Vol 110, No 17, October 26, 2004
`TeReneeye
`http://circ.ahajournals.org
`
`SUPPLEMENT TO)
`tt
`
`;
`American Heart
`BUSUUEHOHE
`Learn and Live:.
`
`rd
`
`JOURNAL OF THE AMERICAN HEART ASSOCIATION
`
`Abstracts
`
`from
`
`ToTie
`PITS
`
`Sessions: November 7—10
`Exhibits: November 7—9
`New Orleans, Louisiana
`
`scientificsessions.org
`
`Circulation.
`
`Page 1
`
`Named and Invited Lectures 2004
`
`2004 Russell Ross Memorial Lectureship in Vascular Biology * 2004 George Lyman Duff Memorial Lecture * 2004 Sol Sherry
`Distinguished Lecture in Thrombosis « 2004 Thomas W. Smith Memorial Lecture + 2004 George E. Brown Memorial Lecture
`* 2004 Dickinson W. Richards Memorial Lecture * 2004 Katharine A. Lembright Award ¢ 2004 William W. L. Glenn Lecture
`« 2004 William J. Rashkind Memorial Lecture « 2004 T. Duckett Jones Memorial Lecture * 2004 Charles T. Dotter Memorial
`Lecture * 2004 Laennec Society Lecture * 2004 Ancel Keys Lecture + 2004 Lewis K. Dahl Memorial Lecture * 2004 Robert
`Roam ecee mMeyarltlici
`
`CAVEUCM CCMmACameemerl
`
`
`
`
`icemaneticeeeinieenteeniecoresecmeencielciemttcileanne
`
`Lewis N. and Arnold M.Katz Basic Science Research Prize for Young Investigators * Melvin L. Marcus Young Investigator
`Awards in Cardiovascular Science * Cournand and Comroe Young Investigators Prizes in Cardiopulmonaryand Critical
`Care * Outstanding Research Award in Pediatric Cardiology « Melvin Judkins Young Investigator Award in Cardiovascular
`Radiology *« Vivian Thomas Young Investigator Award « Martha N. Hill New Investigator Awards * Elizabeth Barrett-
`Connor Research Award in Epidemiology and Prevention for Investigators in Training * Samuel A. Levine Young Clinical
`Investigator Awards * Laennec Society Young Clinician Award * NPAM NewInvestigator Award
`
`Abstracts From the Scientific Sessions 2004
`
`Liquidia's Exhibit 1095
`
`Liquidia's Exhibit 1095
`Page 1
`
`

`

`As with other drugsthat block angiotensinII orits effects, concomitant use of potassium sparing diuretics(e.¢.,
`Diovan®
`Spironolactone, triamterene, amiloride), potassium supplements,orsalt substitutes containing potassium maylead
`to increases in serum potassium andin heart failure patients to increases in serum creatinine.
`(valsartan)
`Carcinogenesis, Mutagenesis, Impairment ofFertility: There was no evidence of carcinogenicity when valsartan
`was administered in the diet to mice andrats for up to 2 years at doses up to 160 and 200 mg/kg/day. respec-
`Tablets
`tively, These doses in mice andrats are about 2.6 and6times, respectively, the maximum recommended human
`Rx only
`dose on a mg/m?basis. (Calculations assumean oral dose of 320 mg/day and a 60-kg patient.)
`BRIEF SUMMARY:Please see package insert forfull prescribing information.
`Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chramosomelevel. These
`assaysincluded baclerial mutagenicity tests with Saimonella (Ames) andEcoli: a gene mutation test with Chinese
`IN PREGNANCY: When used in pregnancy during
`the second andthird trimesters, drugs that act
`hamster V79cells; a cytogenetic test with Chinesa hamsterovary cells; and a rat micronucleustest
`vee an the renin-angiotensin system can cause bir and even death to the developing fetus. When
`Valsartan had no adverseeffects on the reproductive performanceof male orfemale rats at oral doses up to
`pregnancy is detected, Diovan should be discontinued as soon as possible.
`200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m?basis. (Calculations
`assume an oral dose of 320 mg/day and a 60-kg patient.)
