Moxifloxacin in the Treatment of Community-Acquired Pneumonia (CAP) Please see Sales Representative for Full Prescribing Information.

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1 Moxifloxacin in the Treatment of Community-Acquired Pneumonia (CAP) Please see Sales Representative for Full Prescribing Information. AI /08

2 Moxifloxacin: An Advanced-Generation C8-methoxy Fluoroquinolone 1,2 Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin O OH Bulky bicycloamine substituent at C-7 prevents active efflux associated with some Gram-positive bacteria NH H N H F H 3 C *In vitro activity does not necessarily imply clinical effectiveness. O N O C8-methoxy moiety contributes to enhanced activity, lower selection of resistant mutants of Gram-positive bacteria 1. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October Dong Y et al. Antimicrob Agents Chemother. 1998;42:

3 In Vitro* Activity Against Common CAP Pathogens MIC 90 (µg/ml) Organism MOXI GEMI LEVO # Isolates Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Chlamydia pneumoniae ND Mycoplasma pneumoniae *In vitro activity does not necessarily imply clinical effectiveness. Moxifloxacin is indicated for treatment of CAP caused by S pneumoniae (including multidrug-resistant strains), H influenzae, M catarrhalis, methicillin-susceptible Staphylococcus aureus, Klebsiella pneumoniae, M pneumoniae, or C pneumoniae. MDRSP, Multidrug-resistant S pneumoniae includes isolates previously known as PRSP (penicillin-resistant S pneumoniae), and are strains resistant to 2 or more of the following antibiotics: penicillin (MIC 2 µg/ml), second-generation cephalosporins (eg, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. MIC=minimum inhibitory concentration; MOXI=moxifloxacin; GEMI=gemifloxacin; LEVO=levofloxacin. 1. Jones RN et al. Int Diagn Microbiol Infect Dis. 2003;45: Miyashita N et al. J Infect Chemother. 2002;8: Waites K et al. Int J Antimicrob Agents. 2003;21:

4 AUC/MIC Ratio* Range for S pneumoniae (89-149) (96-134) 120 Free AUC/MIC (30-37) (56-70) 100 Resistance Prevention ~AUC/MIC = LEVO 500 mg QD LEVO 750 mg QD GEMI 320 mg QD MOXI 400 mg QD Efficacy ~AUC/MIC = 35 *In vitro activity does not necessarily imply clinical effectiveness. AUC 24 =24-hour area under plasma concentration curve; free AUC=free drug area under plasma concentration curve. Ranges based on protein binding ranges and MIC 90 data. Jones RN et al. Antimicrob Agents Chemother. 2003;45: ; full Prescribing Information used for multi-dose oral 24-h AUC values for each agent listed; Adapted from Scheld WM. Emerg Infect Dis. 2003;9:1-9; Lacy MK et al. Antimicrob Agents Chemother. 1999;43: ; Lister PD et al. J Antimicrob Chemother. 1999;43:79-86; Schentag JJ. Clin Infect Dis. 2001;32(suppl 1):S39-S46.

5 Moxifloxacin vs Levofloxacin Lung Tissue Penetration After 24 Hours* Alveolar Macrophages P= Epithelial Lining Fluid P=NS Moxifloxacin (n=4) Levofloxacin (n=4) Tissue Concentration (mg/l) *Tissue/fluid penetration is regarded as essential to therapeutic efficacy, but penetration levels have not been correlated with specific therapeutic results. Capitano B et al. Chest. 2004;125:

6 Moxifloxacin vs Levofloxacin: Mean Serum Bactericidal Titers* vs S pneumoniae Serum Bactericidal Titer 1:32 1:8 1:64 1:16 1:32 1:8 1:32 1:4 Moxifloxacin 400 mg QID Levofloxacin 750 mg QID 1:16 1:4 1:8 1:< Hours *In vitro activity does not necessarily imply clinical effectiveness. Hart DH, Weinstein MP. Diagn Microbiol Infect Dis. 2007;58:

7 Moxifloxacin: Reduced S pneumoniae Resistance Potential vs Levofloxacin References Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72. Chen DK et al. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med. 1999;341: Blondeau JM, Hansen GT. The mutant prevention concentration (MPC) for ciprofloxacin (Cpx) and levofloxacin (Lfx) against non-urinary isolates of Pseudomonas aeruginosa and the relationship to achievable serum drug concentration following IV dosing. ICAAC Abstract Urban C et al. Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J Infect Dis. 2001;184: Allen GP et al. Activities of mutant prevention concentration-targeted moxifloxacin and levofloxacin against Streptococcus pneumoniae in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2003;47: Li X et al. Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin. Antimicrob Agents Chemother. 2002;46: Klugman KP. Bacteriological evidence of antibiotic failure in pneumococcal lower respiratory tract infections. Eur Respir J. 2002;20(suppl 36):3s-8s. Scheld WM. Maintaining fluoroquinolone class efficacy: review of influencing factors. Emerg Infect Dis. 2003;9:1-9.

