DEFENDANTS' MOTION AND SUPPORTING MEMORANDUM FOR JUDGMENT AS A MATTER OF LAW PURSUANT TO FEDERAL RULE OF CIVIL PROCEDURE 50(a)

This Document Relates to:

Mitchell v. AbbVie, Case No. 1:14-cv-09178.

MATTHEW F. KENNELLY, District Judge.

The Court should enter judgment for Defendants AbbVie Inc. and Abbott Laboratories (collectively, "AbbVie") because no reasonable jury could find for Plaintiff on his three claims. See Fed. R. Civ. P. 50(a). First, all three fail because Plaintiff's causation expert, Dr. Ardehali, conceded that Plaintiff had numerous risk factors that completely explained his heart attack. Second, his strict liability and negligence warning claims fail because he did not demonstrate the "reasonable evidence of a causal association" required to add a warning without prior Food and Drug Administration (FDA) approval; he did not prove that it was unreasonable not to include additional cardiovascular (CV) warnings; and his prescriber, Dr. Canzler, expressly warned him of potential CV risk. Third, the strict liability claim fails because Plaintiff did not introduce evidence of consumer expectations. Fourth, Plaintiff's misrepresentation claim fails because he did not prove any false statements, let alone any reliance; the claim rests on inherently contradictory testimony; and Plaintiff admitted that he did not rely on any AbbVie ads in deciding to use AndroGel, while Dr. Canzler admitted that he independently assessed the benefits and risks of AndroGel and relied solely on his medical judgment and experience in making his prescribing decision and continues to prescribe AndroGel today even after Plaintiff's heart attack and reports of potential CV risks in 2014. Finally, the Court should strike Plaintiff's punitive damages request due to the absence of any nexus between Plaintiff's AndroGel treatment and the supposed punitive conduct identified by Plaintiff's counsel.

ARGUMENT

I. PLAINTIFF DID NOT OFFER SUFFICIENT EVIDENCE THAT ANDROGEL WAS A BUT-FOR CAUSE OF HIS HEART ATTACK

Each of Plaintiff's claims required him to prove that AbbVie caused his heart attack. Tr. 152:13-19, attached hereto as Exhibit A. To satisfy this burden under Oregon law, Plaintiff had to demonstrate that the heart attack "would not have occurred but for AbbVie's conduct." Ex. A at 152:18-19; see Joshi v. Providence Health Sys. of Or. Corp., 149 P.3d 1164, 1169 (Or. 2006). Dr. Ardehali therefore needed to rule out the possibility of Plaintiff having the heart attack without AndroGel. Ex. A at 152:20-22; Joshi, 149 P.3d at 1169 ("[T]he defendant's conduct is not a cause of the event, if the event would have occurred without it.").

Dr. Ardehali's opinion did not meet this standard. To the contrary, Dr. Ardehali conceded that Plaintiff suffered from many risk factors that alone sufficed to cause his heart attack. Ex. A at 1445:7-1447:3, 1449:21-1450:9, 1451:6-1453:4, 1454:9-14. At the time of his heart attack, Plaintiff undisputedly had several cardiac risk factors, including a 34-year history of smoking, hypertension, hyperlipidemia, obesity, a family history of heart disease, and lack of exercise. Ex. A at 1449:21-1450:9, 1451:6-1453:4. Dr. Ardehali agreed that without AndroGel, Plaintiff's risk factors gave him a 15-18% 10-year risk estimate for having a heart attack—at least double what Dr. Ardehali considers "high risk." Ex. A at 1463:15-19, 1469:1-12.

Significantly, Dr. Ardehali would have told Plaintiff between 2010 and 2012 that he was at risk of a heart attack "any day" due to those factors. Ex. A at 1459:1-11, 1459:24-1460:2. Dr. Ardehali further admitted that there was nothing unusual about Plaintiff's heart attack in his hospital records to suggest a cause besides his risk factors; to the contrary, those records identified the same cardiac risk factors. Ex. A at 1460:24-1462:9. Plaintiff therefore failed to satisfy the requirement under Oregon law of demonstrating that he would have avoided his heart attack had he not used AndroGel. Because Plaintiff produced insufficient evidence on the core causation element, the Court should enter judgment for AbbVie on all claims.

II. PLAINTIFF DID NOT OFFER SUFFICIENT EVIDENCE OF INADEQUATE WARNINGS TO SUPPORT STRICT LIABILITY AND NEGLIGENCE

Plaintiff's strict liability and negligence claims fail for the independent reason that AndroGel's labeling included adequate warnings, as measured by the "scientific knowledge that was reasonably available at the time" of Plaintiff's prescription. Ex. A at 149:7-17, 150:19— 151:5; see McEwen v. Ortho Pharm. Corp., 528 P.2d 522, 528-29 (Or. 1974).

Plaintiff's claims in this case "are not claims for violation of FDA regulations." Ex. A at 153:25-154:1. Rather, Plaintiff's strict liability and negligence claims required him to prove that AbbVie gave unreasonable warnings for purposes of Oregon law. See Ex. A at 149:7-9, 150:20-22. Plaintiff had to establish that reasonable evidence of a causal association existed before Plaintiff's heart attack and that AbbVie unreasonably did not provide additional CV warnings based on the state of science at the time Plaintiff used AndroGel.