`Pregnancy: Pregnancy Eatepanss C (first trimester) andD (secondand third trimesters):See WARNINGS.
`Fetal/Neonatal Morbidity and Mortality.
`Nursing Mothers: It is not known whethervalsartanis excreted in human milk, but valsartan was excreted in the
`milk of lactating rats. Becauseof the potential for adverseeffects on the nursing Infant, a decision should be made
`whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
`Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
`Geriatric Use: In the controlled clinical trials ofvalsartan, 1,214 (36.2%) of hypertensive patients treated with
`valsartan were = 65 years and 265 (7.9%) were = 75 years. No overall difference in theefficacy or safety of
`valsartan wasobserved in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
`Of the 2,511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1.141) were
`65 years of age or older. There were no notable differences in efficacy or safety between older and yaunger patients.
`ADVERSE REACTIONS: Hypertension: Diovan® (valsartan) has been evaluated for safaty in more than 4,000
`patients, including over 400
`treated for over 6 months, and more than 160for over 1 year. Adverse experiences
`have generally heen mild and transientin nature and have only infrequently required discontinuation of therapy.
`The overall incidence of adverse experiences with Diovan was similar to placebo.
`The overall frequency of adverse experiences was neither dose-related nor related to gender, age, race. or regimen.
`Discontinuation of therapy dueto side effects was required in 2.3%of valsartanpatients and 2.0% of placebo
`patients. The most common reasonsfor discontinuation of therapy with Diovan were headache anddizziness.
`‘The adverse experiences that occurred in placebo-controlled clinical trials in at least 1%of patients treated with
`Diovan andat a higherincidencein valsartan (n=2,316) than placebo (n=888)patients includedviral infection (3%
`vs. 2%), fatigue (2% vs. 1%), and abdominal pain (2% vs, 1%).
`Headache, dizziness, upperrespiratory infection, cough,diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema,
`andarthralgia occurred at a more than 1% rate but at about the sameincidence in placebo and valsartan patients,
`In trials in which valsartan was compared to an ACE inhibitor with or withoutplacebo, the incidence of dry cough
`was significantly greater in the ACE-inhibitor group (7.9%) than in the groups whoreceived valsartan (2.6%) or
`placebo (1.5%). In a 129-patienttrial limited to patients who had had dry cough when they had previously received
`ACEinhibitors, the incidences of cough in patients who received valsartan, HCTZ, orlisinopril were 20%. 19%, and
`69% respectively (p < 0.001).
`Dose-related orthostatic effects were seen in less than 1%of patients. An increase in the incidenceof dizziness
`was observed in patients treated with Diovan 320 mg (8%) compared to 10 to 160 mg (2% to 4%).
`Diovan has been used concomitantly with hydrochlorothiazide without evidenceof clinically important adverse
`interactions.
`Other adverse experiences that occurred in controlled clinicaltrials of patients treated with Diovan (> 0.2%of
`valsartan patients)are listed below. It cannot be determined whether these events were causally related to Diovan.
`Bady as a Whole:Allergic reaction and asthenia: Cardiavaseular: Palpitations; Dermatologic: Pruritus and rash;
`Digestive: Constipation. dry mouth, dyspepsia, and flatulence: Musculoskeletal: Back pain, muscle cramps, and
`myalgia; Nearologic and Psychiatrie: Anxiety, insomnia, paresthesia, and somnolence; Respiratory: Dyspnea;
`Special Senses: Vertigo; Urogenital: Impotence
`Otherreported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vorniting, and
`angioedema.
`Heart Failure: The adverse experience profile of Diovan in heart failure patients was consistent with the pharma-
`cology of the drug and the health status of thepatients. In the Valsartan Heart Failure Trial, comparing valsartan in
`total daily doses up to 320 mg (n=2,506) to placaba (n=2,494), 10% of valsartan patients discontinued for adverse
`events vs. 7% of placebopatients.
