ‡ ‹ Œ † „ ‹ ‡ ˆ † ƒ ” ‡ € ” ~ ‡ ˆ ‹ ƒ ‰ ˆ ˜ ™ ‡ ˆ ‹ € Æ ƒ ƒ ‰ ˆ ˜ ” ‹ — ‡ ˆ ‹ — € „ ‡ Ä — € ‡ € ™ — ‡ ™ † ƒ ‡ ˆ € ˆ ™ ˜ ƒ Œ ” ˆ ˆ † ‡ † ˜ ‚ ˆ ‡ ƒ € ˆ ‚ † ˆ ‰ ” „ ˆ ƒ ˜ „ ‡ ” ‡ „ „ — ‚ ƒ ˆ • ƒ „ ‰ € ˆ ‹ƒ € † † € „ ³ ƒ — † „ ˆ ‚ € † · ž Ÿ Ÿ ¡ ¢ £ ¤ £ ¥ ž ¡ £ ¦ § ¢ Ÿ ¨ ¡ © ª ¤ « £ ž ¬ - ® - ° ± ® TAXOTERE is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. TAXOTERE as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. TAXOTERE in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. TAXOTERE in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer. TAXOTERE in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 3 of 63 TAXOTERE in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). For all indications, toxicities may warrant dosage adjustments Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô ×Þ ß à á â ã . Administer in a facility equipped to manage possible complications (e.g. anaphylaxis). For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of TAXOTERE is 60 mg/m 2 to 100 mg/m 2 administered intravenously over 1 hour every 3 weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended TAXOTERE dose is 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × ØÙ Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . For treatment after failure of prior platinum-based chemotherapy, TAXOTERE was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials Ð Ñ Ò Ò ä Ô å Ò Øæ Õ Ý × Û × Ö ç Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë â ç ì í Û × Û é Õ íî Ü ê Ø Û Ò Ñ Þ ï ð â ã . For chemotherapy-naïve patients, TAXOTERE was evaluated in combination with cisplatin. The recommended dose of TAXOTERE is 75 mg/m 2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m 2 over 30-60 minutes every 3 weeks Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . For hormone-refractory metastatic prostate cancer, the recommended dose of TAXOTERE is 75 mg/m 2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × ØÙ Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 4 of 63 For gastric adenocarcinoma, the recommended dose of TAXOTERE is 75 mg/m 2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m 2 , as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the TAXOTERE containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics. ñ × Ø ê é Ü Û Ô × é ò Ò Ú Ô Ü ò Ò Ý Õ ó ô õ Ô í í Ô ö Ò Ø ÷ ô Ý Õ Ø Û Ô Ü ò Ò Ý Õ ó ô Þ ø Ù ù ú ß ú â For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of TAXOTERE is 75 mg/m 2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m 2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m 2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . ñ × Ø ê é Ü Û Ô × é ò Ò Ú Ô Ü ò Ò Ý Õ ó ô õ Ô í í Ô ö Ò Ø ÷ ô é ò Ò Ú Ô Ý Õ Ø Û Ô Ü ò Ò Ý Õ ó ô Þ ø Ù ù ú ß ð â For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of TAXOTERE is 75 mg/m 2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m 2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m 2 /day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to TAXOTERE administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Øè Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ð â ã . For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the TAXOTERE infusion Ð Ñ Ò Ò æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ð â ã . ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 5 of 63 Breast Cancer Patients who are dosed initially at 100 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, or severe or cumulative cutaneous reactions during TAXOTERE therapy should have the dosage adjusted from 100 mg/m 2 to 75 mg/m 2 . If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m 2 to 55 mg/m 2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m 2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during TAXOTERE therapy may tolerate higher doses. Patients who develop grade 3 peripheral neuropathy should have TAXOTERE treatment discontinued entirely. Combination Therapy with TAXOTERE in the Adjuvant Treatment of Breast Cancer TAXOTERE in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is 1,500 cells/mm 3 . Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their TAXOTERE dose reduced to 60 mg/m². Patients who experience grade 3 or 4 stomatitis should have their TAXOTERE dose decreased to 60 mg/m². Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during TAXOTERE therapy should have their dosage of TAXOTERE reduced from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², treatment should be discontinued. Non-Small Cell Lung Cancer û Ô × Ô Ü ò Ò Ý Õ ó ô ö Û Ü ò ø Ù ù ü ø ý þ ý õ Ô Ý ÿ î ì ì Ü Ý Ò Õ Ü Ú Ò × Ü Õ õ Ü Ò Ý õ Õ Û í ê Ý Ò Ô õ ó Ý Û Ô Ý ó í Õ Ü Û × ê Ú ÷ Õ Ñ Ò Øé ò Ò Ú Ô Ü ò Ò Ý Õ ó ô Patients who are dosed initially at 75 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during TAXOTERE treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m 2 . Patients who develop grade 3 peripheral neuropathy should have TAXOTERE treatment discontinued entirely. ì Ô Ú ÷ Û × Õ Ü Û Ô × Ü ò Ò Ý Õ ó ô ö Û Ü ò ø Ù ù ü ø ý þ ý õ Ô Ý é ò Ò Ú Ô Ü ò Ò Ý Õ ó ô × Õ Ò ÿ î ì ì For patients who are dosed initially at TAXOTERE 75 mg/m 2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm 3 , in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the TAXOTERE dosage in subsequent cycles should be reduced to 65 mg/m 2 . In patients who require a further dose reduction, a dose of 50 mg/m 2 is recommended. For cisplatin dosage adjustments, see manufacturers’ prescribing information. Prostate Cancer ì Ô Ú ÷ Û × Õ Ü Û Ô × Ü ò Ò Ý Õ ó ô ö Û Ü ò ø Ù ù ü ø ý þ ý õ Ô Ý ò Ô Ý Ú Ô × Ò Ý Ò õ Ý Õ é Ü Ô Ý ô Ú Ò Ü Õ Ñ Ü Õ Ü Û é ó Ý Ô Ñ Ü Õ Ü Ò é Õ × é Ò Ý` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 6 of 63 TAXOTERE should be administered when the neutrophil count is 1,500 cells/mm 3 . Patients who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during TAXOTERE therapy should have the dosage of TAXOTERE reduced from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued. Gastric or Head and Neck Cancer ø Ù ù ü ø ý þ ý Û × é Ô Ú ÷ Û × Õ Ü Û Ô × ö Û Ü ò é Û Ñ ó í Õ Ü Û × Õ × Ø õ í ê Ô Ý Ô ê Ý Õ é Û í Û × Ö Õ Ñ Ü Ý Û é é Õ × é Ò Ý Ô Ý ò Ò Õ Ø Õ × Ø × Ò é é Õ × é Ò Ý Patients treated with TAXOTERE in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the TAXOTERE dose should be reduced from 75 to 60 mg/m 2 . If subsequent episodes of complicated neutropenia occur the TAXOTERE dose should be reduced from 60 to 45 mg/m 2 . In case of grade 4 thrombocytopenia the TAXOTERE dose should be reduced from 75 to 60 mg/m 2 . Patients should not be retreated with subsequent cycles of TAXOTERE until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . Discontinue treatment if these toxicities persist ® Ð Ñ Ò Ò æ Õ Ý × Û × Ö Ñ Õ × Øè Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ú â ã à Recommended dose modifications for toxicities in patients treated with TAXOTERE in combination with cisplatin and fluorouracil are shown in Table 1. } ˆ • ‹ š Š “ ‚ „ ‰ ‰ ƒ ƒ „ „ ƒ € € ‚ ˆ † € „ „ ‡ } „ » € ‚ € † € € ¾ ˆ † € † } ‡ ˆ † ƒ Ž € † ~} ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ Ž € † ~ € ” ‹ ˆ † € ˆ ƒ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ Diarrhea grade 3 First episode: reduce fluorouracil dose by 20%. Second episode: then reduce TAXOTERE dose by 20%. Diarrhea grade 4 First episode: reduce TAXOTERE and fluorouracil doses by 20%. Second episode: discontinue treatment. Stomatitis/mucositis grade 3 First episode: reduce fluorouracil dose by 20%. Second episode: stop fluorouracil only, at all subsequent cycles. Third episode: reduce TAXOTERE dose by 20%. Stomatitis/mucositis grade 4 First episode: stop fluorouracil only, at all subsequent cycles. Second episode: reduce TAXOTERE dose by 20%. Liver dysfunction: In case of AST/ALT >2.5 to 5 x ULN and AP 2.5 x ULN, or AST/ALT >1.5 to 5 x ULN and AP >2.5 to 5 x ULN, TAXOTERE should be reduced by 20%. In case of AST/ALT >5 x ULN and/or AP >5 x ULN TAXOTERE should be stopped. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 7 of 63 The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below: Cisplatin dose modifications and delays Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade: • Grade 2: Reduce cisplatin dose by 20%. • Grade 3: Discontinue treatment. Ototoxicity: In the case of grade 3 toxicity, discontinue treatment. Nephrotoxicity: In the event of a rise in serum creatinine grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2). For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribing information. } ˆ • ‹ ½ „ “ ƒ — ‚ † € „ „ ‡ ’ – ˆ ‹ — ˆ † € „ „ ‡ ˆ † € € ‹ ˆ ‡ ˆ ‚ ‡ ˆ † € € ‚ ‹ ˆ ‡ ˆ ‚ ‡ — ‹ †• „ ‡ » † ‚ Œ ‚ ‹ € ” ‹ ˆ † € ƒ „ » † ‚ Œ ‚ ‹ CrCl 60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. CrCl between 40 and 59 mL/min Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle. If no recovery was observed, then cisplatin was omitted from the next treatment cycle. CrCl <40 mL/min Dose of cisplatin was omitted in that treatment cycle only. If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued. If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle. CrCl = Creatinine clearance Fluorouracil dose modifications and treatment delays For diarrhea and stomatitis, see Table 1. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 8 of 63 In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%. For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade 1 and then recommenced, if medically appropriate. For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information. Combination Therapy with Strong CYP3A4 inhibitors: Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. Ð Ñ Ò Ò Ó Ý ê Ö ñ × Ü Ò Ý Õ é Ü Û Ô × Ñ Þ á â ç ì í Û × Û é Õ í è ò Õ Ý Ú Õ é Ô í Ô Ö ô Þ ï ß à ú â ã à TAXOTERE is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing TAXOTERE solutions. The use of gloves is recommended à Please refer to Ð Ñ Ò Ò Ô ö î ê ó ó í Û Ò Ø î Ü Ô Ý Õ Ö Ò Õ × Ø Õ × Ø í Û × Ö Þ ï à ú â ã à If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water. Contact of the TAXOTERE concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final TAXOTERE dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. TAXOTERE Injection Concentrate requires two dilutions prior to administration. Please follow the preparation instructions provided below. ¶ „ † Ï Both the TAXOTERE Injection Concentrate and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the † € ‡ contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL docetaxel. The table below provides the fill range of the Diluent, the approximate extractable volume of Diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the initial diluted solution for TAXOTERE 20 mg and TAXOTERE 80 mg (see Table 3). ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 9 of 63 } ˆ • ‹ Ç Ã € † € ˆ ‹ € ‹ — † € „ „ } ‘ } ’ “ ’ Ã ‚ † € „ „ ‚ † ‡ ˆ † Product Diluent 13% (w/w) ethanol in water for Approximate extractable volume of Diluent when Concentration of the initial diluted injection Fill Range (mL) entire contents are withdrawn (mL) solution (mg/mL docetaxel) Taxotere® 1.88 - 2.08 mL 1.8 mL 10 mg/mL 20 mg/0.5 mL Taxotere® 80 mg/2 mL 6.96 - 7.70 mL 7.1 mL 10 mg/mL ‘ ¶ ‘ } — † ~ † Ž „ Š – € ˆ ‹ „ ‡ ‰ — ‹ ˆ † € „ ³ Ã ‚ † € „ „ ‚ † ‡ ˆ † ˆ ƒ ƒ € ‹ — † · Ž € † ~ † ~ „ Š – € ˆ ‹ „ ‡ ‰ — ‹ ˆ † € „ ¹ A.Initial Diluted Solution 1. TAXOTERE vials should be stored between 2°C and 25°C (36°F and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of TAXOTERE Injection Concentrate and diluent (13% ethanol in water for injection) vials to stand at room temperature for approximately 5 minutes. 2. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 1.8 mL for TAXOTERE 20 mg and approximately 7.1 mL for TAXOTERE 80 mg) into a syringe by partially inverting the vial, and transfer it to the appropriate vial of TAXOTERE Injection Concentrate. Ã † ~ ” ‡ „ ‚ ƒ — ‡ € „ ‹ ‹ „ Ž ƒ ˆ ƒ ‚ ‡ € • ƒ ˜ ˆ € € † € ˆ ‹ ƒ € ‹ — † ƒ „ ‹ — † € „ „ š › ‰ ™ƒ „ ‚ † ˆ » ‹ œ ‰ µ Ž € ‹ ‹ ‡ — ‹ † . 3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixture of the concentrate and diluent. Do not shake. 4. The initial diluted TAXOTERE solution (10 mg docetaxel/mL) should be clear; however, there may be some foam on top of the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate prior to continuing the preparation process. The initial diluted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours. B.Final Dilution for Infusion 1. Aseptically withdraw the required amount of initial diluted TAXOTERE solution (10 mg docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle of ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 10 of 63 either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of TAXOTERE is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL TAXOTERE is not exceeded. 2. Thoroughly mix the infusion by manual rotation. 3. As with all parenteral products, TAXOTERE should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the TAXOTERE initial diluted solution or final dilution for intravenous infusion is not clear or appears to have precipitation, these should be discarded. The final TAXOTERE dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature and lighting conditions. TAXOTERE final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours. TAXOTERE final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration). TAXOTERE (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 2 mL polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in water for injection). Both items are in a blister pack in one carton. TAXOTERE (docetaxel) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel in 0.5 mL polysorbate 80 and Diluent for TAXOTERE 20 mg (13% (w/w) ethanol in water for injection). Both items are in a blister pack in one carton. TAXOTERE is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred Ð Ñ Ò Ò æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ð â ã . TAXOTERE should not be used in patients with neutrophil counts of <1500 cells/mm 3 . ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 11 of 63 Breast Cancer TAXOTERE administered at 100 mg/m 2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m 2 , mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths. Non-Small Cell Lung Cancer TAXOTERE administered at a dose of 100 mg/m 2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m 2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry Ð Ñ Ò ÒÓ Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à ß â ç ì í Û × Û é Õ í î Ü ê Ø Û Ò Ñ Þ ï ð â ã à Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with TAXOTERE Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç Ñ Ò Û × î ó Ò é Û õ Û é è Ô ó ê í Õ Ü Û Ô × Ñ Þ à â ç ì í Û × Û é Õ íÑ Ü ê Ø Û Ò Ñ Þ ï ð â ã . Perform frequent peripheral blood cell counts on all patients receiving TAXOTERE. Patients should not be retreated with subsequent cycles of TAXOTERE until neutrophils recover to a level >1500 cells/mm 3 and platelets recover to a level > 100,000 cells/mm 3 . A 25% reduction in the dose of TAXOTERE is recommended during subsequent cycles following severe neutropenia (<500 cells/mm 3 ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a TAXOTERE cycle Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . Neutropenia (<2000 neutrophils/mm 3 ) occurs in virtually all patients given 60 mg/m 2 to 100 mg/m 2 of TAXOTERE and grade 4 neutropenia (<500 cells/mm 3 ) occurs in 85% of patients given 100 mg/m 2 and 75% of patients given 60 mg/m 2 . Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. TAXOTERE should not be administered to patients with neutrophils <1500 cells/mm 3 . ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 12 of 63 Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2 but was very uncommon in patients given 60 mg/m 2 . Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related Ð Ñ Ò Ò Ù Ø Ò Ý Ñ Ò þ Ò Õ é Ü Û Ô × Ñ Þ à ï â ç ì í Û × Û é Õ í î Ü ê Ø Û Ò ÑÞ ï ð â ã . Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × ØÙ Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ç Ù Ø Ò Ý Ñ Ò þ Ò Õ é Ü Û Ô × Ñ Þ â ã à Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the TAXOTERE infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with TAXOTERE. Hypersensitivity reactions may occur within a few minutes following initiation of a TAXOTERE infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of TAXOTERE Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à â ã ® Severe fluid retention has been reported following TAXOTERE therapy. Patients should be premedicated with oral corticosteroids prior to each TAXOTERE administration to reduce the incidence and severity of fluid retention Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß .6)ã ® Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions. When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg. Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m 2 . Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m 2 . Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 13 of 63 TAXOTERE to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, Ò à Ö ., salt restriction, oral diuretic(s). Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial Þ ø Ù ù ú ï â AML occurred in 3 of 744 patients who received TAXOTERE, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide Ð Ñ Ò Ò ì í Û × Û é Õ í î Ü ê Ø Û Ò Ñ Þ ï ð à ß â ã . In TAC- treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × ØÙ Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued TAXOTERE due to skin toxicity. Severe neurosensory symptoms (Ò à Ö à paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ã . Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965). Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease. TAXOTERE can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 14 of 63 There are no adequate and well-controlled studies in pregnant women using TAXOTERE. If TAXOTERE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TAXOTERE Ð Ñ Ò Ò Ñ Ò Û × î ó Ò é Û õ Û é è Ô ó ê í Õ Ü Û Ô × Ñ Þ à ï â ã ® The most serious adverse reactions from TAXOTERE are: • Toxic Deaths Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ï â ã • Hepatotoxicity Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ß â ã • Neutropenia Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ú â ã • Hypersensitivity Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ð â ã • Fluid Retention Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ë â ã The most common adverse reactions across all TAXOTERE indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication. Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established. Breast Cancer û Ô × Ô Ü ò Ò Ý Õ ó ô ö Û Ü ò ø Ù ù ü ø ý þ ý õ Ô Ý í Ô é Õ í í ô Õ Ø Õ × é Ò Ø Ô Ý Ú Ò Ü Õ Ñ Ü Õ Ü Û é ÷ Ý Ò Õ Ñ Ü é Õ × é Ò Ý Õ õ Ü Ò Ý õ Õ Û í ê Ý Ò Ô õó Ý Û Ô Ý é ò Ò Ú Ô Ü ò Ò Ý Õ ó ô TAXOTERE 100 mg/m 2 : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received TAXOTERE administered at 100 mg/m 2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to TAXOTERE. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving TAXOTERE for the treatment of breast cancer and in patients with other tumor types (See Table 4). ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 15 of 63 } ˆ • ‹ ¿ Š ¸ — ‰ ‰ ˆ ‡ Œ „ ƒ – ‡ “ ˆ ‚ † € „ € ¾ ˆ † € † “ ‚ € – € ™ } ‘ } ’ “ ’ ˆ † š › › ‰ ™ œ ‰ Q ƒ – ‡ “ ˆ ‚ † € „ ‹ ‹ } — ‰ „ ‡ } Œ ” ¶ „ ‡ ‰ ˆ ‹ µ } ! " ½ › ¿ ºÍ ‹ ‹ } — ‰ „ ‡ } Œ ” ’ ‹ – ˆ † ƒ µ } ! ! " Ì šÍ À ‡ ˆ † ˆ ‚ ‡¶ „ ‡ ‰ ˆ ‹ µ } ! " Î Ì ºÍÈ ‰ ˆ † „ ‹ „ ™ € ‚ Neutropenia <2000 cells/mm 3 96 96 99 <500 cells/mm 3 Leukopenia 75 88 86 <4000 cells/mm 3 96 98 99 <1000 cells/mm 3 Thrombocytopenia 32 47 44 <100,000 cells/mm 3 Anemia 8 25 9 <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia*** 11 26 12 ¸ ” † € ‚ ˆ † ~¶ „ Š ¸ ” † € ‚ ˆ † ~ 2 1 5 7 1 1 Ã ‚ † € „ Any Severe 22 6 33 16 22 6 – ‡ € • ‚ „ Ã ‚ † € „ Any 31 41 35 Severe 2 8 2 È Œ ” ‡ € † € – € † Œ “ ˆ ‚ † € „ Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 16 of 63 ƒ – ‡ “ ˆ ‚ † € „ ‹ ‹ } — ‰ „ ‡ } Œ ” ¶ „ ‡ ‰ ˆ ‹ µ } ! " ½ › ¿ ºÍ ‹ ‹ } — ‰ „ ‡ } Œ ” ’ ‹ – ˆ † ƒ µ } ! ! " Ì šÍ À ‡ ˆ † ˆ ‚ ‡¶ „ ‡ ‰ ˆ ‹ µ } ! " Î Ì ºÍ ‹ — € ƒ “ † † € „ Regardless of Premedication Any Severe With 3-day Premedication Any Severe 47 7 n=92 64 7 39 8 n=3 67 33 60 9 n=92 64 7 ¶ — ‡ „ „ ‡ Œ Any Severe 49 4 34 0 58 6 — † ˆ „ — Any Severe 48 5 54 10 47 5 ¶ ˆ € ‹ ~ ˆ ™ Any Severe 31 3 23 5 41 4 # ˆ † ‡ „ € † † € ˆ ‹ Nausea Vomiting Diarrhea Severe 39 22 39 5 38 23 33 5 42 23 43 6 ¸ † „ ‰ ˆ † € † € Any Severe 42 6 49 13 52 7 ‹ „ ” ‚ € ˆ 76 62 74 † ~ € ˆ Any Severe 62 13 53 25 66 15 Œ ˆ ‹ ™ € ˆ Any Severe 19 2 16 2 21 2 ‡ † ~ ‡ ˆ ‹ ™ € ˆ 9 7 8 Ã — € „ ¸ € † “ ˆ ‚ † € „ 4 3 4 *Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Febrile Neutropenia: ANC grade 4 with fever >38oC with intravenous antibiotics and/or hospitalization ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 17 of 63 È ‰ ˆ † „ ‹ „ ™ € ‚ “ ˆ ‚ † € „ Reversible marrow suppression was the major dose-limiting toxicity of TAXOTERE Ð Ñ Ò Òæ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ú â ã à The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm 3 ) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles. Febrile neutropenia (<500 cells/mm 3 with fever >38 o C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids. Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm 3 ) associated with fatal gastrointestinal hemorrhage has been reported. È Œ ” ‡ € † € – € † Œ “ ˆ ‚ † € „ Severe hypersensitivity reactions have been reported Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Øè Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ð â ã . Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy. ‹ — € ƒ “ † † € „ ¹ Fluid retention can occur with the use of TAXOTERE Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç Ó Ô Ñ Õ Ö Ò Õ × ØÙ Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à â ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ë â ã à — † ˆ „ — “ ˆ ‚ † € „ Severe skin toxicity is discussed elsewhere in the label Ð Ñ Ò Ò æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à á â ã à Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after TAXOTERE infusion, recovered before the next infusion, and were not disabling. Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain. ¶ — ‡ „ ‹ „ ™ € ‚ “ ˆ ‚ † € „ Neurologic reactions are discussed elsewhere in the label Ð Ñ Ò Ò æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à â ã# ˆ † ‡ „ € † † € ˆ ‹ “ ˆ ‚ † € „ ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 18 of 63 Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3- 5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. ˆ ‡ ƒ € „ – ˆ ‚ — ‹ ˆ ‡ “ ˆ ‚ † € „ Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely. Seven of 86 (8.1%) of metastatic breast cancer patients receiving TAXOTERE 100 mg/m 2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by 10% associated with a drop below the institutional lower limit of normal. Ã — € „ ¸ € † “ ˆ ‚ † € „ Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. È ” ˆ † € ‚ “ ˆ ‚ † € „ In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on TAXOTERE, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established. È ‰ ˆ † „ ‹ „ ™ € ‚ ˆ ƒ ‘ † ~ ‡ } „ » € ‚ € † Œ Ï “ ‹ ˆ † € „ † „ ƒ „ ˆ ƒ • ˆ ‹ € ‹ € – ‡ ‚ ~ ‰ € † ‡ Œˆ • „ ‡ ‰ ˆ ‹ € † € Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given TAXOTERE at 100 mg/m 2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given TAXOTERE at 60 mg/m 2 who had normal LFTs (see Tables 5 and 6). ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 19 of 63 } ˆ • ‹ º Š È ‰ ˆ † „ ‹ „ ™ € ‚ ƒ – ‡ “ ˆ ‚ † € „ € À ‡ ˆ † ˆ ‚ ‡ ¾ ˆ † € † ¾ ‡ – € „ — ‹ Œ } ‡ ˆ † ƒŽ € † ~ ~ ‰ „ † ~ ‡ ˆ ” Œ } ‡ ˆ † ƒ ˆ † } ‘ } ’ “ ’ š › › ‰ ™ œ ‰ Q Ž € † ~ ¶ „ ‡ ‰ ˆ ‹ „ ‡ ’ ‹ – ˆ † ƒ µ € – ‡ — ‚ † € „ } † „ ‡ Ì › ‰ ™ œ ‰ Q Ž € † ~ ¶ „ ‡ ‰ ˆ ‹ µ € – ‡ — ‚ † € „ } † ƒ – ‡ “ ˆ ‚ † € „ } ‘ } ’ “ ’š › › ‰ ™ œ ‰ Q } ‘ } ’ “ ’Ì › ‰ ™ œ ‰ Q¶ „ ‡ ‰ ˆ ‹µ } ! " $ Ç ›Í ’ ‹ – ˆ † ƒµ } ! ! " š ÊÍ ¶ „ ‡ ‰ ˆ ‹µ } ! " š $ ¿Í¶ — † ‡ „ ” € ˆ Any <2000 cells/mm 3 Grade 4 <500 cells/mm 3 98 84 100 94 95 75 } ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ Any <100,000 cells/mm 3 Grade 4 <20,000 cells/mm 3 11 1 44 17 14 1 ‰ € ˆ <11 g/dL 95 94 65 Ã ‚ † € „ ! ! ! Any Grade 3 and 4 23 7 39 33 1 0 • ‡ € ‹ ¶ — † ‡ „ ” € ˆ **** By Patient By Course 12 2 33 9 0 0 ¸ ” † € ‚ ˆ † ~ 2 6 1 ¶ „ Š ¸ ” † € ‚ ˆ † ~ 1 11 0 *Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. ****Febrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever >38.1°C ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 20 of 63 } ˆ • ‹ Ì Š ¶ „ Š È ‰ ˆ † „ ‹ „ ™ € ‚ ƒ – ‡ “ ˆ ‚ † € „ € À ‡ ˆ † ˆ ‚ ‡ ¾ ˆ † € † ¾ ‡ – € „ — ‹ Œ} ‡ ˆ † ƒ Ž € † ~ ~ ‰ „ † ~ ‡ ˆ ” Œ } ‡ ˆ † ƒ ˆ † } ‘ } ’ “ ’ š › › ‰ ™ œ ‰ Q Ž € † ~ ¶ „ ‡ ‰ ˆ ‹ „ ‡ ’ ‹ – ˆ † ƒµ € – ‡ — ‚ † € „ } † „ ‡ Ì › ‰ ™ œ ‰ Q Ž € † ~ ¶ „ ‡ ‰ ˆ ‹ µ € – ‡ — ‚ † € „ } † ƒ – ‡ “ ˆ ‚ † € „ } ‘ } ’ “ ’š › › ‰ ™ œ ‰ Q } ‘ } ’ “ ’Ì › ‰ ™ œ ‰ Q¶ „ ‡ ‰ ˆ ‹µ } ! " $ Ç ›Í ’ ‹ – ˆ † ƒµ } ! ! " š ÊÍ ¶ „ ‡ ‰ ˆ ‹µ } ! " š $ ¿Í ‚ — † È Œ ” ‡ € † € – € † Œ“ ˆ ‚ † € „ “ ™ ˆ ‡ ƒ ‹ „ ¾ ‡ ‰ ƒ € ‚ ˆ † € „ Any Severe 13 1 6 0 1 0 ‹ — € ƒ “ † † € „ *** “ ™ ˆ ‡ ƒ ‹ „ ¾ ‡ ‰ ƒ € ‚ ˆ † € „ Any Severe 56 8 61 17 13 0 ¶ — ‡ „ „ ‡ Œ Any Severe 57 6 50 0 20 0 Œ ˆ ‹ ™ € ˆ 23 33 3 — † ˆ „ — Any Severe 45 5 61 17 31 0 † ~ € ˆ Any Severe 65 17 44 22 66 0 € ˆ ‡ ‡ ~ ˆ Any Severe 42 6 28 11 NA ¸ † „ ‰ ˆ † € † € Any Severe 53 8 67 39 19 1 *Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN ** Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m2 dose NA = not available ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 21 of 63 In the three-arm monotherapy trial, TAX313, which compared TAXOTERE 60 mg/m 2 , 75 mg/m 2 and 100 mg/m 2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with TAXOTERE 60 mg/m 2 compared to 55.3% and 65.9% treated with 75 mg/m 2 and 100 mg/m 2 respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m 2 vs. 6.9% and 16.5% for patients treated at 75 and 100 mg/m 2 respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m 2 compared to 5.3% and 1.6% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively. The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2 , 75 mg/m 2 , and 100 mg/m 2 respectively), thrombocytopenia (7%, 11% and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively). % & ' ( ) * + , ) & * , - . / + 0 1 2 ) , - 3 4 5 6 3 7 8 7 ) * , - . + 9 : ; < + * , , / . + , ' . * , & = ( / . + > , ? + * ? . / The