8 Moxifloxacin in Community-Acquired Pneumonia: Clinical Trial Review

9 Moxifloxacin vs b-lactam ± Macrolide Combination Therapy: Study Design Design Study Drugs Efficacy Outcomes Randomized, open, parallel-group, multinational, controlled study; adult patients with CAP requiring initial IV therapy (N=628) IV to PO moxifloxacin 400 mg QD vs amoxicillin/clavulanate 1.2 g TID IV (625 mg when transitioning to PO) ± clarithromycin 500 mg BID (IV or PO) for 7 to 14 days Clinical response at test-of-cure (TOC) visit 5 to 7 days after end of therapy (1 0 efficacy endpoint) Time to resolution of fever, bacteriologic response 5 to 7 days after end of therapy, bacteriologic and clinical responses 21 to 28 days posttreatment, duration of IV therapy, duration of hospital admission (2 0 endpoints) Finch R et al. Antimicrob Agents Chemother. 2002;46:

10 Moxifloxacin vs b-lactam ± Macrolide Combination Therapy: Clinical Cure and Bacteriologic Success Patients (%) / / / / 71 Clinical Cure Bacteriologic (P=0.004; 95% CI, Success 2.91% to 13.19%) (95% CI, 1.21% to 22.91%) Moxifloxacin Comparator* Monotherapy with moxifloxacin was superior (P<0.01) to combination comparator at TOC (days 5-7 posttherapy) in 538 patients with CAP admitted to hospital (primary outcome) *Amoxicillin/clavulanate ± clarithromycin IV/PO. Comparator IV formulation is not approved in the United States. Per protocol population. CI=confidence interval. Finch R et al. Antimicrob Agents Chemother. 2002;46:

11 Moxifloxacin vs b-lactam ± Macrolide Combination Therapy: Time to Afebrile and IV/PO Conversion Moxifloxacin Comparator* 40 Patients (%) / / / / 320 Duration of hospital admission was approximately 1 day less for patients receiving moxifloxacin (9.49 days) than for comparator group (10.41 days) (P=not reported) Patients Afebrile Day 2 IV to PO Conversion Day 3 (P=0.025) (P=not reported) *Amoxicillin/clavulanate ± clarithromycin IV/PO. Comparator IV formulation is not approved in the United States. Intent-to-treat population. Finch R et al. Antimicrob Agents Chemother. 2002;46:

12 Moxifloxacin vs High-Dose Ceftriaxone ± Erythromycin (MOXIRAPID): Study Design Design Study Drugs Efficacy Outcomes Prospective, multicenter, randomized, open-label controlled study in hospital-admitted adult patients with CAP requiring initial IV treatment (N=397) IV/PO moxifloxacin 400 mg QD vs IV ceftriaxone 2 g QD with or without IV erythromycin 1 g q6-8h for 7 to 14 days Clinical response at TOC visit 5 to 20 days after end of therapy (1 0 efficacy endpoint) Clinical response 3 to 5 days after starting treatment and at end of treatment, bacteriologic response at TOC visit and at end of treatment, clinical and bacteriologic response at TOC visit for patients with proven bacterial pneumonia (2 0 endpoints) Welte T et al. Clin Infect Dis. 2005;41:

13 Moxifloxacin vs High-Dose Ceftriaxone ± Erythromycin (MOXIRAPID): Clinical Success Clinical Success (%) / / 156 Moxifloxacin Comparator (95% CI, -7.9% to 7.1%) Moxifloxacin monotherapy was clinically equivalent in efficacy to high-dose ceftriaxone with or without erythromycin at the TOC visit (5 to 20 days after end of study) in 317 patients hospitalized with CAP (primary endpoint) Validated per-protocol population. Welte T et al. Clin Infect Dis. 2005;41:

14 Moxifloxacin vs High-Dose Ceftriaxone ± Erythromycin (MOXIRAPID): Fever (>38 o C) Resolution Moxifloxacin (n=82) 3.8 Moxifloxacin monotherapy resolves fever faster (P=0.0027) than high-dose ceftriaxone with or without erythromycin Comparator (n=74) P= Mean Time to Defervescence (Days) Welte T et al. Clin Infect Dis. 2005;41:

15 Moxifloxacin vs High-Dose Ceftriaxone ± Erythromycin (MOXIRAPID): Timing of IV/PO Conversion and Discharge Moxifloxacin Ceftriaxone ± erythromycin Duration of IV Treatment (P=not reported) Duration of Hospitalization (P<0.001) Days Validated per-protocol population. Welte T et al. Clin Infect Dis. 2005;41:

16 Trends in Pneumonia Hospitalizations Among US Persons 65 Years of Age, Rate per 1000 Population* Rate of hospitalizations for pneumonia increased 30% between and (95% CI, 17% to 43%) Proportion of persons with first-listed diagnosis of pneumonia with 1 of the following: chronic cardiac disease, chronic pulmonary disease, or diabetes mellitus, increased 16% (95% CI, 13% to 20%) Patients (%) With 1 Comorbid Diagnosis* *Data are based on National Hospital Discharge Survey estimates for the United States. Fry AM et al. JAMA. 2005;294:

17 Moxifloxacin vs Levofloxacin (CAPRIE): Study Design Elderly Hospitalized CAP Design Study Drugs Safety and Efficacy Outcomes Prospective, double blind, randomized, multicenter trial in patients ³65 years, hospitalized with CAP who required initial IV therapy (N=401) 1 IV/PO moxifloxacin 400 mg QD vs IV levofloxacin 500 mg (or PO mg) QD for 7 to 14 days 1 Primary goal was to compare cardiac safety of moxifloxacin vs levofloxacin by means of 72-hour digital 12-lead ambulatory ECG (Holter) data 2 Clinical response at TOC visit 5 to 21 days after end of therapy (1 0 efficacy endpoint) 1 Clinical response 3 to 5 days after start of therapy, bacteriologic response (2 0 endpoints) 1 1. Anzueto A et al. Clin Infect Dis. 2006;42: Morganroth J et al. Chest. 2005;128:

18 Moxifloxacin vs Levofloxacin (CAPRIE): Select Demographics and Comorbidities Age, yr Mean Range Cardiac disorders (any) Coronary artery disease Congestive heart failure Ischemic disorder Moxifloxacin (n=141) 77.9 ± (72%) 54 (38%) 45 (32%) 27 (19%) Levofloxacin (n=140) 77.4 ± (76%) 48 (34%) 51 (36%) 27 (19%) Bronchospasm and obstruction 87 (62%) 96 (69%) Diabetes mellitus 40 (28%) 38 (27%) Clinically valid population. Anzueto A et al. Clin Infect Dis. 2006;42:73-81.

19 Moxifloxacin vs Levofloxacin (CAPRIE): Clinical Success Moxifloxacin Levofloxacin Patients (%) Primary efficacy outcome: At TOC visit (5 to 21 days posttherapy), the difference between treatment groups was not statistically significant / / / /140 Clinical Recovery Days 3-5 Clinical Cure Days 5-21 (P=0.01; 95% CI, 1.7% to 14.1%) (P=NS; 95% CI, -1.9% to 11.9%) Significantly more patients on moxifloxacin achieved recovery at days 3 to 5 (P=0.01) Clinically valid population. NS=not significant. Anzueto A et al. Clin Infect Dis. 2006;42:73-81.

20 Moxifloxacin vs Levofloxacin (CAPRIE): Cardiac Safety Endpoints Moxifloxacin (n=195) % Patients Levofloxacin (n=199) % Patients Confidence Interval Holter monitor findings* Investigatorobserved cardiac events % to 8.2% P=NS % to 1.7% P=NS *Primary safety composite variable: Holter monitor findings of fatal and nonfatal cardiac arrest, sustained and nonsustained monomorphic or polymorphic ventricular tachycardia. Safety population. Morganroth J et al. Chest. 2005;128:

21 Moxifloxacin vs Levofloxacin (CAPRIE): Drug-Related Adverse Events >1.5% Moxifloxacin (n=195) n (%) Levofloxacin (n=199) n (%) Diarrhea 11 (5.6%) 10 (5.0%) Oral candidiasis 7 (3.6%) 7 (3.5%) Cardiac events 2 (1.0%) 7 (3.5%) Nausea 3 (1.5%) 4 (2.0%) Clostridium difficile infection/colitis 1 (0.5%) 6 (3.0%) Safety population. Anzueto A et al. Clin Infect Dis. 2006;42:73-81.