Plaintiff failed to offer this proof. First, Plaintiff did not show that AbbVie lawfully could have added CV warnings. To satisfy this requirement, Plaintiff had to meet the FDA standard prohibiting additional warnings absent "reasonable evidence of a causal association." 21 C.F.R. § 201.57(c)(6)(i). AbbVie could only use the "changes being effected" (CBE) process to bypass prior FDA approval and add "newly acquired" safety information if it established such reasonable evidence of a causal association. See 21 C.F.R. § 314.70(c)(6)(iii). Under FDA Guidance, an adverse event "safety signal," standing alone, does not meet this standard. See Ex. 3094.7; see also Matrixx Initiatives, Inc. v. Siracusano, 563 U.S. 27, 44 (2011) ("[T]he mere existence of reports of adverse events . . . says nothing in and of itself about whether the drug is causing the adverse events[.]"). Nor was there even a "safety signal" under FDA Guidance given Dr. Ardehali's admission that the heart attack incidence rate did not exceed the background rate. Ex. A at 1507:9-15. Without meeting this standard, federal law preempts Plaintiff's state-law warning claims. See Utts v. Bristol-Myers Co., 251 F.Supp.3d 644, 661 (S.D.N.Y. 2017) (to avoid preemption, "the plaintiff must show that there existed `newly acquired information' such that the defendants could unilaterally change the label pursuant to the CBE regulation without FDA approval"). No reasonable jury could conclude that Plaintiff met his burden where the FDA itself, even today, has found no reasonable evidence of a causal association based on the same evidence that Plaintiff now points to.

Second, Plaintiff failed to demonstrate that AbbVie gave unreasonable warnings under Oregon law. None of Plaintiff's experts offered such an opinion, and without this proof, the jury cannot reasonably find the AndroGel warnings inadequate for purposes of the warning claims.

Third, Plaintiff's warning claims fail because his prescribing physician expressly warned him about a potential heart attack risk, and still prescribes AndroGel today, even after Plaintiff's heart attack and reports of possible CV risk in 2014.

A. Plaintiff Failed to Demonstrate Reasonable Evidence of a Causal Association

1. Dr. Ardehali's Flawed Adverse Event Analysis Was Insufficient to Establish Reasonable Evidence of a Causal Association in 2007

Dr. Ardehali testified that adverse event reports, one small clinical trial, and one metaanalysis that reported non-statistically significant imbalances in CV events provided "reasonable evidence of a causal association" as of 2007. Ex. A at 1373:22-1374:1, 1384:22-1385:15. However, Dr. Ardehali simply disagreed with the FDA's findings to the contrary; he did not provide a sufficient factual basis for the FDA to have permitted or required a labeling change prior to Plaintiff's AndroGel use. Ex. A at 1372:9-18, 1492:16-19, 1516:20-24. Dr. Ardehali received the adverse event reports from counsel and did not independently review AbbVie's adverse event database, let alone assess such reports in context of the number of AndroGel users and/or the incidence of heart attacks in the general population. Ex. A at 1499:14-1500:12. He also acknowledged that the adverse event reports went to the FDA. Ex. A at 1496:17-1497:1.

Dr. Ardehali conceded that the FDA has never, even today, found reasonable evidence of a causal association based on these reports. Ex. A at 1521:18-20. And Dr. Pence agreed that "the FDA never thought there should be a warning [about CV risk] prior to 2015." Ex. A at 1890:6-24. Both experts likewise acknowledged that the FDA expressly found in a 2010 review that the studies "do not support an association between [testosterone replacement therapy (TRT)] and an increased risk of cardiovascular events in men." Ex. A at 1516:5-8, 1894:18-1895:1. In addition, Dr. Pence conceded that, in 2010, the FDA reviewed a number of studies and found that "one cannot make the conclusion based on these studies that testosterone therapy increases the risk of cardiovascular disease." Ex. A at 1896:23-1897:2. Moreover, Plaintiff's experts agreed that "the FDA never mandated a warning or mandated additional testing prior to and through the time Mr. Mitchell had a heart attack." Ex. A at 1516:9-19, 1901:18-21.

Dr. Pence also acknowledged that "the FDA would not draw conclusions about drug event causality from post-marketing spontaneous reports for CV events with testosterone use." Ex. A at 1882:25-1883:4; Ex. 3258.65. And Dr. Ardehali conceded that even by 2014—two years after Plaintiff's heart attack—the FDA Advisory Committee did not find reasonable evidence of a causal association. Ex. A at 1517:23-1520:6. The mere "weak signal for possible risk" identified then does not suffice as a matter of law to permit a label change. See Ex. 3094.7; Utts, 251 F. Supp. 3d at 670 (holding state-law claims preempted despite FDA identifying "a potential signal of a `serious risk/new safety information' based on adverse event reports). Thus, the adverse event reports through 2007 and two studies relied on by Dr. Ardehali do not constitute the "reasonable evidence of a causal association" necessary to avoid preemption.

2. The Basaria Study Was Not Reasonable Evidence of a Causal Association

The 2010 Basaria study also does not provide reasonable evidence of a causal association to support a label change. No expert offered a contrary opinion. Dr. Ardehali and Dr. Pence both conceded that the FDA did not find reasonable evidence of a causal association after reviewing this study. Ex. A at 1515:4-1516:12, 1896:2-1897:11. Moreover, the FDA undisputedly found limitations with the Basaria study. Ex. A at 1519:15-20. Given these concessions, the Basaria study could not have required or permitted an additional warning.1

B. Plaintiff Did Not Prove Inadequate Warnings Under State Law

Plaintiff also has not presented evidence that AbbVie's CV warning was unreasonable as a matter of Oregon law. See Ex. A at 1878:23-25 (Dr. Pence opining that AbbVie should have added a warning by 2007 merely "because there was reasonable evidence of a causal association" with CV events). A claim that AbbVie did not comply with the FDA regulation requiring reasonable evidence of a causal association to change the label does not mean that the warnings were unreasonable as a matter of state law. Indeed, Plaintiff (and this Court) have expressly rejected the suggestion that his state-law claims are really an impermissible attempt to privately enforce the Food, Drug, and Cosmetic Act, which contains no private right of action. Ex. A at 153:25-154:1; see Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 349 n.4 (2001). Given the absence of any proof that AbbVie failed to satisfy Oregon's state-law standard, the Court should enter judgment for AbbVie on Plaintiff's warning claims.