following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with TAXOTERE 75 mg/m² every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 7). } ˆ • ‹ $ Š ‹ € € ‚ ˆ ‹ ‹ Œ Ã ‰ ” „ ‡ † ˆ † } ‡ ˆ † ‰ † ’ ‰ ‡ ™ † ƒ – ‡ “ ˆ ‚ † € „ “ ™ ˆ ‡ ƒ ‹ „ ˆ — ˆ ‹ “ ‹ ˆ † € „ ~ € ” € ¾ ˆ † € † “ ‚ € – € ™ } ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ Ž € † ~ „ » „ ‡ — • € ‚ € ˆ ƒ Œ ‚ ‹ „ ” ~ „ ” ~ ˆ ‰ € ƒ ³ } Ç š Ì · ¹} ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q @ „ » „ ‡ — • € ‚ € º › ‰ ™ œ ‰ Q @ Œ ‚ ‹ „ ” ~ „ ” ~ ˆ ‰ € ƒ º › ›‰ ™ œ ‰ Q ³ } · " $ ¿ ¿Í ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ º › › ‰ ™ œ ‰ Q @ „ » „ ‡ — • € ‚ € º › ‰ ™ œ ‰ Q @ Œ ‚ ‹ „ ” ~ „ ” ~ ˆ ‰ € ƒ º › ›‰ ™ œ ‰ Q ³ · " $ Ç ÌÍ ƒ – ‡ “ ˆ ‚ † € „ Œ # ‡ ˆ ƒ Ç œ ¿ Œ # ‡ ˆ ƒ Ç œ ¿ ‰ € ˆ 92 4 72 2 ¶ — † ‡ „ ” € ˆ 71 66 82 49 – ‡ € ˆ • ‚ „ € ‚ † € „ 47 1 17 0 Ã ‚ † € „ 39 4 36 2 } ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ 39 2 28 1 • ‡ € ‹ — † ‡ „ ” € ˆ 25 N/A 3 N/A ¶ — † ‡ „ ” € ‚ € ‚ † € „ 12 N/A 6 N/A È Œ ” ‡ € † € – € † Œ ‡ ˆ ‚ † € „ 13 1 4 0 µ Œ ‰ ” ~ ƒ ‰ ˆ 4 0 1 0 ‹ — € ƒ “ † † € „ ! Peripheral edema Weight gain 35 27 13 1 0 0 15 7 9 0 0 0 ¶ — ‡ „ ” ˆ † ~ Œ „ ‡ Œ 26 0 10 0 ¶ — ‡ „ Š ‚ „ ‡ † € ‚ ˆ ‹ 5 1 6 1 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 22 of 63 } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q @ „ » „ ‡ — • € ‚ € º › ‰ ™ œ ‰ Q @ Œ ‚ ‹ „ ” ~ „ ” ~ ˆ ‰ € ƒ º › ›‰ ™ œ ‰ Q ³ } · " $ ¿ ¿Í ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ º › › ‰ ™ œ ‰ Q @ „ » „ ‡ — • € ‚ € º › ‰ ™ œ ‰ Q @ Œ ‚ ‹ „ ” ~ „ ” ~ ˆ ‰ € ƒ º › ›‰ ™ œ ‰ Q ³ · " $ Ç ÌÍ ƒ – ‡ “ ˆ ‚ † € „ Œ # ‡ ˆ ƒ Ç œ ¿ Œ # ‡ ˆ ƒ Ç œ ¿¶ — ‡ „ ” ˆ † ~ Œ ‰ „ † „ ‡ 4 0 2 0 ¶ — ‡ „ Š ‚ ‡ • ‹ ‹ ˆ ‡ 2 0 2 0 ¸ Œ ‚ „ ” 2 1 1 0 ‹ „ ” ‚ € ˆ 98 N/A 97 N/A ¸ ¼ € † „ » € ‚ € † Œ 27 1 18 0 ¶ ˆ € ‹ ƒ € „ ‡ ƒ ‡ 19 0 14 0 ¶ ˆ — ˆ 81 5 88 10 ¸ † „ ‰ ˆ † € † € 69 7 53 2 A „ ‰ € † € ™ 45 4 59 7 € ˆ ‡ ‡ ~ ˆ 35 4 28 2 „ † € ” ˆ † € „ 34 1 32 1 } ˆ † ” ‡ – ‡ € „ 28 1 15 0 „ ‡ » € ˆ 22 2 18 1 • ƒ „ ‰ € ˆ ‹ ¾ ˆ € 11 1 5 0 ‰ „ ‡ ‡ ~ ˆ 62 N/A 52 N/A „ — ™ ~ 14 0 10 0 ˆ ‡ ƒ € ˆ ‚ ƒ Œ ‡ ~ Œ † ~ ‰ € ˆ 8 0 6 0 A ˆ „ ƒ € ‹ ˆ † ˆ † € „ 27 1 21 1 È Œ ” „ † € „ 2 0 1 0 ¾ ~ ‹ • € † € 1 0 1 0 † ~ € ˆ 81 11 71 6 Œ ˆ ‹ ™ € ˆ 27 1 10 0 ‡ † ~ ‡ ˆ ‹ ™ € ˆ 19 1 9 0 µ ˆ ‚ ‡ € ‰ ˆ † € „ ƒ € „ ‡ ƒ ‡ 11 0 7 0 „ — ‚ † € – € † € 5 0 7 0 * COSTART term and grading system for events related to treatment. Of the 744 patients treated with TAC, 36.3% experienced severe treatment emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 23 of 63 – ‡ ˆ ƒ Ã ‚ † € „ Fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC- and FAC-treated patients respectively. Infection was seen in 39.4% of TAC-treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated and FAC-treated patients respectively. There were no septic deaths in either treatment arm. # ˆ † ‡ „ € † † € ˆ ‹ “ ˆ ‚ † € „ In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation vs. one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred. ˆ ‡ ƒ € „ – ˆ ‚ — ‹ ˆ ‡ “ ˆ ‚ † € „ More cardiovascular reactions were reported in the TAC arm vs. the FAC arm; dysrhythmias, all grades (7.9% vs. 6.0%), hypotension, all grades (2.6% vs. 1.1%) and CHF (2.3% vs. 0.9%, at 70 months median follow-up). One patient in each arm died due to heart failure. ‚ — † Œ ‹ „ € ƒ µ — ¼ ‰ € ˆ ³ µ · Treatment-related acute myeloid leukemia or myelodysplasia is known to occur in patients treated with anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at 5 years in TAX316 was 0.4% for TAC- treated patients and 0.1% for FAC-treated patients. This risk of AML is comparable to the risk observed for other anthracyclines/cyclophosphamide containing adjuvant breast chemotherapy regimens. Lung Cancer B & * & , - . / + 0 1 2 ) , - 3 4 5 6 3 7 8 7 = & / ; * / . > . ? , + ( C . D C & ? + C C 1 + 9 < + * ? . 9 & / ' . , + > , + , ) ? E F % G %0 / . < ) & ; > C 1 , / . + , . 9 2 ) , - 0 C + , ) * ; ' H ( + > . 9 ? - . ' & , - . / + 0 1 TAXOTERE 75 mg/m 2 : Treatment emergent adverse drug reactions are shown in Table 8. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 24 of 63 } ˆ • ‹ Ê Š } ‡ ˆ † ‰ † ’ ‰ ‡ ™ † ƒ – ‡ “ ˆ ‚ † € „ “ ™ ˆ ‡ ƒ ‹ „ “ ‹ ˆ † € „ ~ € ” † „ } ‡ ˆ † ‰ †€ ¾ ˆ † € † “ ‚ € – € ™ } ‘ } ’ “ ’ ˆ „ „ † ~ ‡ ˆ ” Œ „ ‡ ¶ „ Š ¸ ‰ ˆ ‹ ‹ ‹ ‹ µ — ™ ˆ ‚ ‡¾ ‡ – € „ — ‹ Œ } ‡ ˆ † ƒ Ž € † ~ ¾ ‹ ˆ † € — ‰ Š À ˆ ƒ ~ ‰ „ † ~ ‡ ˆ ” Œ ! ƒ – ‡ “ ˆ ‚ † € „ } ‘ } ’ “ ’$ º ‰ ™ œ ‰ Q " š $ ÌÍ À † ¸ — ” ” „ ‡ † € – ˆ ‡ " ¿ ÎÍ A € „ ‡ ‹ • € œÃ „ ˆ ‰ € ƒ " š š ÎÍ¶ — † ‡ „ ” € ˆ Any Grade 3/4 84 65 14 12 83 57 µ — ¼ „ ” € ˆ Any Grade 3/4 84 49 6 0 89 43 } ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ Any Grade 3/4 8 3 0 0 8 2 ‰ € ˆ Any Grade 3/4 91 9 55 12 91 14 • ‡ € ‹ ¶ — † ‡ „ ” € ˆ ! ! 6 NA † 1 Ã ‚ † € „ Any Grade 3/4 34 10 29 6 30 9 } ‡ ˆ † ‰ † “ ‹ ˆ † ƒ „ ‡ † ˆ ‹ € † Œ 3 NA † 3 È Œ ” ‡ € † € – € † Œ “ ˆ ‚ † € „ Any Grade 3/4 6 3 0 0 1 0 ‹ — € ƒ “ † † € „ Any Severe 34 3 ND †† 23 3 ¶ — ‡ „ „ ‡ Œ Any Grade 3/4 23 2 14 6 29 5 ¶ — ‡ „ ‰ „ † „ ‡ Any Grade 3/4 16 5 8 6 10 3 ¸ ¼ € Any Grade 3/4 20 1 6 2 17 1 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 25 of 63 ƒ – ‡ “ ˆ ‚ † € „ } ‘ } ’ “ ’$ º ‰ ™ œ ‰ Q " š $ ÌÍ À † ¸ — ” ” „ ‡ † € – ˆ ‡ " ¿ ÎÍ A € „ ‡ ‹ • € œÃ „ ˆ ‰ € ƒ " š š ÎÍ# ˆ † ‡ „ € † † € ˆ ‹ Nausea Any 34 31 31 Grade 3/4 5 4 8 Vomiting Any 22 27 22 Grade 3/4 3 2 6 Diarrhea Any 23 6 12 Grade 3/4 3 0 4 ‹ „ ” ‚ € ˆ 56 35 50 † ~ € ˆ Any Severe*** 53 18 57 39 54 23 ¸ † „ ‰ ˆ † € † € Any 26 6 8 Grade 3/4 2 0 1 ¾ — ‹ ‰ „ ˆ ‡ Œ Any 41 49 45 Grade 3/4 21 29 19 ¶ ˆ € ‹ € „ ‡ ƒ ‡ Any 11 0 2 Severe*** 1 0 0 Œ ˆ ‹ ™ € ˆ Any 6 0 3 Severe*** 0 0 0 ‡ † ~ ‡ ˆ ‹ ™ € ˆ Any 3 2 2 Severe*** 0 0 1 } ˆ † ¾ ‡ – ‡ € „ Any 6 0 0 Severe*** 1 0 0 *Normal Baseline LFTs: Transaminases 1.5 times ULN or alkaline phosphatase 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization ***COSTART term and grading system †Not Applicable; †† Not Done ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 26 of 63 % & ' ( ) * + , ) & * , - . / + 0 1 2 ) , - 3 4 5 6 3 7 8 7 ) * ? - . ' & , - . / + 0 1 H * + I < . + 9 < + * ? . 9 ; * / . > . ? , + ( C .& / ' . , + > , + , ) ? E F % G % Table 9 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted. } ˆ • ‹ Î Š ƒ – ‡ “ ˆ ‚ † € „ “ ™ ˆ ‡ ƒ ‹ „ “ ‹ ˆ † € „ ~ € ” † „ } ‡ ˆ † ‰ † € ~ ‰ „ † ~ ‡ ˆ ” Œ Š¶ ˆ J – ƒ – ˆ ‚ ƒ ¶ „ Š ¸ ‰ ˆ ‹ ‹ ‹ ‹ µ — ™ ˆ ‚ ‡ ¾ ˆ † € † “ ‚ € – € ™ } ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ Ž € † ~ € ” ‹ ˆ † € ƒ – ‡ “ ˆ ‚ † € „ } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q@ € ” ‹ ˆ † € $ º ‰ ™ œ ‰ Q " ¿ › ÌÍ A € „ ‡ ‹ • € ½ º ‰ ™ œ ‰ Q @ € ” ‹ ˆ † € š › › ‰ ™ œ ‰ Q " Ç Î ÌÍ¶ — † ‡ „ ” € ˆ Any Grade 3/4 91 74 90 78 • ‡ € ‹ ¶ — † ‡ „ ” € ˆ 5 5 } ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ Any Grade 3/4 15 3 15 4 ‰ € ˆ Any Grade 3/4 89 7 94 25 Ã ‚ † € „ Any Grade 3/4 35 8 37 8 – ‡ € ˆ • ‚ „ € ‚ † € „ Any Grade 3/4 33 < 1 29 1 È Œ ” ‡ € † € – € † Œ “ ˆ ‚ † € „ ! Any Grade 3/4 12 3 4 < 1 ‹ — € ƒ “ † † € „ ! ! Any All severe or life-threatening events Pleural effusion Any All severe or life-threatening events Peripheral edema Any All severe or life-threatening events Weight gain Any 54 2 23 2 34 <1 15 42 2 22 2 18 <1 9 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 27 of 63 ƒ – ‡ “ ˆ ‚ † € „ } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q@ € ” ‹ ˆ † € $ º ‰ ™ œ ‰ Q " ¿ › ÌÍ A € „ ‡ ‹ • € ½ º ‰ ™ œ ‰ Q @ € ” ‹ ˆ † € š › › ‰ ™ œ ‰ Q " Ç Î ÌÍ All severe or life-threatening events <1 <1 ¶ — ‡ „ „ ‡ Œ Any Grade 3/4 47 4 42 4 ¶ — ‡ „ ‰ „ † „ ‡ Any Grade 3/4 19 3 17 6 ¸ ¼ € Any Grade 3/4 16 <1 14 1 ¶ ˆ — ˆ Any Grade 3/4 72 10 76 17 A „ ‰ € † € ™ Any Grade 3/4 55 8 61 16 € ˆ ‡ ‡ ~ ˆ Any Grade 3/4 47 7 25 3 „ ‡ » € ˆ ! ! Any All severe or life-threatening events 42 5 40 5 ¸ † „ ‰ ˆ † € † € Any Grade 3/4 24 2 21 1 ‹ „ ” ‚ € ˆ Any Grade 3 75 <1 42 0 † ~ € ˆ ! ! Any All severe or life-threatening events 74 12 75 14 ¶ ˆ € ‹ € „ ‡ ƒ ‡ ! ! Any All severe events 14 <1 <1 0 Œ ˆ ‹ ™ € ˆ ! ! Any All severe events 18 <1 12 <1 * Replaces NCI term “Allergy” ** COSTART term and grading system ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 28 of 63 Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus TAXOTERE+carboplatin (which did not demonstrate a superior survival associated with TAXOTERE, Ð Ñ Ò Ò ì í Û × Û é Õ íî Ü ê Ø Û Ò Ñ Þ ï ð à ú â ã ) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the TAXOTERE+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm. Prostate Cancer % & ' ( ) * + , ) & * , - . / + 0 1 2 ) , - 3 4 5 6 3 7 8 7 ) * 0 + , ) . * , > 2 ) , - 0 / & > , + , . ? + * ? . / The following data are based on the experience of 332 patients, who were treated with TAXOTERE 75 mg/m² every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 10). } ˆ • ‹ š › Š ‹ € € ‚ ˆ ‹ ‹ Œ Ã ‰ ” „ ‡ † ˆ † } ‡ ˆ † ‰ † ’ ‰ ‡ ™ † ƒ – ‡ “ ˆ ‚ † € „ ³ “ ™ ˆ ‡ ƒ ‹ „ “ ‹ ˆ † € „ ~ € ” · € ¾ ˆ † € † Ž € † ~ ¾ ‡ „ † ˆ † ˆ ‚ ‡ Ž ~ „ “ ‚ € – ƒ } ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ Ž € † ~ ¾ ‡ ƒ € „ ³ } Ç ½ $ ·} ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q – ‡ Œ Ç Ž ¼ @” ‡ ƒ € „ º ‰ ™ † Ž € ‚ ƒ ˆ € ‹ Œ " Ç Ç ½Í € † „ » ˆ † ‡ „ š ½ ‰ ™ œ ‰ Q – ‡ Œ Ç Ž ¼ @” ‡ ƒ € „ º ‰ ™ † Ž € ‚ ƒ ˆ € ‹ Œ " Ç Ç ºÍ ƒ – ‡ “ ˆ ‚ † € „ Œ # ‡ ˆ ƒ Ç œ ¿ Œ # ‡ ˆ ƒ Ç œ ¿ ‰ € ˆ 67 5 58 2 ¶ — † ‡ „ ” € ˆ 41 32 48 22 } ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ 3 1 8 1 • ‡ € ‹ — † ‡ „ ” € ˆ 3 N/A 2 N/A Ã ‚ † € „ 32 6 20 4 ’ ” € † ˆ » € 6 0 2 0 ‹ ‹ ‡ ™ € ‚ “ ˆ ‚ † € „ 8 1 1 0 ‹ — € ƒ “ † † € „ ! Weight Gain* Peripheral Edema ! 