22 2007 IDSA / ATS Community-Acquired Pneumonia Treatment Guidelines IDSA=Infectious Diseases Society of America; ATS=American Thoracic Society.

23 2007 IDSA / ATS CAP Guidelines: Introduction For the first time, the IDSA and ATS convened a joint committee to develop a unified CAP guidelines document Joint guidelines provide an update for clinicians on important advances in CAP management with the aim of the following: Decreasing mortality rate and improving patient care Preserving antibiotic susceptibilities Mandell LA et al. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

24 2007 IDSA / ATS CAP Guidelines: Empiric Antibiotics for Outpatients Previously healthy and no antimicrobials within 3 months A macrolide (strong recommendation; level I evidence) OR doxycycline (weak; level III) Presence of comorbidities* or antimicrobials within 3 months A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg ]) (strong; level I) OR a β-lactam plus macrolide (strong; level I) In regions with high rate of infection (>25%) with high-level (MIC 16 µg/ml), macrolide-resistant S pneumoniae: Consider alternative agents listed above (eg, moxifloxacin, gemifloxacin, or levofloxacin [750 mg ]) for any patients, including those without comorbidities (moderate; level III) *Such as chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs. Levofloxacin 750 mg is the only dose recommended for CAP. Adapted from Mandell LA et al. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

25 2007 IDSA / ATS CAP Guidelines: Empiric Antibiotics for Inpatients Inpatients, non-icu treatment A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg*]) (strong recommendation; level I evidence) OR a β-lactam plus macrolide (strong; level I) Inpatients, ICU treatment A β-lactam (cefotaxime, ceftriaxone, or ampicillin/sulbactam) plus either azithromycin (level II) or a fluoroquinolone (level I) (strong recommendation) *Levofloxacin 750 mg is only dose recommended for CAP. For penicillin-allergic patients, a respiratory fluoroquinolone should be used. For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended. Adapted from Mandell LA et al. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

26 2007 IDSA / ATS CAP Guidelines: Empiric Antibiotics for Inpatients (cont d) For Pseudomonas infection An antipneumococcal, antipseudomonal β-lactam (piperacillin/tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750 mg * ) OR the above β-lactam plus an aminoglycoside and azithromycin OR the above β-lactam plus an aminoglycoside and antipneumococcal fluoroquinolone (moderate) For community-acquired methicillin-resistant S aureus Add vancomycin or linezolid (moderate) *Levofloxacin 750 mg is the only dose recommended for CAP. For penicillin-allergic patients, substitute aztreonam for β-lactam. Adapted from Mandell LA et al. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

27 2007 IDSA / ATS CAP Guidelines: New Considerations in Antibiotic Treatment Empiric antibiotic treatment Experts recommend use of most active agents within each therapeutic class (eg, moxifloxacin, gemifloxacin) Other factors for selection of specific antimicrobials include the following: Pharmacokinetic/pharmacodynamic profile Compliance Safety Cost Mandell LA et al. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

28 2007 IDSA / ATS CAP Guidelines: New Considerations in Antibiotic Treatment (cont d) Maintaining antibiotic susceptibilities Clinical failures have been reported with ciprofloxacin and levofloxacin To date, no failures have been reported with the more active fluoroquinolones (moxifloxacin and gemifloxacin) The more active drugs (eg, moxifloxacin, gemifloxacin) are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance Mandell LA et al. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

29 Moxifloxacin: Summary of Clinical Experience Clinical experience >75 million patient use worldwide >8 years on US market Favorable adverse event (AE) profile AE rates similar to those for comparators, including levofloxacin, as demonstrated in CAPRIE Rates of drug-related colitis and Clostridium difficile similar to those for comparators, including levofloxacin Convenient once-daily 400 mg IV/PO dose for all indications No renal dosage adjustments required No additional glucose monitoring required

30 Moxifloxacin for CAP: Summary Efficacy in multiple CAP trials vs comparators Faster recovery at days 3 to 5 than levofloxacin in hospitalized, elderly patients with comorbidities 1 Earlier time to defervescence, IV-to-PO switch, hospital discharge 2,3 One convenient 400 mg IV/PO dose with no dosage adjustment required for renally impaired patients 4 1. Anzueto A et al. Clin Infect Dis. 2006;42: Finch R et al. Antimicrob Agents Chemother. 2002;46: Welte T et al. Clin Infect Dis. 2005;41: AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.

