EQ-173

Clarithromycin Subject 4003/3212/003with ERSP Isolates, PPb

PresentationPresentation:: • 51 year old female, Fine Score II, no relevant risk factors for pneumonia• Chest X-ray: Right median lobe pneumonia and right inferior lobe• Blood cultures:

− S. pneumoniae: susceptible to TEL (MIC = 0.03 mcg/mL),susceptible to Pen G (MIC = 0.03 mcg/mL),resistant to Ery A (MIC = 512 mcg/mL –

genotype ermA / ermB)resistant to CLA (MIC = 64 mcg/mL)

• Sputum cultures: − S. pneumoniae: susceptible to TEL (MIC = 0.25 mcg/mL),

susceptible to Pen G (MIC = 0.03 mcg/mL),resistant to Ery A (MIC = 256 mcg/mL) resistant to CLA (MIC = 256 mcg/mL)

− M. catarrhalis: susceptible to TEL (MIC = 0.12 mcg/mL)

Clinical course:Clinical course:• Day 6: pneumonia worsened with development of septic arthritis. S. pneumoniae

isolated from the pus of septic arthritis. Chest X-ray unchanged. S. pneumoniae was re-isolated from sputum resistant to CLA (MIC=6 μg/mL). Subject hospitalized, discontinued from study medication.

• Patient was switched to IV antibiotics and received gentamicin ceftazidime, metronidazole, penicillin G, cefuroxime with subsequent clinical cure.

EP-127

All CAP Studies (Pooled): Key Demographics, mITT

Sex Male 118 (63%) 1172 (56%) 357 (51%)Female 69 (37%) 930 (44%) 345 (49%)

Age Mean 45.4 44.7 45.6(yrs) 13–18 1 (1%) 51 (2%) 21 (3%)

18 – 65 156 (83%) 1748 (83%) 557 (79%) 65 30 (16%) 303 (14%) 124 (18%)

Race White 134 (72%) 1427 (68%) 544 (78%) Black 34 (18%) 504 (24%) 123 (18%)Asian 5 (3%) 28 (1%) 8 (1%)Other 14 (8%) 142 (7%) 26 (4%)

TELCOMP

5 d 7–10 d 7–10 dN=187 N=2102 N=702

Post-Marketing Reports of Symptomatic Liver Injury : 200214202DE (1)

• 70 M with history of COPD, Billroth II stomach resection, hepatitis A, diabetes– medications: prednisolone, fenoterol/ipratropium, formoterol,

theophylline, ursodeoxycholic acid, cholestyramine, lactulose, acetylcysteine,

• Treated with TEL for AECB and flu-like illness• Day 14: admitted to hospital for recurrent AECB

– treated with high dose corticosteroids and AMC during 3-week hospitalization

• Day 27: discharged home

HK-136

Post-Marketing Reports of Symptomatic Liver Injury : 200214202DE (2)

• Day 50: readmitted with cholestatic hepatitis with jaundice– peak ALT 132 U/l, AP 735 U/l, TB 25 mg/dl

• Day 51: Ultrasound: homogeneous liver with 2mm (enlarged) common bile duct, gall bladder polyps

• Day 58: Liver biospy: marked cholestasis with mononuclear cell infiltrate, singular cell necrosis with surrounding granulocyte reaction– interpreted as consistent with drug-induced cholestatic hepatitis

• Full recovery after ~ 3 months

HK-137

Post-Marketing Reports of Symptomatic Liver Injury : 200213635DE

• 33 F with no significant medical history – medications: ethinylestradiol-levonorgestrol for 3 years

• Treated with TEL x 5 days for bronchitis/sinusitis• Day 3: Elevation of transaminases

– ALT 388, AP normal, TB 33 (ULN <21)– symptoms: nausea, vomiting, RUQ pain, fever, asthenia– normal eosinophils

• Full recovery noted after 5 weeks

HK-139

Post-Marketing Reports of Symptomatic Liver Injury : 200211855DE

• 44 F with history of COPD – medications: budesonide, beta-agonist inhaler, coritcosteroids