C. Plaintiff's Warning Claims Also Fail Because His Prescribing Physician Expressly Warned Him of a Potential Heart Attack Risk

Plaintiff's physician, Dr. Canzler, gave a "standard warning and clarification" to Plaintiff and other hypogonadal patients before prescribing AndroGel. Ex. A at 1736:10-23. Dr. Canzler "specifically told them that there were risks for heart attacks." Ex. A at 1736:17-18. Moreover, when asked about potential risks that he discussed with Plaintiff, Dr. Canzler confirmed, "I know we spoke of heart problems." Ex. A at 1744:15-16. Thus, Dr. Canzler knew and appreciated the potential risks, and expressly warned Plaintiff. Furthermore, Dr. Canzler prescribed AndroGel based on his independent medical judgment, not anything that AbbVie said. Ex. A at 1761:22-25, 1764:22-1765:3. An additional warning therefore would not have changed Dr. Canzler's prescribing decision. Indeed, he specifically testified that he exercised his medical judgment to determine that the benefits outweighed the risks for Plaintiff and that he still prescribes AndroGel today, even after Plaintiff's heart attack and reports of possible CV risk in 2014. Ex. A at 1725:8-11, 21-25, 1735:19-20, 1744:10-1745:1, 1745:15-18. Dr. Canzler's express warning and his reliance on his own medical judgment both sever any causal link between the allegedly inadequate warning and Plaintiff's injury. See Vaughn v. G.D. Searle & Co., 536 P.2d 1247, 1250-51 (Or. 1975) (en banc). Thus, the jury could not reasonably find a failure to warn that caused Plaintiff's injury.

III. PLAINTIFF'S STRICT LIABILITY CLAIM ALSO FAILS BECAUSE HE DID NOT PRODUCE EVIDENCE THAT ANDROGEL WAS DEFECTIVE OR UNREASONABLY DANGEROUS

Plaintiff's strict liability claim required proof that AndroGel was "in a defective condition that was unreasonably dangerous." Ex. A at 148:18-19. In addition to the foregoing failures of proof on causation and the inadequacy of warnings, this claim fails because Plaintiff has not satisfied this standard. He presented no evidence of any design defect, relying exclusively on an alleged warnings defect. However, Plaintiff cannot establish any such defect because he has not produced evidence that "is sufficient for the jury to make an informed decision about what ordinary consumers expect[ed]" with respect to AndroGel. McCathern v. Toyota Motor Corp., 23 P.3d 320, 331 (Or. 2001). Plaintiff's own expectations would not meet this standard, but if they did, Plaintiff offered no evidence as to those expectations. Indeed, he conceded that he knew nothing about AndroGel before Dr. Canzler prescribed it for him. Ex. A at 1693:16-18. Moreover, to the extent that this standard considers Dr. Canzler's expectations, the evidence shows that Dr. Canzler believed, at the time he initially prescribed AndroGel to Plaintiff, that AndroGel was a safe product for him to use. Ex. A at 1745:15-18. To this day, Dr. Canzler still believes that AndroGel is a good medication, Ex. A at 1740:8-10, and his patients have done well on AndroGel over time and have reported quick improvements in their symptoms after using AndroGel, Ex. A at 1734:10-1735:5. Moreover, Dr. Canzler testified that he has not had any reports from patients of adverse events experienced on TRT, and he still prescribes AndroGel today. Ex. A at 1735:16-20.

IV. THE MISREPRESENTATION CLAIM FAILS BECAUSE THERE IS NO CLEAR AND CONVINCING EVIDENCE THAT PLAINTIFF OR HIS PRESCRIBING PHYSICIAN SAW OR RELIED ON ANY FALSE REPRESENTATION

Plaintiff had to prove each element of his fraudulent misrepresentation claim by "clear and convincing evidence." Ex. A at 151:16-19. He failed to do so because (i) he did not demonstrate any false representation, (ii) his marketing expert, Dr. Kessler, rested his opinion on FDA regulations but offered no opinion that AbbVie violated any of those regulations, and (iii) Plaintiff did not show that he or his prescriber saw or relied on any false representation.

A. No Reasonable Jury Could Find that AbbVie Made a False Representation

Plaintiff had to prove by clear and convincing evidence that AbbVie made a "material misrepresentation that was false." Strawn v. Farmers Ins. Co. of Or., 258 P.3d 1199, 1209 (Or. 2011) (emphasis added); see Oksenholt v. Lederle Labs., 656 P.2d 293, 299 (Or. 1982) ("Misrepresentation requires a false representation[.]"); Ex. A at 151:20-21 (instructing that Plaintiff's misrepresentation claim required clear and convincing proof of a "false representation regarding a material matter"). As these cases demonstrate, Oregon law imposes a "falsity" standard; allegations of "misleading" or "confusing" statements do not suffice.

Dr. Kessler's opinion fails to satisfy this "falsity" standard. While he purported to offer a general opinion that the marketing and promotion of AndroGel was "false and misleading," Ex. A at 797:20-798:11, he did not identify a single "false" statement in any AndroGel ad, let alone an ad that Plaintiff or his doctor saw. To the contrary, Dr. Kessler expressly conceded that the FDA has never found any AndroGel ads that ran, whether branded or unbranded, to be false or misleading, despite having reviewed and commented upon several of these ads "frame by frame," "line by line." Ex. A at 878:19-879:4; 834:9-10, 17-19; 836:12-25; 843:25-844:3. He also identified no instance where the FDA told AbbVie that it was marketing off-label or "overpromoting." Ex. A at 872:9-874:2. Plaintiff has presented no claim or evidence that AbbVie failed to follow any specific FDA directive to change or discontinue its ads.

Plaintiff cannot save this claim by arguing that the FDA did not act due to a lack of jurisdiction to review unbranded ads. Indeed, while Dr. Kessler asserted that AndroGel's unbranded ads improperly implied benefits and were improperly linked to branded ads, he conceded that the FDA has jurisdiction over unbranded ads that imply benefits or are so linked. Ex. A at 864:24-865:15. Thus, by Dr. Kessler's own testimony, the FDA had jurisdiction to review these unbranded ads if they did in fact improperly imply benefits or link to branded ads, and its inaction with respect to them is telling. Further, although Dr. Kessler claimed that unbranded ads were improper because they discussed signs and symptoms of low testosterone without FDA approval, he conceded that branded, FDA-approved ads also discussed signs and symptoms of lower testosterone. Ex. A at 846:10-20. He also conceded that these same signs and symptoms were listed in the AndroGel 1% label until 2015. Ex. A at 860:8-12, 977:6-9.