`The table shows adverse events in double-blind shart-term heart failuretrials, including the first 4 manths of the
`Valsartan Heart FailureTrial, with an incidence of at least 2% that were more frequentin valsartan-treated patients
`than in placebo-treated patients. All patients received standard drug therapyfor heart failure,frequently as multiple
`Medications, which could include diuretics, digitalis, beta-blockers, or ACE inhibitors.
`Valsartan (n=3,282) Placebo (n=2,740)
`Valsartan (n=3,282) Placebo (n=2,740)
`Back Pain
`17%
`9%
`3%
`2%
`Dizziness
`T%
`2%
`Dizzinass, postural
`2%
`1%
`Hypotension
`5%
`4%
`Hyperkalemia
`2%
`%
`Diarrhea
`3%
`2%
`Hypotension, postural
`2%
`1%
`Arthralgia
`2%
`3%
`Fatigue
`Other adverse events with an incidence greater than 1% and greater than placebo included headache NOS, nausea,
`renal impairment NOS, syncope,blurred vision, upper abdominal pain and vertigo, (NOS = not otherwise specified).
`From the long term data in the Valsartan Heart Failure Trial, there did not appear to be anysignificant adverse
`events not previously identiflad.
`
`Post-Marketing Experience: Thefollowing additional adverse reactions have been reportedin post-marketingexperience:
`Hypersensitivity: There are rare reports of angioedema; Digestive: Elevatedliver enzymes and very rare reports of
`hepatitis; Renal: Impairedrenal function; Clinical Laboratory Tests: Hyperkalemia: Dermatologic: Alopecia.
`Clinical Laboratory Test Findings: n controlled clinical trials, clinically important changes in standard laboratory
`parameters were rarely associated with administration of Diovan.
`Creatinine: Minor elevationsin creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in
`controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine
`were observedin 3.9% of Diovan-treated patients compared to 0.9% ofplacebo-treated patients.
`Hemoglobin and Hematocril: Greater than 20% decreases in hemoglobin and hematocrit ware observed in 0.4%
`and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treatedpatients. One
`valsartan patient discontinued treatmentfor microcytic anemia.
`Liver Function Tests: Occasionalelevations(greater than 150%)of liver chemistries occurred in Diovan-treated
`patients. Three patients (< 0.1%)treated with valsartan discontinued treatment for elevated liver chemistries
`placebo.
`Heapsnia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8%of patients treated with
`Serum Potassium: \n hypertensive patients, greater than 20% increases in serum potassium were observed in
`4.4% of Diovan-treated patients compared to 2.9% of placebo-treatedpatients. In heart failure patients, greater
`than 20% increases in serum potassium were observed in 10.0% of Diavan-treated patients compared to 5.1% of
`placebo-treated patients.
`Blood Urea Nitrogen (BUN): \n heart failure trials, greater than 50% increases in BUN were observed in 16.8%of
`Diovan-treated patients compared to 6.3% of placebo-treated patients.
`Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
`[see USP Controlled Room Temperature].
`Protect from moisture.
`Dispensein tight container (USP).
`PRINTEDIN U.S.A.
`REV: NOVEMBER 2003
`Distributed by:
`Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936
`©Novartis
`
`2003-71
`89004209
`
`See WARNINGS: Fetal/Neonatal Morbidity and Mortality.
`
`INDICATIONS AND USAGE: Hypertension: Diovan®(valsartan) is indicated for the treatment of hypertension. It
`may be used alone or in combination with other antihypertensive agents.
`Heart Failure: Diovan is indicated for the treatment of heart failure (NYHA class II-IV) in patients who are intoler-
`ant of angiotensin converting enzymeinhibitors. In a controlled clinical trial, Diovan significantly reduced hospital-
`izations for heart failure. There is no evidence that Diovan provides added benefits when it is used with an
`adequate dose of an ACEinhibitor. (See CLINICAL PHARMACOLOGY, Pharmacodynamics andClinical Effects,
`Heart Failure in the full prescribing information for details.)
`CONTRAINDICATIONS:Diovan® (valsartan)is contraindicated in patients who are hypersensitive to any component
`of this product.