• Treated with TEL x 10 days for febrile infection• Day 2: Onset of fatigue, right upper quadrant pain• Day 3: hospitalized

– transaminases in 2-300 range (no values provided), alkaline phosphatase 800U/l, normal bilirubin

– autoimmune and viral serology negative– ultrasound normal

• Full recovery noted in 15 days

HK-141

Post-Marketing Reports of Symptomatic Liver Injury : 200211440DE

• 61 F with history of recurrent endocarditis– medications: acetyldigoxin

• Treated with TEL x ~ 10 days for Sinusitis/tonsillitis• ~ Day 14: Limited effect with relapse of fever

– hospitalized for suspected endocardititis; work-up negative• Had LFT , hepatic labs and work-up (eg viral serology and other infectious causes) not

provided• Discharged with improvement• Biopsy performed several days after discharge:

– focal fatty degeneration (mixed vacuole size) with moderate intrahepatic cholestasis; mild inflammatory (lymphocyte) infiltrate; no eosinophils

– Interpreted as nutritive-toxic origin• Reporting Physician felt overall course not suggestive of drug-induced etiology

HK-142

Telithromycin: Anaerobes – MIC Ranges (μg/mL)

• B. fragilis 0.03 - >128• Bacteroides spp. 0.03 - >64• Prevotella spp. 0.01 - 8.0• Porphyromonas spp. 0.001 - >32• Fusobacterium spp. 0.015 ->64• Actinomyces spp. <0.015• Peptostreptococcus spp. <0.008 - 16• Propionibacterium spp. <0.015 - 0.03• Clostridium spp. <0.008 - 0.25• C. difficile 0.06 - >64

MI-38

Subject 3014/2004/00202-HS-598-Live-4x-2

LB-2

Subject 3014/2004/00202-HS-598-Live-4x-T

LB-3

Subject 3014/2004/00202-HS-598-Live-40x-4

LB-4

Subject 3014/2004/00202-HS-598-Live-40x-2

LB-5

Subject 3014/2004/00202-HS-598-Live-10x-2

LB-7

Subject 3000/502/10692758470-99-4879-4x001

LB-9

Subject 3000/502/10692758470-99-4879-10x001

LB-10

Subject 3000/502/10692758470-99-4879-20x002

LB-11

Subject 3000/502/1069 2758470-99-4879-40x001

LB-12

Subject 3000/502/10692758470-99-4879-40x003

LB-14

Subject 3000/502/10692758470-liver-4x-T001

LB-16

Subject 3000/502/10692758470-liver-20x001

LB-17

Subject 3000/502/10692758470-liver-40x001

LB-18

Telithromycin Subject 3000/605/1091PresentationPresentation:: • 78 year old female, Fine score III• Chest X-ray: consolidation• Blood cultures:

− S. pneumoniae: susceptible to TEL (MIC = 0.03 mcg/mL),susceptible to Pen G (MIC = 2 mcg/mL),resistant to Ery A (MIC = 32 mcg/mL) –

genotype ermB− Respiratory cultures:

H. influenzae: susceptible to TEL (MIC = 1 mcg/mL)M. catarrhalis: TEL MIC not performed, susceptible by disk

Clinical course:Clinical course:• Initial improvement and sterilization of blood culture at day 12 of therapy,

subject had a recurrence of dyspnea and fever associated with a secondary UTI (S. aureus), treated with intravenous antibiotics

• Clinical status at TOC was improved, blood culture negative for S. pneumoniae (presumed persistent because of the IV antibiotic)

EQ-146

QTc vs Telithromycin Plasma Concentration in Phase III Studies

Concentration (µg/mL)

QTc

(m

s)

0 2 4 6 8 10 12-160

-120

-80

-40

0

40

80

120

Concs 5µg/mLConc QTc QTc

5.2 410 -7.45.2 364 -24.55.2 411 13.15.2 409 -3.35.3 428 -0.95.8 431 17.06.2 425 1.56.2 410 10.16.4 391 -38.86.4 381 -5.16.4 393 -6.06.7 435 18.07.2 408 17.87.8 396 0.19.9 427 8.7

N=1512 patientsSlope=0.88 ms/µg/mLr2=0.0025, p0.05

CK-12

Study 3014: Usual Care • Large experience of co-morbidities (e.g. elderly, elderly female,

CHF, CAD) known to increase TdP risk without any clinical signal (death, arrhythmic death, syncope).