Nor has Plaintiff produced sufficient evidence of fraud based on his new theory that AbbVie fraudulently concealed AndroGel's lack of demonstrated safety and efficacy outside its indication.2 This concealment theory requires proof of "active concealment," as distinct from a "simple nondisclosure." Paul v. Kelley, 599 P.2d 1236, 1238 (Or. Ct. App. 1979); see In re Conduct of Brown, 956 P.2d 188, 196 (Or. 1998). Yet Plaintiff pointed to no affirmative conduct by AbbVie to actively conceal any lack of safety or efficacy outside the indication.

In the absence of such active concealment, Plaintiff could only establish fraud based on nondisclosure if AbbVie possessed an affirmative "duty to disclose." State Const. Corp. v. Scoggins, 485 P.2d 391, 393 (Or. 1971) (en banc) ("A failure to disclose facts . . . amounts to fraud only where there is a duty to disclose."); Gebrayel v. Transamerica Title Ins. Co., 888 P.2d 83, 89 (Or. Ct. App. 1995) ("For non-disclosure to form the basis of a fraud claim, defendant must be under a duty to disclose."). But AbbVie bore no such duty to disclose any lack of demonstrated safety and efficacy outside AndroGel's FDA-approved indication.

To recognize an affirmative duty to disclose under these circumstances would turn standard market transactions on their head. See Paulsell v. Cohen, No. CIV-00-1175-ST, 2002 WL 31496397, at *24 (D. Or. May 22, 2002) ("[P]arties to an impersonal market transaction owe no duty of disclosure to one another absent a fiduciary or agency relationship, prior dealings, or circumstances such that one party has placed trust and confidence in the other." (quoting Paracor Fin., Inc. v. Gen. Elec. Capital Corp., 96 F.3d 1151, 1157 (9th Cir. 1996))); see also, e.g., Gebrayel, 888 P.2d at 89 (absent special circumstances, "a duty to disclose cannot be imposed"); Salvas v. McEuen, 704 P.2d 1166, 1168 (Or. Ct. App. 1985) (property sellers generally have no duty to disclose that land is not suitable for the buyer's intended purpose).

Moreover, Plaintiff cannot support a concealment claim given that he and his prescriber both received the AndroGel labeling, setting forth the indication for which the FDA had approved AndroGel as safe and effective, as well as the relevant scientific data. Ex. 640i; see Salvas, 704 P.2d at 1168 (rejecting claim of fraud based on nondisclosure where plaintiff had "an adequate opportunity" to discover the undisclosed fact himself); Paulsell, 2002 WL 31496397, at *26 (same with respect to counterclaim). As Dr. Kessler conceded, prescribing physicians would receive the labeling, which he referred to as "the holy grail" of information about the drug. Ex. A at 710:6-17, 881:22-882:20. And Plaintiff admitted that he likewise received the AndroGel label including the medication guide every time that he filled his prescription. Ex. A at 1692:21-25. Moreover, Dr. Canzler never diagnosed the cause of Plaintiff's hypogonadism, meaning that it was "idiopathic" and therefore within the labeled indication. Ex. A at 538:9-11, 1787:6-9.

Given Plaintiff's failure to demonstrate any false statement, active concealment, or nondisclosure in the face of a duty to disclose, the Court should enter judgment for AbbVie on Plaintiff's fraudulent misrepresentation claim.

B. No Reasonable Jury Could Credit Dr. Kessler's Inherently Contradictory Testimony

Additionally, Plaintiff's misrepresentation claim rests on inherently inconsistent testimony from Dr. Kessler, further demonstrating Plaintiff's inability to prove this claim by clear and convincing evidence.

Dr. Kessler testified that AndroGel's ads were "false and misleading" because the Company marketed and promoted AndroGel outside of the drug's indication. Ex. A at 798:3-7. However, this opinion rests on matters that Dr. Kessler readily admitted are governed by FDA regulations, including the intended use of AndroGel, Ex. A at 821:14-21, and what AndroGel can be promoted for, Ex. A at 821:25-822:2. Dr. Kessler further opined on whether AndroGel's branded and unbranded ads were improperly linked—something that is only potentially unlawful under FDA regulations. See FDA, Guidance for Industry: "Help-Seeking" Other Disease Awareness Communications by or on Behalf of Drug and Device Firms 5-7 (2004).

Yet, at the same time, Dr. Kessler testified that he is not offering an opinion on whether any actions by AbbVie violated FDA law or regulations. Ex. A at 825:16-18. No reasonable jury could reconcile these contradictory opinions upon which Plaintiff relies to prove his fraudulent misrepresentation claim. Moreover, to the extent that Dr. Kessler's opinion rests on FDA regulations, Plaintiff's reliance on that opinion violates Buckman. See 531 U.S. at 353.

C. There Is No Evidence that Plaintiff or His Prescribing Physician Saw or Relied on Any False Representation

Plaintiff also failed to prove by clear and convincing evidence that he or his prescriber saw and relied on any false representation when deciding to use or prescribe AndroGel. Ex. A at 152:8-9.3 Indeed, Plaintiff admitted that he did not start using AndroGel because of any AbbVie ads. Ex. A at 1693:19-23. Plaintiff further conceded that he never heard of low testosterone or AndroGel before Dr. Canzler diagnosed him and prescribed it for him. Ex. A at 1661:12-14, 1693:16-18. He did not recall seeing any advertisement for AndroGel or any other particular brand of TRT or low testosterone generally, but believes that he saw disease awareness ads about low testosterone after he began using AndroGel. Ex. A at 1666:14-22, 1693:12-15. Nor did Plaintiff recall Dr. Canzler ever giving him any questionnaire (such as ADAM) or ever visiting the IsItLowT.com website, Ex. A at 1693:24-1694:10, and Dr. Canzler confirmed that he did not use the ADAM questionnaire with Plaintiff, Ex. A at 1790:17-19. Moreover, Plaintiff relied not on any statement by AbbVie in advertisements or the label, but on Dr. Canzler's judgment in deciding to use AndroGel. Ex. A at 1692:21-1693:8. Finally, Plaintiff did not recall reading any materials that came with his AndroGel prescriptions. Ex. A at 1692:21-1693:2. Thus, no reasonable jury could conclude that Plaintiff relied on any false representation by AbbVie.