`WARNINGS:Fetal/Neanatal Morbidity and Mortality: Drugs that act directly on the ranin-angiotensin system can
`cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozencases have
`beenreported in the world literaturein patients who were taking angiotensin-converting enzymeinhibitors. When
`pregnancyis detected, Diovan®(valsartan) should be discontinued as soon as possible.
`The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of preg-
`nancy has been associated with fetal and neonatalinjury, including hypotension, neonatal skull hypoplasia, anuria,
`reversible or irreversible renal failure, and death. Oligahydramnios has also been reported, presumably resulting
`from decreased fetal renal function: oligohydrammniosin this setting has been associated withfetal limb contrac-
`tures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation,
`and patent ductus arteriosus have also been reported. althoughit is not clear whether these occurrences were due
`to exposure to the drug
`These adverse effects do not appear to have resulted fram intrauterine drug exposure that has beanlimited to the
`first trimester. Mothers whose embryosand fetuses are exposed to an angiotensin II receptor antagonist only dur-
`ingthe first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should
`advise the patient to discontinue the use of valsartan as soon as possible.
`Rarely (probably less often than once in every thousand pregnancies). no alternative to a drug acting an the renin-
`angiotensin system will be found. In these rare cases, the mothers should be apprised ofthe potential hazards to
`their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
`{f oligohydramnios is observed. valsartan should be discontinued unlessit is considered life-saving for the mother.
`Contraction stress testing (CST), a nonstress test (NST), or biophysicalprofiling (BPP) may be appropriate,
`depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios
`may not appearuntil after the fetus has sustainedirreversible injury.
`infants with histories of in ufero exposureto an angiotensin {I receptor antagonist should be closely observed for
`hypotension, oliguria, and hyperkalemia.If oliguria occurs, attention should be directed toward support of blood
`pressure and renal perfusion. Exchangetransfusion or dialysis may be required as means of reversing hypotension
`and/or substituting for disordered renal function.
`Noteratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up
`to 600 mo/kg/day and to pregnantrabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal
`waight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in stud-
`ies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and
`food consumption) doses of 600 mg/kg/day during organogenesis orlate gestation and lactation.In rabbits, feto~
`toxicity (i.¢., resorptions,litter loss, abortions, and low body weight) associated with maternal toxicity (mortality)
`was observed at doses of 5 and 10 rngikg/day. The no observed adverseeffect doses of 600, 200 and 2 mg/kg/day
`in mice, rats and rabbits represent9,
`6, and 0.1 times, respectively, the maximum recommended human dose on a
`mg/mébasis. (Calculations assume anoral dose of 320 mg/day and a 60-kg patient.)
`Hypotension: Excessive hypotension wasrarely seen (0.19)in patients with uncomplicated hypertension treated
`with Diovan alone. In patients with an activated renin-angiotensin system, such as valume- and/or Salt-depleted
`patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected
`Prior to administration of Diovan, orthe treatmentshould start under close medical supervision.
`if excessive hypotension occurs, the patient should be placed in the supine position and,if necessary, given an
`intravenous infusion of normalsaline, A transient hypotensive rasponse is nota contraindication to furthertreat-
`Ment, which usually can be continued withoutdifficulty once the blood pressure has stabilized.
`Hypotensionin Heart Failure Patients: Caution should be observed when initiating therapy in patients with heart
`failure. Patients with heart failure given Diovan commonly have somereduction in bload pressure, but discontinua-
`tion of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions
`are followed, In controlled trials, the incidence of hypotensionin valsartan-treated patients was 5.5% compared to
`1.8% in placebo-treated patients.
`PRECAUTIONS:General: Impaired Hepatic Function: As the majority
`of valsartan is eliminated in the bile, patients
`with mild-to-moderate hepatic impairment, including patients with bil liary obstructive disorders, showed lower
`valsartan clearance (higher AUCs). Gare should be exercised in administering Diavan® (valsartan)to these patients.