31 AVELOX (moxifloxacin HCl) Broad Indications and Usage Infections Pathogens AVELOX Acute Bacterial Sinusitis (ABS) Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) Community-Acquired Pneumonia (CAP) Uncomplicated Skin and Skin Structure Infections (usssi) Complicated Skin and Skin Structure Infections (csssi) Complicated Intra- Abdominal Infections (ciai) Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis S pneumoniae, H influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus, M catarrhalis S pneumoniae (including multidrug-resistant strains [MDRSP*]), H influenzae, M catarrhalis, methicillin-susceptible S aureus, K pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae Methicillin-susceptible S aureus, Streptococcus pyogenes Methicillin-susceptible S aureus, Escherichia coli, K pneumoniae, Enterobacter cloacae E coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, Peptostreptococcus spp 400 mg IV/PO q24h 10 days 400 mg IV/PO q24h 5 days 400 mg IV/PO q24h 7-14 days 400 mg IV/PO q24h 7 days 400 mg IV/PO q24h 7-21 days 400 mg IV/PO q24h 5-14 days *MDRSP, Multidrug-resistant S pneumoniae includes isolates previously known as PRSP (penicillin-resistant S pneumoniae), and are strains resistant to 2 or more of the following antibiotics: penicillin (MIC 2 µg/ml), second-generation cephalosporins (eg, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. For complicated intra-abdominal infections, therapy should usually be initiated with the IV formulation. AVELOX [package insert]. Please see full enclosed full Prescribing Information. Bayer Pharmaceuticals Corporation: October 2007.

32 AVELOX (moxifloxacin HCl) Important Safety Information Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antimicrobial agents. Serious and occasionally fatal events, such as hypersensitivity and/or anaphylactic reactions, as well as some of unknown etiology have been reported in patients receiving therapy with quinolones, including moxifloxacin. These reactions may include effects on the liver, including hepatitis, jaundice, and acute hepatic necrosis or failure, and hematologic effects, including agranulocytosis, thrombocytopenia, and other hematologic abnormalities. (cont d on next slide) Please see enclosed full Prescribing Information. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.

33 AVELOX (moxifloxacin HCl) Important Safety Information (cont d) (cont d from previous slide) These reactions may occur following the first dose or multiple doses. The drug should be discontinued at the first appearance of a skin rash, jaundice or any other sign of hypersensitivity The safety and effectiveness of moxifloxacin in pediatric patients, adolescents (less than 18 years of age), pregnant women, and lactating women have not been established Please see enclosed full Prescribing Information. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.

34 AVELOX (moxifloxacin HCl) Important Safety Information (cont d) Moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients. The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) antiarrhythmic agents, due to limited clinical experience. Moxifloxacin should be used with caution when given together with drugs that may prolong the QT interval (eg, erythromycin, antipsychotics, antidepressants) and in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia or acute myocardial ischemia Please see enclosed full Prescribing Information. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.

35 AVELOX (moxifloxacin HCl) Important Safety Information (cont d) Central nervous system (CNS) effects, including convulsions, confusion, dizziness, tremors, and depression, may occur after the first dose. As with other quinolones, moxifloxacin should be used with caution in patients with known or suspected CNS disorders or risk factors that may predispose them to seizures or lower the seizure threshold Rare cases of peripheral neuropathy have been reported in patients receiving quinolones, including moxifloxacin Please see enclosed full Prescribing Information. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.

36 AVELOX (moxifloxacin HCl) Important Safety Information (cont d) Tendon ruptures that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including moxifloxacin, during and after therapy. This risk is increased in patients over 65 years old, and is further increased with concomitant corticosteroid therapy. The quinolone should be discontinued in patients experiencing pain, inflammation, or rupture of a tendon Please see enclosed full Prescribing Information. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.

37 AVELOX (moxifloxacin HCl) Important Safety Information (cont d) Moxifloxacin tablets should be taken at least 4 hours before or 8 hours after multivitamins (containing iron or zinc), antacids (containing magnesium, aluminum), sucralfate, or Videx (didanosine) chewable/buffered tablets or the pediatric powder for oral suspension In large clinical trials, the most common adverse events occurring in 2% of patients were nausea (6%), diarrhea (5%), and dizziness (2%) Please see enclosed full Prescribing Information. AVELOX [package insert]. Bayer Pharmaceuticals Corporation; October 2007.