Similarly, the evidence establishes that Dr. Canzler's treatment decisions for Plaintiff rested on his training, experience, and medical judgment, rather than on anything AbbVie said. Ex. A at 1764:22-1765:3. Dr. Canzler received marketing from TRT manufacturers but could not recall any medical articles that sales representatives left behind, and he independently stayed abreast of medical developments. Ex. A at 1760:2-4, 17-20. Furthermore, he made independent prescribing decisions based on his medical judgment, notwithstanding any marketing. Ex. A at 1761:18-25. Dr. Canzler never "committed" to using a medication at a sales representative's behest, Ex. A at 1774:15-17, and he did not do anything in his practice simply because a representative told him to do so, Ex. A at 1791:18-22. Although Dr. Canzler acknowledged that advertising sometimes influenced men to ask about low testosterone or for TRT, there is no evidence that that occurred in this case. Ex. A at 1772:23-1773:6.

Dr. Canzler's testimony likewise established that he was not confused or misled about the scope of AndroGel's indication, even under Plaintiff's theory of the case. He reportedly understood "age-related" hypogonadism to be outside the indication and did not recall any representative telling him that he should prescribe AndroGel for that condition. Ex. A at 1787:14-16, 21-24. In any event, Plaintiff's theory of "age-related" fraud has no bearing on this case where Dr. Canzler never diagnosed Plaintiff with "age-related" hypogonadism. Ex. A at 1786:21-1787:5. Indeed, Plaintiff was only 43, with unequivocally low testosterone, at the time of his first prescription. Ex. A at 1743:23-1744:6. Finally, any suggestion that Dr. Canzler was somehow deceived or misled by AbbVie's risk information is belied by the fact that he warned Plaintiff of the potential CV risks. Ex. A at 1736:10-20.

V. OREGON LAW AND DUE PROCESS BAR ANY PUNITIVE DAMAGES

The Court should enter judgment for AbbVie with respect to punitive damages. First, AbbVie respectfully maintains that the Court should apply Oregon punitive damages law to the claims of an Oregon man who used AndroGel and had his heart attack in Oregon. See Townsend v. Sears, Roebuck, & Co., 879 N.E.2d 893, 908-09 (Ill. 2007). Under Oregon law, a drug manufacturer "shall not be liable for punitive damages" where the drug either (i) "was manufactured and labeled in relevant and material respects in accordance with the terms of an approval or license issued by the federal Food and Drug Administration," or (ii) "[i]s generally recognized as safe and effective" by the FDA. O.R.S. § 30.927(1)(a)-(b). There is no dispute that ever since AndroGel's initial approval in 2000, it has remained approved as safe and effective by the FDA, and has been accompanied by FDA-approved labeling.4 Allowing punitive damages here would violate due process given that Oregon, where Plaintiff resides and had his heart attack, would not permit such damages. Cf. BMW of N. Am., Inc. v. Gore, 517 U.S. 559, 572-75 (1996).

Second, even applying Illinois punitive damages law, Plaintiff has not shown that AbbVie's conduct reflects either "an actual or deliberate intention to harm" or an "utter indifference to or conscious disregard for the safety of others." Ex. A at 155:9-11. Plaintiff has identified no evidence that AbbVie intended to cause harm or consciously disregarded consumer safety. Plaintiff's counsel promised a punitive damages case premised on allegations of long-standing "off-label" promotion for "age-related hypogonadism." ECF 1962 at 3-5. But counsel did not link any of these allegations or evidence to Plaintiff. No advertising influenced Plaintiff's decision to use AndroGel. See supra at Section IV.C. Dr. Canzler did not determine that Plaintiff suffered from "age-related hypogonadism" and, regardless, understood that the product was not approved for such condition. Id. When prescribing a medication to a patient, Dr. Canzler made his own independent decisions based on his medical judgment. Ex. A at 1725:21-25. And, with respect to Plaintiff in particular, Dr. Canzler testified that he made his decision based on his own experience with the medication, not because of something any sales representative told him. Ex. A at 1764:22-1765:3.

Given the absence of any link between the supposed punitive damages evidence and the facts relevant to Plaintiff's care and treatment, permitting a punitive damages award in this case would violate due process. As the Supreme Court has cautioned: "A defendant's dissimilar acts, independent from the acts upon which liability was premised, may not serve as the basis for punitive damages. A defendant should be punished for the conduct that harmed the plaintiff, not for being an unsavory individual or business. Due process does not permit courts, in the calculation of punitive damages, to adjudicate the merits of other parties' hypothetical claims against a defendant under the guise of the reprehensibility analysis." State Farm Mut. Auto Ins. v. Campbell, 538 U.S. 408, 422-23 (2003); see Philip Morris USA v. Williams, 549 U.S. 346, 353-58 (2007) (due process bars punitive damages to punish for harm caused to others).

CONCLUSION

For the foregoing reasons, the Court should enter judgment in AbbVie's favor on all of Plaintiff's claims.

Exhibit A

(The following proceedings were had in open court in the presence and hearing of the jury:)

Exhibit 06401

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use AndroGel safely and effectively. See full prescribing information for AndroGel.