`Impaired Renal Function - Hypertension: \n studies of ACE inhibitors in hypertensive patients with unilateral or
`bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have beenreported. Ina 4-day
`trial of valsartan in 12 hypertensive patients with unilateralrenal arlery stenosis, no significant increases in serum
`creatinine or blood urea nitrogen were observed. There has baen no long-term use of Diovan in patients with uni-
`lateral orbilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.
`Impaired Renal Function - Heart Failure: As a consequence ofinhibiting the renin-angiotensin-aldosteronesys~
`tem, changes in renalfunction may beanticipated in susceptible individuals, In patients with severe heart failure
`whose renal function may depend onthe activity of the renin-angiotensin-aldosterone system,treatmentwith
`angiotensin-converting enzyme inhibitors and angiatensin receptor antagonists has been associated with oliguria
`and/or progressive azotemia and (rarely) with acute renal failure and/or death, Similar outcomes have been
`reported with Diovan,
`Somepatients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potas-
`sium. These effects are usually minorand transient, and they are morelikely to occur in patients with pre-existing
`renal impairment. Dosage reduction and/or discontinuationof the diuretic and/or Diovan may be required, In the
`Valsartan Heart Failure Trial, in which 93% of patients were on concomitant ACEinhibitors, treatment was discan-
`tinued for elevationsin creatinine or potassium (total of 1.0% on valsartan vs, 0.2% on placebo). Evaluation of
`patients with heart failure should always include assessmentof renal function.
`Concomitant Therapy in Patients with Heart Failure: \n patients with heart failure, concomitant use of Diovan, an
`ACE inhibitor, and a beta blocker is not recommended.In the Valsartan Heart FailureTrial, this triple combination
`was associated with an unfavorable heart failure outcome (see CLINICAL PHARMACOLOGY. Pharmacodynamics
`andClinical Effects, Heart Failure in the fullprescribing information).
`Information for Patients: Pregnancy: Female patients of childbearing age should be told aboutthe consequences
`of second- and third-trimester exposureto drugs that act on the renin-angiotensin system, and they should also be
`told that these consequences do not appear to have resulted from intrauterine drug exposure that has beenlimited
`to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
`Drug Interactions: Noclinically significant pharmacokinetic interactions were observed whenvalsartan was coad-
`ministered with amlodipine,atenolol, cimetidine, digoxin, furosemide,glyburide, hydrochlorothiazide, or indo-
`methacin. The valsartan-atanolol combination was more antihypertensive thaneither component, butit did not
`lower the heart rate more than atenololalone.
`Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of
`the anticoagulant properties of warfarin,
`CYP 450 Interactions: The enzyme(s) responsible for valsartan metabolism have not been identified but do not
`seem to be CYP 450 isozymes. The inhibitary or induction potential of valsartan on CYP 450is also unknown.
`
`
`
`NOVARTIS
`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey 07936
`
`Reference: 1. Hermida RC, Calvo C, Ayala DE, et al. Administration time-dependent effects of valsartan on
`ambulatory blood pressure in hypertensive subjects. Hypertension. 2003:42:283-290.
`
`©2004 Novartis
`
`Printed in U.S.A.
`
`6/04
`
`C-DIO-1101
`
`Printed on Recycled Paper @
`
`Liquidia's Exhibit 1095
`Page 2
`
`Liquidia's Exhibit 1095
`Page 2
`
`

`

`Page 3
`
`DIOVAN is contraindicated in patients who
`are hypersensitive to any component of this
`peae
`LPOMSMcmctora
`DIOVAN than placebo: viralinfection (3% vs
`2A), fatigue (2% vs 1%), abdominal pain (2%
`memeTowSom eras
`and dizziness, An increase in dizziness was
`oNAa ree
`160 mg (2% to 4%),
`Because of the risk of hypotension, caution
`SeRelaaaeMUSI Ey
`acom eco oa Lact
`SITEMeee ere
`Coa CHA TeaTCe
`concomitant use of DIOVAN, an ACE
`inhibitor,
`and
`a
`beta-blocker
`is
`not
`recommended.In theValsartan Heart Failure
`TMU)ReENOM KES
`with an unfavorable Heart Failure outcome.