24 8 18 1 0 0 5 3 2 0 0 0 ¶ — ‡ „ ” ˆ † ~ Œ ¸ „ ‡ Œ 30 2 7 0 ¶ — ‡ „ ” ˆ † ~ Œ „ † „ ‡ 7 2 3 1 “ ˆ ~ œ Ä — ˆ ‰ ˆ † € „ 6 0 3 1 ‹ „ ” ‚ € ˆ 65 N/A 13 N/A ¶ ˆ € ‹ ~ ˆ ™ 30 0 8 0 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 29 of 63 } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q – ‡ Œ Ç Ž ¼ @” ‡ ƒ € „ º ‰ ™ † Ž € ‚ ƒ ˆ € ‹ Œ " Ç Ç ½Í € † „ » ˆ † ‡ „ š ½ ‰ ™ œ ‰ Q – ‡ Œ Ç Ž ¼ @” ‡ ƒ € „ º ‰ ™ † Ž € ‚ ƒ ˆ € ‹ Œ " Ç Ç ºÍ ƒ – ‡ “ ˆ ‚ † € „ Œ # ‡ ˆ ƒ Ç œ ¿ Œ # ‡ ˆ ƒ Ç œ ¿¶ ˆ — ˆ 41 3 36 2 € ˆ ‡ ‡ ~ ˆ 32 2 10 1 ¸ † „ ‰ ˆ † € † € œ ¾ ~ ˆ ‡ Œ ™ € † € 20 1 8 0 } ˆ † € † — ‡ • ˆ ‚ 18 0 7 0 A „ ‰ € † € ™ 17 2 14 2 „ ‡ » € ˆ 17 1 14 0 „ — ™ ~ 12 0 8 0 Œ ” ˆ 15 3 9 1 ˆ ‡ ƒ € ˆ ‚ ‹ † – † ‡ € ‚ — ‹ ˆ ‡ — ‚ † € „ 10 0 22 1 ˆ † € ™ — 53 5 35 5 Œ ˆ ‹ ™ € ˆ 15 0 13 1 } ˆ ‡ € ™ 10 1 2 0 ‡ † ~ ‡ ˆ ‹ ™ € ˆ 8 1 5 1 *Related to treatment Gastric Cancer % & ' ( ) * + , ) & * , - . / + 0 1 2 ) , - 3 4 5 6 3 7 8 7 ) * K + > , / ) ? + 9 . * & ? + / ? ) * & ' + Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with TAXOTERE 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 11). } ˆ • ‹ š š Š ‹ € € ‚ ˆ ‹ ‹ Œ Ã ‰ ” „ ‡ † ˆ † } ‡ ˆ † ‰ † ’ ‰ ‡ ™ † ƒ – ‡ “ ˆ ‚ † € „ “ ™ ˆ ‡ ƒ ‹ „ “ ‹ ˆ † € „ ~ € ” † „ } ‡ ˆ † ‰ † € † ~ # ˆ † ‡ € ‚ ˆ ‚ ‡ ¸ † — ƒ Œ} ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q @‚ € ” ‹ ˆ † € $ º ‰ ™ œ ‰ Q @ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ $ º › ‰ ™ œ ‰ Q " ½ ½ š € ” ‹ ˆ † € š › › ‰ ™ œ ‰ Q @ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ š › › › ‰ ™ œ ‰ Q " ½ ½ ¿ ƒ – ‡ “ ˆ ‚ † € „ ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ‰ € ˆ 97 18 93 26 ¶ — † ‡ „ ” € ˆ 96 82 83 57 – ‡ € † ~ ˆ • ‚ „ € ‚ † € „ 36 2 23 1 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 30 of 63 } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q @‚ € ” ‹ ˆ † € $ º ‰ ™ œ ‰ Q @ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ $ º › ‰ ™ œ ‰ Q " ½ ½ š € ” ‹ ˆ † € š › › ‰ ™ œ ‰ Q @ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ š › › › ‰ ™ œ ‰ Q " ½ ½ ¿ ƒ – ‡ “ ˆ ‚ † € „ ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í} ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ 26 8 39 14 Ã ‚ † € „ 29 16 23 10 • ‡ € ‹ — † ‡ „ ” € ˆ 16 N/A 5 N/A ¶ — † ‡ „ ” € ‚ € ‚ † € „ 16 N/A 10 N/A ‹ ‹ ‡ ™ € ‚ ‡ ˆ ‚ † € „ 10 2 6 0 ‹ — € ƒ ‡ † † € „ ! 15 0 4 0 ’ ƒ ‰ ˆ ! 13 0 3 0 µ † ~ ˆ ‡ ™ Œ 63 21 58 18 ¶ — ‡ „ „ ‡ Œ 38 8 25 3 ¶ — ‡ „ ‰ „ † „ ‡ 9 3 8 3 € Æ Æ € 16 5 8 2 ‹ „ ” ‚ € ˆ 67 5 41 1 “ ˆ ~ œ € † ‚ ~ 12 1 9 0 ¶ ˆ € ‹ ‚ ~ ˆ ™ 8 0 0 0 ¸ ¼ € ƒ Ä — ˆ ‰ ˆ † € „ 2 0 0 0 ¶ ˆ — ˆ 73 16 76 19 A „ ‰ € † € ™ 67 15 73 19 „ ‡ » € ˆ 51 13 54 12 ¸ † „ ‰ ˆ † € † € 59 21 61 27 € ˆ ‡ ‡ ~ ˆ 78 20 50 8 „ † € ” ˆ † € „ 25 2 34 3 ’ „ ” ~ ˆ ™ € † € œ ƒ Œ ” ~ ˆ ™ € ˆ œ„ ƒ Œ „ ” ~ ˆ ™ € ˆ 16 2 14 5 # ˆ † ‡ „ € † † € ˆ ‹” ˆ € œ ‚ ‡ ˆ ‰ ” € ™ 11 2 7 3 ˆ ‡ ƒ € ˆ ‚ ƒ Œ ‡ ~ Œ † ~ ‰ € ˆ 5 2 2 1 Œ „ ‚ ˆ ‡ ƒ € ˆ ‹ € ‚ ~ ‰ € ˆ 1 0 3 2 } ˆ ‡ € ™ 8 0 2 0 ‹ † ‡ ƒ ~ ˆ ‡ € ™ 6 0 13 2 Clinically important treatment emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. *Related to treatment ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 31 of 63 Head and Neck Cancer % & ' ( ) * + , ) & * , - . / + 0 1 2 ) , - 3 4 5 6 3 7 8 7 ) * - . + 9 + * 9 * . ? L ? + * ? . / Table 12 summarizes the safety data obtained from patients that received induction chemotherapy with TAXOTERE 75 mg/m 2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6. } ˆ • ‹ š ½ ‹ € € ‚ ˆ ‹ ‹ Œ Ã ‰ ” „ ‡ † ˆ † } ‡ ˆ † ‰ † ’ ‰ ‡ ™ † ƒ – ‡ “ ˆ ‚ † € „ ³ “ ™ ˆ ‡ ƒ ‹ „ “ ‹ ˆ † € „ ~ € ” · € ¾ ˆ † € † Ž € † ~ ¸ È ¶ “ ‚ € – € ™ Ã ƒ — ‚ † € „ ~ ‰ „ † ~ ‡ ˆ ” Œ Ž € † ~} ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ Ž € † ~ ‚ € ” ‹ ˆ † € ˆ ƒ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ „ ‹ ‹ „ Ž ƒ • Œ ‡ ˆ ƒ € „ † ~ ‡ ˆ ” Œ³ } Ç ½ Ç · „ ‡ ‚ ~ ‰ „ ‡ ˆ ƒ € „ † ~ ‡ ˆ ” Œ ³ } Ç ½ ¿ ·} Ç ½ Ç³ " Ç º º · } Ç ½ ¿³ " ¿ Î ¿ ·} ‘ } ’ “ ’ˆ ‡ ‰ ³ " š $ ¿ · „ ‰ ” ˆ ‡ ˆ † „ ‡ˆ ‡ ‰ ³ " š Ê š · } ‘ } ’ “ ’ˆ ‡ ‰ ³ " ½ º š · „ ‰ ” ˆ ‡ ˆ † „ ‡ˆ ‡ ‰ ³ " ½ ¿ Ç · ƒ – ‡ “ ˆ ‚ † € „ (by Body System) ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í¶ — † ‡ „ ” € ˆ 93 76 87 53 95 84 84 56 ‰ € ˆ 89 9 88 14 90 12 86 10 } ~ ‡ „ ‰ • „ ‚ Œ † „ ” € ˆ 24 5 47 18 28 4 31 11 Ã ‚ † € „ 27 9 26 8 23 6 28 5 • ‡ € ‹ — † ‡ „ ” € ˆ ! 5 N/A 2 N/A 12 N/A 7 N/A ¶ — † ‡ „ ” € ‚ € ‚ † € „ 14 N/A 8 N/A 12 N/A 8 N/A ˆ ‚ ‡ ” ˆ € 21 5 16 3 17 9 20 11 µ † ~ ˆ ‡ ™ Œ 41 3 38 3 61 5 56 10 – ‡ € † ~ ˆ • ‚ „ € ‚ † € „ 32 1 37 0 30 4 28 3 Œ ˆ ‹ ™ € ˆ 10 1 7 0 7 0 7 2 M € ™ ~ † ‹ „ 21 1 27 1 14 2 14 2 ‹ ‹ ‡ ™ Œ 6 0 3 0 2 0 0 0 ‹ — € ƒ ‡ † † € „ ! !’ ƒ ‰ ˆ „ ‹ ŒM € ™ ~ † ™ ˆ € „ ‹ Œ 20 13 6 0 0 0 14 7 6 1 0 0 13 12 0 1 1 0 7 6 1 2 1 0 € Æ Æ € 2 0 5 1 16 4 15 2 ¶ — ‡ „ „ ‡ Œ 18 1 11 1 14 1 14 0 ‹ † ‡ ƒ ~ ˆ ‡ € ™ 6 0 10 3 13 1 19 3 ¶ — ‡ „ ‰ „ † „ ‡ 2 1 4 1 9 0 10 2 ‹ „ ” ‚ € ˆ 81 11 43 0 68 4 44 1 “ ˆ ~ œ € † ‚ ~ 12 0 6 0 20 0 16 1 ‡ Œ ¼ € 6 0 2 0 5 0 3 0 Ä — ˆ ‰ ˆ † € „ 4 1 6 0 2 0 5 0 ¶ ˆ — ˆ 47 1 51 7 77 14 80 14 ¸ † „ ‰ ˆ † € † € 43 4 47 11 66 21 68 27 A „ ‰ € † € ™ 26 1 39 5 56 8 63 10 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 32 of 63 } Ç ½ Ç³ " Ç º º · } Ç ½ ¿³ " ¿ Î ¿ ·} ‘ } ’ “ ’ˆ ‡ ‰ ³ " š $ ¿ · „ ‰ ” ˆ ‡ ˆ † „ ‡ˆ ‡ ‰ ³ " š Ê š · } ‘ } ’ “ ’ˆ ‡ ‰ ³ " ½ º š · „ ‰ ” ˆ ‡ ˆ † „ ‡ˆ ‡ ‰ ³ " ½ ¿ Ç · ƒ – ‡ “ ˆ ‚ † € „ (by Body System) ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í ŒÍ # ‡ ˆ ƒ Ç œ ¿Í € ˆ ‡ ‡ ~ ˆ 33 3 24 4 48 7 40 3 „ † € ” ˆ † € „ 17 1 16 1 27 1 38 1 „ ‡ » € ˆ 16 1 25 3 40 12 34 12 ’ „ ” ~ ˆ ™ € † € œ ƒ Œ ” ~ ˆ ™ € ˆ œ‘ ƒ Œ „ ” ~ ˆ ™ € ˆ 13 1 18 3 25 13 26 10 } ˆ † ˜ „ ‰ ‹ ‹ˆ ‹ † ‡ ƒ 10 0 5 0 20 0 17 1 # ˆ † ‡ „ € † † € ˆ ‹” ˆ € œ ‚ ‡ ˆ ‰ ” € ™ 8 1 9 1 15 5 10 2 È ˆ ‡ † • — ‡ 6 0 6 0 13 2 13 1 # ˆ † ‡ „ € † † € ˆ ‹• ‹ ƒ € ™ 4 2 0 0 5 1 2 1 ˆ ‡ ƒ € ˆ ‚ ƒ Œ ‡ ~ Œ † ~ ‰ € ˆ 2 2 2 1 6 3 5 3 A „ — ! ! ! 3 2 6 2 4 2 5 4 Ã ‚ ~ ‰ € ˆ ‰ Œ „ ‚ ˆ ‡ ƒ € ˆ ‹ 2 2 1 0 2 1 1 1 } ˆ ‡ € ™ 2 0 1 0 2 0 2 0 „ — ‚ † € – € † € 1 0 1 0 1 0 0.4 0 Clinically important treatment emergent adverse reactions based upon frequency, severity, and clinical impact. *Febrile neutropenia: grade 2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. **Related to treatment. *** Includes superficial and deep vein thrombosis and pulmonary embolism The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. À „ ƒ Œ ˆ ˆ Ž ~ „ ‹ : diffuse pain, chest pain, radiation recall phenomenon. ˆ ‡ ƒ € „ – ˆ ‚ — ‹ ˆ ‡ : atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. — † ˆ „ — : very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 33 of 63 # ˆ † ‡ „ € † † € ˆ ‹ : abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported. È ‰ ˆ † „ ‹ „ ™ € ‚ : bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with TAXOTERE when used in combination with other chemotherapy agents and/or radiotherapy. È Œ ” ‡ € † € – € † Œ : rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication. È ” ˆ † € ‚ : rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported. ¶ — ‡ „ ‹ „ ™ € ‚ : confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug. ‘ ” ~ † ~ ˆ ‹ ‰ „ ‹ „ ™ € ‚ : conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. È ˆ ‡ € ™ : rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs. “ ” € ‡ ˆ † „ ‡ Œ : dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy. “ ˆ ‹ : renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs. Docetaxel is a CYP3A4 substrate. ñ × Û Ü Ý Ô studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. ñ × Û Ô studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of TAXOTERE ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 34 of 63 and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with TAXOTERE, close monitoring for toxicity and a TAXOTERE dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â Õ × Ø ì í Û × Û é Õ í è ò Õ Ý Ú Õ é Ô í Ô Ö ô Þ ï ß à ú â ã à Pregnancy Category D Ð Ñ Ò Ò N æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ O Ñ Ò é Ü Û Ô × ã Based on its mechanism of action and findings in animals, TAXOTERE can cause fetal harm when administered to a pregnant woman. If TAXOTERE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TAXOTERE. TAXOTERE can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses 0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m 