AndroGel® (testosterone gel) 1% for topical use CIII

Initial U.S. Approval: 1953

_______________________ INDICATIONS AND USAGE _______________

AndroGel is an androgen indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone:

To report SUSPECTED ADVERSE REACTIONS, contact Solvay Pharmaceuticals, Inc. at 1-800-241-1643 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

FULL PRESCRIBING INFORMATION: CONTENTS*

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Testosterone Replacement Therapy

AndroGel, an androgen, is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing

The recommended starting dose of AndroGel is 5 g once daily (preferably in the morning) to clean, dry, intact skin of the shoulders and upper arms and/or abdomen. AndroGel must not be applied to the genitals. AndroGel is supplied as either a pump or in individual packets. After applying the gel, the application site should be allowed to dry for a few minutes prior to dressing. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel, are flammable. Hands should be washed with soap and water after AndroGel has been applied. [see Warnings and Precautions (5.2, 5.10)].

2.2 Administration

Multi-Dose Pump

Patients should be instructed to prime the pump before using it for the first time by fully depressing the pump mechanism (actuation) 3 times and discard this portion of the product to assure precise dose delivery. After the priming procedure, patients should completely depress the pump one time (actuation) for every 1.25 g (AndroGel Pump) of product required to achieve the daily prescribed dosage. The product may be delivered directly into the palm of the hand and then applied to the desired application sites, either one pump actuation at a time or upon completion of all pump actuations required for the daily dose. Alternatively, the product can be applied directly to the application sites. Application directly to the sites may prevent loss of product that may occur during transfer from the palm of the hand onto the application sites. Table 1 has specific dosing guidelines for adult males when the 75 g AndroGel Pump is used.

Table 1: Specific Dosing Guidelines for Using the Adult Multi-Dose Pump

Packets

The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.

2.3 Dose Adjustment and Patient Assessments

The following is general advice for treating and monitoring adult patients on AndroGel. No specific recommendations can be made.

3 DOSAGE FORMS AND STRENGTHS

AndroGel (testosterone gel) 1% for topical use is available in either unit-dose packets or multiple-dose pumps. The 75 g (60 metered-dose) pump delivers 1.25 g of product when the pump mechanism is fully depressed once. AndroGel is available in the following three package containers:

4 CONTRAINDICATIONS

AndroGel should not be used in any of the following patients:

5 WARNINGS AND PRECAUTIONS

5.1 Worsening of BPH and Potential Risk of Prostate Cancer

5.2 Potential for Testosterone Transfer to Others

Transfer of testosterone to others (including women and children) can occur when vigorous skin-to-skin contact is made with the application site [see Clinical Studies (14.3)]. The following precautions are recommended to minimize potential transfer of testosterone from AndroGel-treated skin to another person:

5.3 Use in Women

Due to lack of controlled evaluations in women and potential virilizing effects, Androgel is not indicated for use in women [see Use in Specific Populations (8.1, 8.3)].

5.4 Potential for Adverse Effects on Spermatogenesis

At large doses of exogenous androgens, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

5.5 Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Longterm therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. AndroGel is not known to produce these adverse effects.

There are rare reports of hepatocellular carcinoma in patients receiving long-term oral therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.

5.6 Edema

Drugs in the androgen class may promote retention of sodium and water. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse Reactions (6.2)].

5.7 Gynecomastia

Gynecomastia may develop and may persist in patients being treated with androgens, including AndroGel, for hypogonadism.

5.8 Sleep Apnea

The treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases [see Adverse Reactions (6.2)].

5.9 Laboratory Tests

5.10 Flammable until Dry

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

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.

Clinical Trials in Hvpogonadal Men

Table 2 shows the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel and reported by >1% of patients in a 180 Day, Phase 3 study.

Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 180-Day Controlled Clinical Trial

Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.

In this 180 day clinical trial, skin reactions at the site of application were reported with AndroGel, but none was severe enough to require treatment or discontinuation of drug.

Six patients (4%) in this trial had adverse events that led to discontinuation of AndroGel. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to AndroGel administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension No AndroGel patient discontinued due to skin reactions.

In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other.

In a 3 year, flexible dose, extension study, the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel and reported by > 1% of patients is shown in Table 3.

Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP).

Discontinuation for adverse events in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient).

Increases in Serum PSA Observed in Clinical Trials of Hvpogonadal Men

During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on AndroGel in the 3-year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL.

Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as >2X the baseline or any single serum PSA >6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still <2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%).

Four patients met this criterion by having a serum PSA >6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient's PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient's PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of AndroGel. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hvpogonadal Men

Table 4 includes adverse reactions that have been identified postmarketing.

7 DRUG INTERACTIONS

7.1 Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

7.2 Corticosteroids

The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.

7.3 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X: AndroGel is contraindicated during pregnancy or in women who may become pregnant. It is teratogenic and may cause fetal harm [see Contraindications (4)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8.3 Nursing Mothers

Although it is not known how much testosterone transfers into human milk, AndroGel is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants [see Contraindications (4)].

Testosterone and other androgens may adversely affect lactation.

8.4 Pediatric Use

Safety and efficacy of AndroGel in males < 18 years old has not been established.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AndroGel to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer.

8.6 Renal or Hepatic Impairment

No formal studies were conducted involving patients with renal or hepatic insufficiencies.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

AndroGel contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.

Oral ingestion of AndroGel will not result in clinically significant serum testosterone concentrations due to extensive first-pass metabolism.

10 OVERDOSAGE

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of AndroGel together with appropriate symptomatic and supportive care.

11 DESCRIPTION

AndroGel (testosterone gel) 1% is a clear, colorless hydroalcoholic gel containing 1% testosterone. Topical administration of AndroGel 5 g, 7.5 g, or 10 g contains 50 mg, 75 mg, or 100 mg of testosterone, respectively, is to be applied daily to the skin's surface. Approximately 10% of the applied testosterone dose is absorbed across skin of average permeability during a 24-hour period.

The active pharmacologic ingredient in AndroGel is testosterone. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

Inactive ingredients in AndroGel are carbomer 980, ethanol 67.0%, isopropyl myristate, purified water, and sodium hydroxide. These ingredients are not pharmacologically active.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis.