`In Val-HeFT, discontinuation due to adverse
`SC ORCne)Sb td
`Teele mCoNacme
`dizziness (I7% vs 9%), hypotension (7% vs
`2), and diarrhea (5%vs 4%)
`
`www.DIOVAN.com
`
`ea
`
`1/05 a11m1-9nn wa
`
`efinitely...DIOVAN
`
`®
`
`Liquidia's Exhibit 1095
`
`SUCNACictani
`demeiTHCy
`
`USE IN PREGNANCY: Whenused in
`PESUEUTSMeueeReg
`trimesters, drugs that act directly on
`MCCUENT CL te
`CMs meuameee ome
`Caecan SEIUOmS
`detected, DIOVAN should be discontinued
`SAECM eSoomnat)TICST
`brief summary of complete aRNog
`luoeMac
`
`ety Cardiovascular. benefits;
`Exclusive ARBindication or
`EenHUMenie nH =
`
`Proven excellent
`eyeGist
`
`Liquidia's Exhibit 1095
`Page 3
`
`

`

`
`
`Greater LDL-C reductions
`
`Greater reductions in LDL-C
`O In a comparison of dose-response curves, CRESTOR10 mg to 40 mg reduced LDL-C
`significantly more than atorvastatin 10 mg to 80 mg (4.1%; P<.001)'
`In patients without CHD/CHDrisk equivalents
`94%of patients reached LDL-C goalat a low 10-mg dose*
`
`CRESTORis indicated as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB,
`non-HDL-C, and TG levels and to increase HDL-Cin patients with primary
`hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
`
`
`
`
`
`
`CRESTORis contraindicated in patients with active liver disease or with unexplained
`persistent elevations of serum transaminases, in women whoare or may become pregnant,
`andinnursing mothers.
`
`
`domyolysis with acute renalfailure secondary to myoglobinuria have
`
`ed with CRESTOR and with other drugsin this class. Patients should be advised
`
`explained muscle pain, tenderness, or weakness, particularly if
`
`e orfever. Therapy with CRESTORshould be discontinuedif
`
`levels occur or myopathyis diagnosed or suspected.
`
`
`
` ; without CHD or CHDrisk equivalents:
`—
`*NCEP ATPIll goal
`eee. <10
`1g)
`tors, <130 mg/dL; 0-1 risk factor, <160 mg/dL.
`
`Liquidia's Exhibit 1095
`Page 4
`
`Liquidia's Exhibit 1095
`Page 4
`
`

`

`
`°64 Countrfees Wor}
`LANE MEDICAL LIBRARY
`STANFORDUNIVMEDCENTER
`
`:
`ee
`| dw. 2
`widele
`@
`s
`.
`: *
`
`@
`
`NOV 1 1 2004
`
`‘STANFORD, CA94305-5123
`with proven safety
`
`as an adjunct to dietfor manypatients with dyslipidemia
`
`Proven safety similar to other leading statins’
`O Adverse reactions were mild and transient; incidence and discontinuation rates
`similar to placebo and otherstatins**
`
`O The most frequent adverse events were myalgia (3.3%), constipation (1.4%),
`asthenia (1.3%), abdominal pain (1.3%), and nausea (1.3%)?°
`
`CRESTORwasevaluatedin over 10,000 patients in
`preapprovalclinical trials—more than any otherstatin
`prior to approval**™"
`Overall, more than 42,000 patients have taken
`CRESTORin clinicaltrials, including ongems trials
`in the GALAXY” Program”
`O The GALAXY Programis a large, comprehensive, long-term evolving global research
`initiative evaluating the efficacy and safety of CRESTOR and demonstrating the
`AstraZeneca confidence in, and commitmentto, this important therapeutic option
`
`It is recommendedthatliver function tests be performed before and at 12 weeks
`followingboththeinitiation of therapy and any elevation of dose, and periodically
`(eg, semiannually) thereafter.
`
`The effect of CRESTOR on cardiovascular morbidity and
`mortality has not been determined; long-term outcome
`
`studies are currently under way.