2 basis), administered during the period of organogenesis, have shown that TAXOTERE is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity. It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from TAXOTERE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The efficacy of TAXOTERE in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of TAXOTERE in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults. TAXOTERE has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluoruracil (TCF). TAXOTERE Monotherapy TAXOTERE monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1-22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m 2 as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 35 of 63 The recommended dose for TAXOTERE monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1-26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. TAXOTERE in Combination TAXOTERE was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to TAXOTERE (75 mg/m²) in combination with cisplatin (75 mg/m²) and 5-fluorouracil (750 mg/m²) (TCF) or to cisplatin (80 mg/m²) and 5-fluorouracil (1000 mg/m²/day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response. Pharmacokinetics: Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m 2 to 235 mg/m 2 in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m 2 . Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m 2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m 2 , corresponding to an AUC of 4.20±2.57 g.h/mL. In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults Ð Ñ Ò Ò ì í Û × Û é Õ í è ò Õ Ý Ú Õ é Ô í Ô Ö ô Þ ï ß à ú â ã . In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. ÿ Ô × î Ú Õ í í ì Ò í í ê × Ö ì Õ × é Ò Ý In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the TAXOTERE+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the TAXOTERE+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with TAXOTERE+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 36 of 63 peripheral edema 20%, stomatitis 20%). Patients treated with TAXOTERE+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). When TAXOTERE was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with TAXOTERE+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. è Ý Ô Ñ Ü Õ Ü Ò ì Õ × é Ò Ý Of the 333 patients treated with TAXOTERE every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with TAXOTERE every three weeks, the following treatment emergent adverse reactions occurred at rates 10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively. ä Ý Ò Õ Ñ Ü ì Õ × é Ò Ý In the adjuvant breast cancer trial (TAX316), TAXOTERE in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. P Õ Ñ Ü Ý Û é ì Õ × é Ò Ý Among the 221 patients treated with TAXOTERE in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates 10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored. Ò Õ Ø Õ × Ø ÿ Ò é ì Õ × é Ò Ý Among the 174 and 251 patients who received the induction treatment with TAXOTERE in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively. These clinical studies of TAXOTERE in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 37 of 63 this treatment regimen has not identified differences in responses between elderly and younger patients. Patients with bilirubin >ULN should not receive TAXOTERE. Also, patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not receive TAXOTERE Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç æ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ß â ç ì í Û × Û é Õ í è ò Õ Ý Ú Õ é Ô í Ô Ö ôÞ ï ß à ú â ã . There is no known antidote for TAXOTERE overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. In two reports of overdose, one patient received 150 mg/m 2 and the other received 200 mg/m 2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident. In mice, lethality was observed following single intravenous doses that were 154 mg/kg (about 4.5 times the human dose of 100 mg/m 2 on a mg/m 2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m 2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs. Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-Ü Ò Ý Ü -butyl ester, 13-ester with 5 -20-epoxy-1,2 ,4,7 ,10 ,13 -hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel has the following structural formula: ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 38 of 63 Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14• 3H2O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. TAXOTERE (docetaxel) Injection Concentrate is a clear yellow to brownish-yellow viscous solution. TAXOTERE is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80. TAXOTERE Injection Concentrate requires dilution with Diluent prior to addition to the infusion bag. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The diluent for TAXOTERE contains 13% ethanol in water for injection, and is supplied in vials. Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m 2 to 115 mg/m 2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m 2 to 115 mg/m 2 with infusion times of 1 to 2 hours. Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the , , and phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m 2 . ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 39 of 63 Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. ñ × Û Ü Ý Ô studies showed that docetaxel is about 94% protein bound, mainly to 1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the Û × Û Ü Ý Ô binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel. Metabolism: ñ × Û Ü Ý Ô drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 Ð Ñ Ò Ò Ó Ý ê Öñ × Ü Ò Ý Õ é Ü Û Ô × Ñ Þ á â ã à Elimination: A study of 14 C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the Ü Ò Ý Ü -butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug. Effect of Age: A population pharmacokinetic analysis was carried out after TAXOTERE treatment of 535 patients dosed at 100 mg/m 2 . Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age. Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel. Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with TAXOTERE. Patients with severe hepatic impairment have not been studied à Ð Ñ Ò Òæ Õ Ý × Û × Ö Ñ Õ × Ø è Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ß â Õ × Ø Ñ Ò Û × î ó Ò é Û õ Û é è Ô ó ê í Õ Ü Û Ô × Ñ Þ à â ã Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 to 90 mg/m 2 was similar to that of European/American populations dosed at 100 mg/m 2 , suggesting no significant difference in the elimination of docetaxel in the two populations. Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m² intravenous) alone or docetaxel (10 mg/m² intravenous) in ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 40 of 63 combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administration with ketoconazole Ð Ñ Ò Ò Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â Õ × Ø Ó Ý ê Ö Ó Ý ê Öñ × Ü Ò Ý Õ é Ü Û Ô × Ñ Þ á â ã . Effect of Combination Therapies: Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone. Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone. Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug. Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone. Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug-interactions between docetaxel (75 mg/m²), doxorubicin (50 mg/m²), and cyclophosphamide (500 mg/m²) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy. Carcinogenicity studies with docetaxel have not been performed. Docetaxel was clastogenic in the Û × Û Ü Ý Ô chromosome aberration test in CHO-K1 cells and in the Û × Û Ô micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m 2 basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 41 of 63 Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50 th the recommended human dose on a mg/m 2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 rd and 1/15 th the recommended human dose on a mg/m 2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels. The efficacy and safety of TAXOTERE have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens). Randomized Trials In one randomized trial, patients with a history of prior treatment with an anthracycline- containing regimen were assigned to treatment with TAXOTERE (100 mg/m 2 every 3 weeks) or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks). Two hundred three patients were randomized to TAXOTERE and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the TAXOTERE arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (See Table 13). } ˆ • ‹ š Ç Š ’ € ‚ ˆ ‚ Œ „ } ‘ } ’ “ ’ € † ~ } ‡ ˆ † ‰ † „ À ‡ ˆ † ˆ ‚ ‡ ¾ ˆ † € † ¾ ‡ – € „ — ‹ Œ} ‡ ˆ † ƒ Ž € † ~ ˆ † ~ ‡ ˆ ‚ Œ ‚ ‹ € Š „ † ˆ € € ™ “ ™ € ‰ ³ Ã † † Š † „ Š } ‡ ˆ † ˆ ‹ Œ € ·’ € ‚ ˆ ‚ Œ ¾ ˆ ‡ ˆ ‰ † ‡ „ ‚ † ˆ » ‹³ " ½ › Ç · € † „ ‰ Œ ‚ € œA € • ‹ ˆ † € ³ " š Ê Î · ” Š – ˆ ‹ — Median Survival 11.4 months 