Male hypogonadism has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.3 Pharmacokinetics

Adult Males

Absorption

AndroGel delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (298-1043 ng/dL) seen in healthy men. AndroGel provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

AndroGel is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from AndroGel is absorbed into systemic circulation. Therefore, 5 g and 10 g of AndroGel systemically deliver approximately 5 mg and 10 mg of testosterone, respectively. In a study with 10 g of AndroGel, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state level by the end of the first 24 hours and are at steady state by the second or third day of dosing.

With single daily applications of AndroGel, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (<300 ng/dL) maintained on 5 g or 10 g of AndroGel for 30 days. The average (± SD) daily testosterone concentration produced by AndroGel 10 g on Day 30 was 792 (± 294) ng/dL and by AndroGel 5 g 566 (± 262) ng/dL.

When AndroGel treatment is discontinued after achieving steady state, serum testosterone levels remain in the normal range for 24 to 48 hours but return to their pretreatment levels by the fifth day after the last application.

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Metabolism

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT.

DHT concentrations increased in parallel with testosterone concentrations during AndroGel treatment. After 180 days of treatment in adult males, mean DHT concentrations were within the normal range with 5 g AndroGel and were about 7% above the normal range after a 10 g dose. The mean steady-state DHT/T ratio during 180 days of AndroGel treatment remained within normal limits and ranged from 0.23 to 0.29 (5 g/day) and from 0.27 to 0.33 (10 g/day).

Excretion

About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

14 CLINICAL STUDIES

14.1 Clinical Trials in Adult Hypogonadal Males

AndroGel was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to AndroGel 5 g daily, 78 patients to AndroGel 10 g daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of AndroGel but open-label for active control. Patients who were originally randomized to AndroGel and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to 7.5 g daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel 5 g daily, 52 patients continued on AndroGel 10 g daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel 7.5 g daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of AndroGel for an additional period of up to 3 years.

Mean peak, trough and average serum testosterone concentrations within the normal range (298-1043 ng/dL) were achieved on the first day of treatment with doses of 5 g and 10 g. In patients continuing on AndroGel 5 g and 10 g, these mean testosterone levels were maintained within the normal range for the 180-day duration of the original study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as AndroGel for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed AndroGel treatment.

Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 5 g, 7.5 g, or 10 g of AndroGel. The 7.5 g dose produced mean concentrations intermediate to those produced by 5 g and 10 g of AndroGel.

Of 129 hypogonadal men who were appropriately titrated with AndroGel and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the normal range on Treatment Day 180.

In patients treated with AndroGel, there were no observed differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypogonadism, or body mass index.

AndroGel 5 g/day and 10 g/day resulted in significant increases over time in total body mass and total body lean mass, while total body fat mass and the percent body fat decreased significantly. These changes were maintained for 180 days of treatment during the original study. Changes in the 7.5 g dose group were similar. Bone mineral density in both hip and spine increased significantly from Baseline to Day 180 with 10 g AndroGel.

AndroGel treatment at 5 g/day and 10 g/day for 90 days produced significant improvement in libido (measured by sexual motivation, sexual activity and enjoyment of sexual activity as assessed by patient responses to a questionnaire). The degree of penile erection as subjectively estimated by the patients, increased with AndroGel treatment, as did the subjective score for "satisfactory duration of erection." AndroGel treatment at 5 g/day and 10 g/day produced positive effects on mood and fatigue. Similar changes were seen after 180 days of treatment and in the group treated with the 7.5 g dose. DHT concentrations increased in parallel with testosterone concentrations at AndroGel doses of 5 g/day and 10 g/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physiologically active androgen. Serum estradiol (E2) concentrations increased significantly within 30 days of starting treatment with AndroGel 5 or 10 g/day and remained elevated throughout the treatment period but remained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during AndroGel treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent manner during treatment with AndroGel.

14.2 Phototoxicity in Humans

The phototoxic potential of AndroGel was evaluated in a double-blind, single-dose study in 27 subjects with photosensitive skin types. The Minimal Erythema Dose (MED) of ultraviolet radiation was determined for each subject. A single 24 (+1) hour application of duplicate patches containing test articles (placebo gel, testosterone gel, or saline) was made to naive skin sites on Day 1. On Day 2, each subject received five exposure times of ultraviolet radiation, each exposure being 25% greater than the previous one. Skin evaluations were made on Days 2 to 5. Exposure of test and control article application sites to ultraviolet light did not produce increased inflammation relative to non-irradiated sites, indicating no phototoxic effect.

14.3 Testosterone Transfer from Male Patients to Female Partners

The potential for dermal testosterone transfer following AndroGel use was evaluated in a clinical study between males dosed with AndroGel and their untreated female partners. Two (2) to 12 hours after AndroGel (10 g) application by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the AndroGel application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration >2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.

16 HOW SUPPLIED/STORAGE AND HANDLING

AndroGel is supplied in non-aerosol, metered-dose pumps. The pump is composed of plastic and stainless steel and an LDPE/aluminum foil inner liner encased in rigid plastic with a polypropylene cap. Each 88 g AndroGel Pump in the twin package is capable of dispensing 75 g or 60 metered 1.25 g doses.

AndroGel is also supplied in unit-dose aluminum foil packets in cartons of 30. Each packet of 2.5 g or 5 g gel contains 25 mg or 50 mg testosterone, respectively.

Keep AndroGel out of the reach of children.

Storage

Store at 25°C (770F); excursions permitted to 150 to 300C (590 to 860F) [see USP Controlled Room Temperature].

Disposal

Used AndroGel pumps or used AndroGel packets should be discarded in household trash in a manner that prevents accidental application or ingestion by children or pets.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (17.3)

17.1 Potential Adverse Reactions with Androgens

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

17.2 Instructions for Use of AndroGel

17.3 FDA-Approved Patient Labeling

AndroGel (testosterone gel) 1% CIII is available packaged with 2 × 75 g pumps (each pump dispenses 60 metered 1.25 g doses) or in a box of 30 packets with 2.5g or 5g gel.