• Large experience of co-therapies (e.g. CYP P450 inhibitors, diuretics, drugs prolonging QTc, digitalis, antiarrhythmics, ) known to increase TdP risk without any clinical signal (death, arrhythmic death, syncope).

• Absence of mortality, arrhythmic death or syncope signals in real-use trial vs. AMC

• Time-course of arrhythmic deaths mitigates against any causal relationship (occurred more than 7 days after telithromycin therapy completed).

( 24,000 subjects comparative study)

CK-13

Study 3014: Cardiac AESIs in Subjects at Risk of TdP (1)

65 years 21/2273 (0.9) 21/2203 (1.0)

Women 65 years 10/1235 (0.8) 10/1204 (0.8)

75 years 10/892 (1.1) 11/873 (1.3)

CHF 5/277 (1.8) 3/271 (1.1)

CAD 15/837 (1.8) 10/872 (1.1)

Co-morbidities TEL AMC

TEL = telithromycin, AMC = amoxicillin-clavulanic acid

No. of subjects with cardiac AESIs

CK-16

Study 3014: Cardiac AESIs in Subjects at Risk of TdP (2)

Diuretics 13/1776 (0.7) 12/1710 (0.7)

Drugs prolonging QTc* 11/1974 (0.6) 10/1906 (0.5)

Digitalis 2/20 (1.0) 4/230 (1.7)

CYP3A4 inhibitors 4/2309 (0.2) 11/2201 (0.5)

Co-therapies TEL AMC

*Includes anti-arrhythmicsTEL = telithromycin, AMC = amoxicillin-clavulanic acid

No. of subjects with cardiac AESIs

CK-17

Subject 200214256DE: Spontaneous Report: Fatal Ventricular Arrhythmia (1)

• 59 y/o male treated with TEL for acute sinusitis

• Med Hx: coronary heart failure, angina pectoris, HTN, cardiac stent 2x, triglycerides/cholesterol, manic depressive, spastic paraplegia, obesity (130 kg), daytime somnolence

• Family Hx: sudden death, brothers (48 yr, 49 yr), mother (59 yr)

• Con Meds: triamterene, baclofen, isosorbide, diazepam, metoprolol, amlodipine, mirtazipine, atorvastatin

CK-26

Subject 200214256DE: Spontaneous Report: Fatal Ventricular Arrhythmia (2)

• 3 Days pretreatment: syncopal episode preceded by pallor, incoherent speech

• Day 6: confusion, normal ECG & BP, neuro exam normal • Day 9: motor vehicle accident from possible syncope and

hospitalized; resolved at admission Labs: K+ 3.6 mmol/L; ECG: NSR, 60 bpm, normal QTc

• Day 10: patient found dead at 16.30 14:57: NSR, 55-57 bpm, no QTc prolongation

15:24: ventricular fibrillation 15:33: ventricular fibrillation • No torsades de pointes documented.

CK-27

Subject 200214256DE: Spontaneous Report: Fatal Ventricular Arrhythmia (3)

• 14:57: normal sinus rhythm, 55-57 bpm, no QTc prolongation

CK-28

Subject 200214256DE: Spontaneous Report: Fatal Ventricular Arrhythmia (4)

• 15:24: reported as ‘torsades de pointes’ • Considered ventricular fibrillation on expert read

CK-29

Subject 200214256DE: Spontaneous Report: Fatal Ventricular Arrhythmia (5)

• 15:33: ventricular fibrillation

CK-30