8.7 months p=0.01 Log Rank Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.73 0.58-0.93 Median Time to Progression 4.3 months 2.5 months p=0.01 Log Rank Risk Ratio*, Progression (Docetaxel: Control) 0.75 ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 42 of 63 95% CI (Risk Ratio) 0.61-0.94 Overall Response Rate Complete Response Rate 28.1% 3.4% 9.5% 1.6% p<0.0001 Chi Square *For the risk ratio, a value less than 1.00 favors docetaxel. In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with TAXOTERE (100 mg/m 2 ) or doxorubicin (75 mg/m 2 ) every 3 weeks. One hundred sixty-one patients were randomized to TAXOTERE and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below (See Table 14). } ˆ • ‹ š ¿ Š ’ € ‚ ˆ ‚ Œ „ } ‘ } ’ “ ’ € † ~ } ‡ ˆ † ‰ † „ À ‡ ˆ † ˆ ‚ ‡ ¾ ˆ † € † ¾ ‡ – € „ — ‹ Œ} ‡ ˆ † ƒ Ž € † ~ ˆ ‹ ¼ Œ ‹ ˆ † € ™ Š „ † ˆ € € ™ “ ™ € ‰ ³ Ã † † Š † „ Š } ‡ ˆ † ˆ ‹ Œ € ·’ € ‚ ˆ ‚ Œ ¾ ˆ ‡ ˆ ‰ † ‡ „ ‚ † ˆ » ‹³ " š Ì š · „ » „ ‡ — • € ‚ € ³ " š Ì º · ” Š – ˆ ‹ — Median Survival 14.7 months 14.3 months p=0.39 Log Rank Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.89 0.68-1.16 Median Time to Progression 6.5 months 5.3 months p=0.45 Log Rank Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) 0.93 0.71-1.16 Overall Response Rate Complete Response Rate 45.3% 6.8% 29.7% 4.2% p=0.004 Chi Square *For the risk ratio, a value less than 1.00 favors docetaxel. In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive TAXOTERE monotherapy 60 mg/m 2 (n=151), 75 mg/m 2 (n=188) or 100 mg/m 2 (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with TAXOTERE dose: 19.9% for the 60 mg/m 2 group compared to 22.3% for the 75 mg/m 2 and 29.8% for the 100 mg/m 2 group; pair-wise comparison between the 60 mg/m 2 and 100 mg/m 2 groups was statistically significant (p=0.037). ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 43 of 63 Single Arm Studies TAXOTERE at a dose of 100 mg/m 2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response rate was 2.1%. TAXOTERE was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m 2 . A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of TAXOTERE for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either TAXOTERE 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclosphosphamide 500 mg/m 2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. TAXOTERE was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients. (See Figure 1). At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). (See Figure 2). There will be further analysis at the time survival data mature. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 44 of 63 € ™ — ‡ š Š } Ç š Ì € ˆ ‡ ¸ — ‡ – € – ˆ ‹ Q Š ‚ — ‡ – RSTU VWX YXZ[Z \ ]_̀̂ a b c d c e d f g a g b f d f e h f b a b bij ik i l im in io i p iq ir ij i i s t uv t u w xyz{ z|}~ y€ |€{}{ ‚ƒ„ † ‡ ˆ ‰ Š ˆ ‰ ‹ Œ ‰ ‰ Ž ‡ Š ‘ ’ ‡ “ ‰ ” “ • – — ˜ ˆ ™ € ™ — ‡ ½ Š } Ç š Ì ‘ – ‡ ˆ ‹ ‹ ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – š › ›œ › ›ž ›Ÿ › ›¡ ›¢ ›£ › ¤ ¥ ¦§ ¥ ¦¨ © ª « ª ¬ « - ® ¨ ® © - « - ¬ ¯ - © ¨ © ©š ›› ° ± ² ³ ´ ³ µ ¶ · ´ ¸ ¹ º ¸ » ¼ ½ ¾ ¿ À The following table describes the results of subgroup analyses for DFS and OS (See Table 15). ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 45 of 63 } ˆ • ‹ š º Š ¸ — • † ˆ ‹ Œ Š ƒ — – ˆ † À ‡ ˆ † ˆ ‚ ‡ ¸ † — ƒ Œ € ˆ ‡ ¸ — ‡ – € – ˆ ‹ ‘ – ‡ ˆ ‹ ‹ ¸ — ‡ – € – ˆ ‹¾ ˆ † € † — • † ¶ — ‰ • ‡ „ ” ˆ † € † È ˆ Æ ˆ ‡ ƒ‡ ˆ † € „ ! Î º Í Ã È ˆ Æ ˆ ‡ ƒ‡ ˆ † € „ ! Î º Í Ã¶ „ ¹ „ ” „ € † € – „ ƒ Overall 1-3 4+ 744 467 277 0.74 0.64 0.84 (0.60, 0.92) (0.47, 0.87) (0.63, 1.12) 0.69 0.45 0.93 (0.53, 0.90) (0.29, 0.70) (0.66, 1.32) “ ‚ ” † „ ‡ † ˆ † — Positive Negative 566 178 0.76 0.68 (0.59, 0.98) (0.48, 0.97) 0.69 0.66 (0.48, 0.99) (0.44, 0.98) Á a hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC. The efficacy and safety of TAXOTERE has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve. Monotherapy with TAXOTERE for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a TAXOTERE dose of 75 mg/m 2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). TAXOTERE at a dose of 100 mg/m 2 , however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used Ð Ñ Ò Ò ä Ô å Ò Ø æ Õ Ý × Û × Ö ç Ó Ô Ñ Õ Ö Ò Õ × Ø Ù Ø Ú Û × Û Ñ Ü Ý Õ Ü Û Ô × Þ ß à á â ç æ Õ Ý × Û × Ö Ñ Õ × Øè Ý Ò é Õ ê Ü Û Ô × Ñ Þ ë à ú â ã à One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status 2 to TAXOTERE or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to TAXOTERE 100 mg/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to TAXOTERE 75 mg/m 2 . A total of 104 patients were randomized in this amended study to either TAXOTERE 75 mg/m 2 or best supportive care. In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non- small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status 2 were randomized to TAXOTERE 75 mg/m 2 , TAXOTERE 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 46 of 63 survival in both trials. The efficacy data for the TAXOTERE 75 mg/m 2 arm and the comparator arms are summarized in Table 16 and Figures 3 and 4 showing the survival curves for the two studies. } ˆ • ‹ š Ì Š ’ € ‚ ˆ ‚ Œ „ } ‘ } ’ “ ’ € † ~ } ‡ ˆ † ‰ † „ ¶ „ Š ¸ ‰ ˆ ‹ ‹ ‹ ‹ µ — ™ ˆ ‚ ‡¾ ˆ † € † ¾ ‡ – € „ — ‹ Œ } ‡ ˆ † ƒ Ž € † ~ ˆ ¾ ‹ ˆ † € — ‰ Š À ˆ ƒ ~ ‰ „ † ~ ‡ ˆ ” Œ “ ™ € ‰ ³ Ã † † Š † „ Š } ‡ ˆ † ˆ ‹ Œ € ·} Ç š $ } Ç ½ › „ ‚ † ˆ » ‹$ º ‰ ™ œ ‰ Q " º º À †¸ — ” ” „ ‡ † € – ˆ ‡ " ¿ Î „ ‚ † ˆ » ‹$ º ‰ ™ œ ‰ Q " š ½ º „ † ‡ „ ‹³ A œ Ã ! · " š ½ Ç Overall Survival Log-rank Test p=0.01 p=0.13 Risk Ratio †† , Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.56 (0.35, 0.88) 0.82 (0.63, 1.06) Median Survival 95% CI 7.5 months** (5.5, 12.8) 4.6 months (3.7, 6.1) 5.7 months (5.1, 7.1) 5.6 months (4.4, 7.9) % 1-year Survival 95% CI 37%** † (24, 50) 12% (2, 23) 30%** † (22, 39) 20% (13, 27) Time to Progression 95% CI 12.3 weeks** (9.0, 18.3) 7.0 weeks (6.0, 9.3) 8.3 weeks (7.0, 11.7) 7.6 weeks (6.7, 10.1) Response Rate 95% CI 5.5% (1.1, 15.1) Not Applicable 5.7% (2.3, 11.3) 0.8% (0.0, 4.5) * Vinorelbine/Ifosfamide ** p 0.05; † uncorrected for multiple comparisons; †† a value less than 1.00 favors docetaxel. Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored TAXOTERE 75 mg/m 2 . ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 47 of 63 € ™ — ‡ Ç Š } Ç š $ ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – Š } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q – ¹ À † ¸ — ” ” „ ‡ † € – ˆ ‡ € ™ — ‡ ¿ Š } Ç ½ › ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – Š } ‘ } ’ “ ’ $ º ‰ ™ œ ‰ Q – ¹ A € „ ‡ ‹ • € „ ‡Ã „ ˆ ‰ € ƒ „ † ‡ „ ‹ Patients treated with TAXOTERE at a dose of 75 mg/m 2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 48 of 63 Combination Therapy with TAXOTERE for Chemotherapy-Naïve NSCLC In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: TAXOTERE 75 mg/m 2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2 administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 administered on day 1 of cycles repeated every 4 weeks; or a combination of TAXOTERE and carboplatin. The primary efficacy endpoint was overall survival. Treatment with TAXOTERE+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of TAXOTERE to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the TAXOTERE+cisplatin arm and the comparator arm are summarized in Table 17. } ˆ • ‹ š $ Š ¸ — ‡ – € – ˆ ‹ ˆ ‹ Œ € „ } ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ } ~ ‡ ˆ ” Œ „ ‡ ~ ‰ „ † ~ ‡ ˆ ” Œ Š¶ ˆ J – ¶ ¸ µ Comparison Taxotere+Cisplatin n=408 Vinorelbine+Cisplatin n=405 Kaplan-Meier Estimate of Median Survival 10.9 months 10.0 months p-value a 0.122 Estimated Hazard Ratio b 0.88 Adjusted 95% CI c (0.74, 1.06) a From the superiority test (stratified log rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin bHazard ratio of TAXOTERE+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that TAXOTERE+cisplatin is associated with a longer survival. cAdjusted for interim analysis and multiple comparisons. The second comparison in the same three-arm study, vinorelbine+cisplatin versus TAXOTERE+carboplatin, did not demonstrate superior survival associated with the TAXOTERE arm (Kaplan-Meier estimate of median survival was 9.1 months for TAXOTERE+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the TAXOTERE+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between TAXOTERE+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 18). ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 49 of 63 } ˆ • ‹ š Ê Š “ ” „ ˆ ƒ } } ¾ ˆ ‹ Œ € „ } ‘ } ’ “ ’ € „ ‰ • € ˆ † € „ } ~ ‡ ˆ ” Œ „ ‡ ~ ‰ „ † ~ ‡ ˆ ” Œ Š ¶ ˆ J – ¶ ¸ µ Endpoint TAXOTERE+Cisplatin Vinorelbine+Cisplatin p-value Objective Response Rate (95% CI) a 31.6% (26.5%, 36.8%) 24.4% (19.8%, 29.2%) Not Significant Median Time to Progression b (95% CI) a 21.4 weeks (19.3, 24.6) 22.1 weeks (18.1, 25.6) Not Significant aAdjusted for multiple comparisons. bKaplan-Meier estimates. The safety and efficacy of TAXOTERE in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) 60 were randomized to the following treatment groups: TAXOTERE 75 mg/m 2 every 3 weeks for 10 cycles. TAXOTERE 30 mg/m 2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles. Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the TAXOTERE every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the TAXOTERE weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the TAXOTERE every 3 week arm versus the control arm are summarized in Table 19 and Figure 5. } ˆ • ‹ š Î Š ’ € ‚ ˆ ‚ Œ „ } ‘ } ’ “ ’ € † ~ } ‡ ˆ † ‰ † „ ¾ ˆ † € † Ž € † ~ ƒ ‡ „ ™ Ã ƒ ” ƒ † ³ È „ ‡ ‰ „ “ ‡ ˆ ‚ † „ ‡ Œ · † ˆ † ˆ † € ‚ ¾ ‡ „ † ˆ † ˆ ‚ ‡ ³ Ã † † Š † „ Š } ‡ ˆ † ˆ ‹ Œ € ·} ‘ } ’ “ ’ @ ¾ ‡ ƒ € „ – ‡ Œ Ç Ž ¼ € † „ » ˆ † ‡ „ @ ¾ ‡ ƒ € „ – ‡ Œ Ç Ž ¼ Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value* 335 18.9 (17.0-21.2) 0.761 (0.619-0.936) 0.0094 337 16.5 (14.4-18.6) -- -- -- *Stratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 50 of 63 € ™ — ‡ º Š } Ç ½ $ ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – Â Ã ÄÄ Ã ÅÄ Ã ÆÄ Ã ÇÄ Ã ÈÄ Ã ÉÄ Ã ÊÄ Ã ËÄ Ã ÌÍÎÏÐÑÐÒÓÔÏÕ ÖÒÖÑÓÑ×Ø Ù Ç É Ú Ë ÛÜ Ú Ë ÛÄ Ë È Å Â Ì Â É Â Æ Ì Â Ì Ê Ì Ç Ë ÄÄ Ã ÂÄ Ã Ä Ý Þ ß à á à â ã Ù á Ü ä å Ü æ ç Ù è Ý é A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of TAXOTERE for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either TAXOTERE (T) (75 mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and fluorouracil (F) (750 mg/m 2 per day for 5 days) or cisplatin (100 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19-1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04-1.61). Efficacy results are summarized in Table 20 and Figures 6 and 7. ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 51 of 63 } ˆ • ‹ ½ › Š ’ € ‚ ˆ ‚ Œ „ } ‘ } ’ “ ’ € † ~ † ‡ ˆ † ‰ † „ ” ˆ † € † Ž € † ~ ™ ˆ † ‡ € ‚ˆ ƒ „ ‚ ˆ ‡ ‚ € „ ‰ ˆ’ ƒ ” „ € † } " ½ ½ š " ½ ½ ¿ Median TTP (months) (95%CI) Hazard ratio † (95%CI) *p-value 5.6 (4.86-5.91) 3.7 (3.45-4.47) 0.68 (0.55-0.84) 0.0004 Median survival (months) (95%CI) Hazard ratio † (95%CI) *p-value 9.2 (8.38-10.58) 8.6 (7.16-9.46) 0.77 (0.62-0.96) 0.0201 Overall Response Rate (CR+PR) (%) 36.7 25.4 p-value 0.0106 *Unstratified log-rank test †For the hazard ratio (TCF/CF), values less than 1.00 favor the TAXOTERE arm. Subgroup analyses were consistent with the overall results across age, gender and race. € ™ — ‡ Ì Š # ˆ † ‡ € ‚ ˆ ‚ ‡ ¸ † — ƒ Œ ³ } Ç ½ º · } € ‰ † „ ¾ ‡ „ ™ ‡ € „ Q Š — ‡ – ê ë ëì ëí ëî ëï ðñò óòôõôö ÷øùú û ëü ëý ëþ ëÿ ëê ëë ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 52 of 63 € ™ — ‡ $ Š # ˆ † ‡ € ‚ ˆ ‚ ‡ ¸ † — ƒ Œ ³ } Ç ½ º · ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – ! "# $% & ' '( ') '* '+ ', '- '. '/ '& '' 0 1 21 23 4 5 6 7 8 7 9 7 : 8 7 8 ; 8 < 4 3 4 4 4 5= > ? @ A @ B C D A E F G E H I J K L M Induction chemotherapy followed by radiotherapy (TAX323) The safety and efficacy of TAXOTERE in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the TAXOTERE arm received TAXOTERE (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 on Day 1, followed by fluorouracil (F) 750 mg/m 2 per day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m 2 on Day 1, followed by fluorouracil (F) 1000 mg/m 2 /day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy-2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 53 of 63 with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 21 and Figures 8 and 9. } ˆ • ‹ ½ š Š ’ € ‚ ˆ ‚ Œ „ } ‘ } ’ “ ’ € † ~ € ƒ — ‚ † € „ † ‡ ˆ † ‰ † „ ” ˆ † € † Ž € † ~ € „ ” ‡ ˆ • ‹ ‹ „ ‚ ˆ ‹ ‹ Œ ˆ ƒ – ˆ ‚ ƒ ¸ È ¶ ³ Ã † † Š † „ Š } ‡ ˆ † ˆ ‹ Œ € ·’ ¶ ¾ ‘ Ã ¶ } } ‘ } ’ “ ’ @ € ” ‹ ˆ † € @ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ " š $ $ € ” ‹ ˆ † € @ ‹ — „ ‡ „ — ‡ ˆ ‚ € ‹ " š Ê š Median progression free survival (months) (95%CI) Adjusted Hazard ratio (95%CI) *p-value 11.4 (10.1-14.0) 8.3 (7.4-9.1) 0.71 (0.56-0.91) 0.0077 Median survival (months) (95%CI) Hazard ratio (95%CI) **p-value 18.6 (15.7-24.0) 14.2 (11.5-18.7) 0.71 (0.56-0.90) 0.0055 Best overall response (CR + PR) to chemotherapy (%) (95%CI) ***p-value 67.8 (60.4-74.6) 53.6 (46.0-61.0) 0.006 Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] (%) (95%CI) ***p-value 72.3 (65.1-78.8) 58.6 (51.0-65.8) 0.006 A Hazard ratio of less than 1 favors TAXOTERE+Cisplatin+Fluorouracil * Stratified log-rank test based on primary tumor site ** Stratified log-rank test, not adjusted for multiple comparisons *** Chi square test, not adjusted for multiple comparisons ` a b a c a d e a f g h i i i j i k j Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 54 of 63 € ™ — ‡ Ê Š } Ç ½ Ç ¾ ‡ „ ™ ‡ € „ Š ‡ ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – N O OP OQ O RST R UVW XWYZY[ \]̂_ ` Oa Ob Oc Od Oe O f g hN O g hO i j k l k m l n o i o j n lg p q r p s t t u q v h p s s w x p y u y z { f u | s } | q v ~ t € € ™ — ‡ Î Š } Ç ½ Ç ‘ – ‡ ˆ ‹ ‹ ¸ — ‡ – € – ˆ ‹ Q Š — ‡ – ‚ ‚ƒ ‚„ ‚ † ‡† ‡ˆ ‰ Š ‹ Š Œ ‹ Ž ˆ Ž ‰ ‹ Œ ‰ ˆ ‰ ‰ ‹‘ ’“ ”• ”–—˜ “™š –š•—•› œžŸ ‚¡ ‚¢ ‚£ ‚¤ ‚¥ ‚ ‚‚ ¦ § ¨ © ª © « ¬ ª - ® ¯ - ° ± ² ³ ´ µ Induction chemotherapy followed by chemoradiotherapy (TAX324) The safety and efficacy of TAXOTERE in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the TAXOTERE arm received TAXOTERE (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. ¶ · ¸ · ¹ · º » · ¼ ½ ¾ ¿ ¿ ¿ À ¿ Á À Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 55 of 63 All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the TAXOTERE-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 - 0.90]. Overall survival results are presented in Table 22 and Figure 10. Â Ã Ä Å Æ Ç Ç È É Ê Ê Ë Ì Ã Ì Í Î Ê Â Ï Ð Ñ Â É Ò É Ë Ó Ô Õ Æ Ë Ó Ö × Ì Ô Ë Î Ó Ô Ø Æ Ã Ô Ù Æ Ó Ô Î Ê Ú Ã Ô Ë Æ Ó Ô Û Ü Ë Ô Õ Å Î Ì Ã Å Å ÍÃ Ö Ý Ã Ó Ì Æ Ö Þ ß ß à á â ã Ó Ô Æ Ó Ô È Ô Î È Â Ø Æ Ã Ô Ï Ó Ã Å Í Û Ë Û äÉ á å æ Ñ ã á Â Â Ï Ð Ñ Â É Ò É çß Ë Û Ú Å Ã Ô Ë Ó ç è Å × Î Ø Î × Ø Ã Ì Ë ÅÓ é Ç ê ê ß Ë Û Ú Å Ã Ô Ë Ó çè Å × Î Ø Î × Ø Ã Ì Ë ÅÓ é Ç ë ì Median overall survival (months) (95% CI) 70.6 (49.0-NE) 30.1 (20.9-51.5) Hazard ratio: (95% CI) *p-value 0.70 (0.54-0.90) 0.0058 A Hazard ratio of less than 1 favors TAXOTERE+cisplatin+fluorouracil * un-adjusted log-rank test NE - not estimable ¶ · ¸ · ¹ · º » · ¼ ½ ¾ ¿ ¿ ¿ À ¿ Á À Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 56 of 63 è Ë í × Ø Æ î ï È Â Ï Ð ð Ç ë Ñ Ý Æ Ø Ã Å Å Þ × Ø Ý Ë Ý Ã Å ñ È ò ß × Ø Ý Æó ô ô õ ö÷øù øúûü ÷ýþ úþùûùÿ ô ô ô ô ô ô ô ôó ôô ! " # $ # % & ' ( ) * + , - . / 0 1 2 3 4 - 5 3 6 2 3 . 4 6 78 9 : ; ó ó ó ó ó ô ô ó ó9 : ; ó ó ó ô ó ô ó ô 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. < = > ? @ A B C D E F G H C I D A J = K 2006;63:1172-1193 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. ¶ · ¸ · ¹ · º » · ¼ ½ ¾ ¿ ¿ ¿ À ¿ Á À Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 57 of 63 Two vial formulation (Injection Concentrate and Diluent) TAXOTERE Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, Diluent (13% ethanol in water for injection) vial. L M N O L P Q P R S T U V W T X Y Z [ \ S S ] ^ _ R S S ` _ R S a TAXOTERE (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 2 mL polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in water for injection). Both items are in a blister pack in one carton. L M N O L P Q P W S T U V S b ^ T X Y Z [ \ S S ] ^ _ R S S ` _ W S a TAXOTERE (docetaxel) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel in 0.5 mL polysorbate 80 and Diluent for TAXOTERE 20 mg (13% (w/w) ethanol in water for injection). Both items are in a blister pack in one carton. Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to protect from bright light. Freezing does not adversely affect the product. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published c H @ @ d @ e @ J @ f g @ H h i j k l . F @ @ m n < E < o o J p q @ r I A C s @ f C t A u @ B s f v • TAXOTERE may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives if receiving TAXOTERE c H @ @ w A J f s f v H A f r I J @ g A x C s p f H h j K i y k A f r z H @ s f F o @ g s e s gI p o x B A C s p f H h { K i k l K • Obtain detailed allergy and concomitant drug information from the patient prior to TAXOTERE administration. • Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen. • Instruct patients to immediately report signs of a hypersensitivity reaction. • Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea. • Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever. ¶ · ¸ · ¹ · º » · ¼ ½ ¾ ¿ ¿ ¿ À ¿ Á À Case 2:16-cv-02250-CM-KGG Document 7-1 Filed 07/25/16 Page 58 of 63 • Instruct patients to report myalgia, cutaneous, or neurologic reactions. • Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss are associated with docetaxel administration. 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