This is a summary of the important information about AndroGel. For details, talk to your healthcare professional and refer to the package insert.

1. What Disease or Condition Does AndroGel Treat?

2. How Should AndroGel (Pump or Packet) Be Applied?

How to use the AndroGel pump?

It is important that you read and follow these directions on how to use the AndroGel Pump properly. Before using the pump for the first time, you must prime the AndroGel pump by fully depressing the pump three times and discarding the gel. The unused gel should be discarded in a manner to avoid accidental exposure or ingestion by household members or pets. Fully depress the pump the appropriate number of times to deliver the daily dose prescribed by your healthcare provider. The product may be delivered directly into the palm of your hand and then applied to the desired application sites, either one pump depression at a time or upon completion of all pump depressions required for the daily dose.

How to use the AndroGel packets?

Open one AndroGel aluminum foil packet by folding the top edge at the perforation and tearing completely across the packet along the perforation. Squeeze the contents into the palm of your hand. Squeeze from the bottom of the packet toward the top. If you like, you may squeeze a portion of the gel from the packet into the palm of your hand and apply to application site(s). Repeat until the entire contents of the packet have been applied.

3. What Should You Discuss With Your Healthcare Professional?

Before you start using AndroGel, tell your healthcare professional if you:

4. What Other Drugs Should Not Be Used Together With AndroGel?

Tell your healthcare provider about all of the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. AndroGel can affect how your body handles other drugs. Changes in your dose or careful monitoring may be needed if you are taking any of the following medications:

5. What Are The Side Effects And Risks?

Possible side effects of AndroGel to discuss with your healthcare professional include:

Most common: Skin irritation where gel is applied, breast development or tenderness, acne, prostate enlargement, changes in lab test results and changes in urinary habits.

Contact your healthcare professional if you experience any of the following adverse reactions:

The major risks of AndroGel include:

Prostate Disorders: Patients treated with testosterone may be at an increased risk for prostate enlargement, and prostate cancer. Talk to your healthcare provider for more information on risk factors and ways to monitor for prostate disorders.

Testosterone Transfer: Transfer of testosterone to others (including women and children) can occur when vigorous skin-to-skin contact is made with the application site. AndroGel must not be used by women, and exposure to the active ingredient testosterone in pregnancy can cause fetal harm. Notify your healthcare provider if your female partner develops changes in hair distribution, increases in acne or other signs of masculinity.

6. How Should AndroGel Be Stored?

Store at 250C (770F); excursions permitted to 150 to 300C (590 to 860F) [see USP Controlled Room Temperature]. Keep out of the reach of children.

7. Is There Anything Else I Need To Know When Using AndroGel?

Your healthcare professional has prescribed AndroGel to meet your specific needs; never share your AndroGel with anyone. If you have any questions or concerns about your AndroGel treatment, ask your healthcare provider or pharmacist.

Exhibit 3094

Comains Nonbinding Recommendations

This guidance document focuses on phannacovigilance activities in the post-approval period. This guidance uses the term pharmacovingilance to mean all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events. This includes the use of pharmacoepidemiologic studies. These activities are undertaken with the goal of identifying adverse events and understanding, to the extent possible, their nature, frequency, and potential risk factors.

Pharmacovigilance principally involves the identification and evaluation of safety signals. In this guidance document, softly signal refers to a concern about an excess of adverse events compared to what would be expected to be associated with a product's use. Signals can arise from postmarketing data and other sources, such as preclinical data and events associated with other products in the same pharmacologic class. It is possible that even a single welldocumented case report can be viewed as a signal, particularly if the report describes a positive rechallenge or if the event is extremely rare in the absence of drug use. Signals generally indicate the need for further investigation, which may or may not lead to the conclusion that the product caused the event. After a signal is identified, it should be further assessed to determine whether it represents a potential safety risk and whether other action should be taken.

IV. IDENTIFYING AND DESCRIBING SAFETY SIGNALS: FROM CASE REPORTS TO CASE SERIES

Good pharmacovigilance practice is generally based on acquiring complete data from spontaneous adverse event reports, also known as case reports. The reports are used to develop case series for interpretation.

A. Good Reporting Practice

Spontaneous case reports of adverse events submitted to the sponsor and FDA, and reports from other sources, such as the medical literature or clinical studies, may generate signals of adverse effects of drugs. The quality of the reports is critical for appropriate evaluation of the relationship between the product and adverse events. FDA recommends that sponsors make a reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up, especially for serious events,4 and encourages sponsors to use trained health care practitioners to query reporters. Computer-assisted interview technology, targeted questionnaires, or other methods developed to target specific events can help focus the line of questioning. When the report is from a consumer, it is often important to obtain permission to contact the health care practitioner familiar with the patient's adverse event to obtain further medical information and to retrieve relevant medical records, as needed.

Exhibit 3214

FULL PRESCRIBING INFORMATION

WARNING: SECONDARY EXPOSURE TO TESTOSTERONE

1 INDICATIONS AND USAGE

AndroGel 1.62% is an androgen indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

Important limitations of use:

2 DOSAGE AND ADMINISTRATION

Dosage and Administration for AndroGel 1.62% differs from AndroGel 1%. For dosage and administration of AndroGel 1% refer to its full prescribing information. (2)

Exhibit 3215

FULL PRESCRIBING INFORMATION

WARNING: SECONDARY EXPOSURE TO TESTOSTERONE

1 INDICATIONS AND USAGE

AndroGel 1% is an androgen indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

Important limitations of use:

2 DOSAGE AND ADMINISTRATION

Dosage and Administration for AndroGel 1% differs from AndroGel 1.62%. For dosage and administration of AndroGel 1.62% refer to its full prescribing information. (2)

Exhibit 3258

Surveillance Data — Postmarketing Spontaneous Reports