`CRESTOR
`rosuvastatin calcium
`
`
`_ Please see brief summary offull Prescribing
`ormation on reverse side ofthis advertisement.
`
`
`
`Liquidia's Exhibit 1095
`Page 5
`
`Liquidia's Exhibit 1095
`Page 5
`
`

`

`warfarin therapy resulted in clinically significant rises in INR (>4, baseline 2-3). in patients
`taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined
`before starting rosuvastatin and frequently enough during early therapy to ensure that no
`significant alteration of INR occurs, Once a stable INR time has been documented, INR can
`be monitored at the intervals usually recommended for patients on coumarin anticoagu-
`fants,
`If the dose of rosuvastatin is changed, the same procedure should be repeated,
`Rosuvastatin therapy has not been associated with bleeding or with changes in INR in
`patients not taking anticoagulants. Gemfibrozil: Coadministration of a single rosuvastatin
`dose to healthy volunteers on gemfibrozil (600 mg twice daily) resulted in a 2.2- and
`1.9-fold, respectively, increase in mean Cmax and mean AUCof rosuvastatin (see DOSAGE
`AND ADMINISTRATION). Endocrine FunctionAlthough clinical studies have shown
`that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair
`adrenal reserve, caution should be,exercised if any HMG-CoA reductase intibitor or other
`agent used to lower cholesterol levels is administered concomitantly with drags that may
`decrease the levels oractivity of endogenous steroid hormones such’as Ketoconazole,
`spironolactone, and cimetidine. CNS Toxicity CNS vascularlesions, characterized by
`perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces,
`have bean observed in dogs treated with several othermembers ofthis drug class. A chem
`ically similar drug in this class produced dose-dependent optic nerve degeneration
`(Wallerian degeneration of retinogeniculate fibers) in dogs, ata dose that produced plasma
`drug levels about 30 times higher than the mean drug level in humans taking the highest
`recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the
`choroid plexus was observed in afemaledog saarificed moribund atday24 at
`90.mg/kg/day
`by oral gavage (systemic exposures 100 timesthe human exposure at40 mg/day based on
`AUC comparisons). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day
`by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on
`AUC comparisons). Cataracts were seen in dogs treated for 12 weeks by oral gavage at
`30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on
`AUC comparisons). Retinal dysplasia andretinal loss were seen in dogs treated for 4 weeks
`by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at
`40 mg/day based on AUC). Doses <30 mg/kg/day (systemic exposures <60 times the
`
`
`
`
`
`
`
`Experiences Adverse experiences, regardless of causality assessment, reported in
`22% of patients in placebo-controlled clinical studies of rosuvastatin are shown in Table 1;
`discontinuations dueto adverse events in these studiesof upto 12 weeks duration occurred
`in 3%of patients on rosuvastatin and 5% on placebo.
`Table 1. Adverse Events in Placeho-Controlled Studies
` Rosuvastatin Placebo
`
`Adverse event
`N=744
`N=382
`Pharyngitis
`$0
`vA
`Headache
`35
`5.0
`Diarrhea
`34
`29
`Dyspepsia
`34
`uM
`Nausea
`34
`34
`Myalgia
`28
`13
`Asthenia
`ai
`26
`Back pain
`26
`24
`Flu syndrome
`23
`18
`Urinarytract infection
`23
`16
`Rhinitis
`22
`24
`Sinusitis
`2.0
`18
`Inaddition, the following adverse events were reported, regardless ofcausalityassessment,
`in >1% of 10,275patients treated with rosuvastatin in clinical studies. The events in italics
`‘occurred in >2% of these patients. Body as a Whale: Abdominal pain, accidental injury,
`chest
`pain,
`infection,
`pain,
`pelvic
`pain,
`and
`neck
`pain. Cardiovascular
`System: Hypertension, angina pectoris, vasodilatation, and palpitation. Digestive
`System: Constipation, gastroenteritis, vomiting, flatulence, periodontal abscess, and
`gastritis. Endocrine: Diabetes mellitus. Hemic and Lymphatic System: Anemia and eochy-
`mosis. Metabolic and Nutritional Disorders: Peripheral edema. Musculoskeletal
`System: Arthritis, arthvalgia, and pathological fracture. Nervous System: Dizziness,
`insomnia, hypertonia, paresthesia, depression, anxiety, vertigo, and neuralgia. Respiratory
`System: Bronchitis, cough increased, dyspnea, pneumonia, and asthma. Skin and
`Appendages: Rashand pruritus. LaboratoryAbnormalities: In the rosuvastatin clinicaltrial
`program, dipstick-positive proteinuria and microscopic hematuria were observed among
`rosuvastatin-treated patients, predominantly in patients dosed above the recommended
`dose range (ie., 80 mg). However, this finding was more frequentin patientstaking rosuva-
`statin 40 mg, when compared to lower doses ofrosuvastatin or comparatorstatins, though
`it was generally transient and was not associated with worsening renal function. (See
`PRECAUTIONS, Laboratory Tests.) Other abnormal
`laboratory values reported were
`elevated creatinine phosphokinase, transaminases, hyperglycemia, glutamyl transpepti-
`dase, alkaline phosphatase, bilirubin, and thyroid function abnormalities. Other adverse
`events reported less frequently than 1% in therosuvastatin clinical study program, regard-
`less of causalityassessment, included arrhythmia, hepatitis, hypersensitivity reactions (ie.,
`face.
`edema,
`thrombocytopenia,
`leukopenia, vesiculobullous
`rash,
`urticaria,
`and
`angioedema), kidney failure, syncope, myasthenia, myositis, pancreatitis, photosensitivity
`reaction, myopathy, and rhabdomyolysis. OVERDOSAGE There is no specific treat-
`ment in the event of overdose. In the event ofoverdose,the patient should be treated symp-
`tomatically and supportive measures instituted as required. Hemodialysis does not
`significantlyenhance clearance of rosuvastatin. DOSAGE AND ADMINISTRA-
`TION The patient should be placed on a standard cholesterolowering diet before
`receiving CRESTOR and should continue on this diet during treatment. CRESTOR
`can be administered as a single dose at any time of day, with or without
`food. Hypercholesterolemia piste
`s
`Familial
`and
`Nonfamilial) and Mixed Dyslipidemia frredridiaon Type Ila
`and Illb) The dose range for CRESTORis 5 to 40 mg oncedaily, Therapy with CRESTOR
`should be individualized according to goal of therapy and response. The usual recom-
`mended starting dase of CRESTORis 10 mgonce daily. Initiation of therapy with 5 mg once
`daily may be considered for patients requiring less aggressive LDL-C reductions or who
`have predisposingfactorsfor myopathy (see WARNINGS, Myopathy/ Rhabdomyolysis). For
`patients with marked hypercholesterolemia (LDL-C > 190 mg/dL) and aggressive lipid
`targets, a 20-mg starting dose may be considered. The 40-mg dose of CRESTORshould be
`reserved forthose patients who have not achieved goal LDL-C at 20 mg (see WARNINGS,
`Myopathy/Rhabdomyolysis). After initiation and/or upon titration of CRESTOR, lipid levels
`should be
`analyzed within 2
`to 4 weeks
`and dosage
`adjusted accordingly.
`Homozygous Familial Hypercholesterolemia The
`recommended
`starting dose of CRESTORis 20 mg once daily in patients with homozygous FH. The
`maximum recommended daily dasa is 40 mg. CRESTOR should be used in these patients
`4San adjunctto other lipid-lowering treatments (e.9., LDL apheresis) or if such treatments
`are unavailable. Response to therapy should be estimated from pre-apheresis LDL-C levels.
`Dosage in Patients Taking CyclosporineIn patients taking cyclosporine,
`therapy should be
`limited to CRESTOR 5 mg once
`daily
`(see WARNINGS,
`Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions). Concomitant
`psd-lovesting Therapy Theeffectof CRESTOR on LDL-C andtotal-C may be
`anced when used in combination with a bile acid binding resin. If CRESTOR is used in
`combination with gemfi