Clarithromycin Subject 40033212003 with ERSP Isolates, PPb

1
Clarithromycin Subject 4003/3212/003with ERSP
Isolates, PPb

• Presentation
• 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
• 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 (MIC6 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.

2
All CAP Studies (Pooled) Key Demographics, mITT
TEL COMP
5 d 710 d 710 d N187 N2102 N702
Sex Male 118 (63) 1172 (56)
357 (51) Female 69 (37) 930 (44) 345 (49)
Age Mean 45.4 44.7 45.6 (yrs) 1318 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) 2
6 (4)
3
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
4
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
5
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
• symptoms nausea, vomiting, RUQ pain, fever,
  asthenia
• normal eosinophils
• Full recovery noted after 5 weeks

HK-139
6
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
7
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
8
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.
• Peptostreptococcus spp.
• Propionibacterium spp.
• Clostridium spp.
• C. difficile 0.06 - 64

MI-38
9
Subject 3014/2004/00202-HS-598-Live-4x-2
LB-2
10
Subject 3014/2004/00202-HS-598-Live-4x-T
LB-3
11
Subject 3014/2004/00202-HS-598-Live-40x-4
LB-4
12
Subject 3014/2004/00202-HS-598-Live-40x-2
LB-5
13
Subject 3014/2004/00202-HS-598-Live-10x-2
LB-7
14
Subject 3000/502/10692758470-99-4879-4x001
LB-9
15
Subject 3000/502/10692758470-99-4879-10x001
LB-10
16
Subject 3000/502/10692758470-99-4879-20x002
LB-11
17
Subject 3000/502/1069 2758470-99-4879-40x001
LB-12
18
Subject 3000/502/10692758470-99-4879-40x003
LB-14
19
Subject 3000/502/10692758470-liver-4x-T001
LB-16
20
Subject 3000/502/10692758470-liver-20x001
LB-17
21
Subject 3000/502/10692758470-liver-40x001
LB-18
22
Telithromycin Subject 3000/605/1091

• Presentation
• 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
• 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
23
?QTc vs Telithromycin Plasma Concentration in
Phase III Studies
Concs ? 5µg/mL
Conc QTc ?QTc 5.2 410 -7.4 5.2 364 -24.5 5.2 4
11 13.1 5.2 409 -3.3 5.3 428 -0.9 5.8 431 17.0
6.2 425 1.5 6.2 410 10.1 6.4 391 -38.8 6.4 381
-5.1 6.4 393 -6.0 6.7 435 18.0 7.2 408 17.8 7
.8 396 0.1 9.9 427 8.7
120
80
40
0
?QTc (ms)
-40
-80
N1512 patients Slope0.88 ms/µg/mL r20.0025,
p?0.05
-120
-160
0
2
4
6
8
10
12
Concentration (µg/mL)
CK-12
24
Study 3014 Usual Care
( 24,000 subjects comparative study)

• 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).

CK-13
25
Study 3014 Cardiac AESIs in Subjects at Risk of
TdP (1)
No. of subjects with cardiac AESIs
Co-morbidities TEL AMC
? 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)
TEL telithromycin, AMC amoxicillin-clavulanic
acid
CK-16
26
Study 3014 Cardiac AESIs in Subjects at Risk of
TdP (2)
No. of subjects with cardiac AESIs
Co-therapies
TEL AMC
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)
Includes anti-arrhythmics TEL telithromycin,
AMC amoxicillin-clavulanic acid
CK-17
27
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
28
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
• 1457 NSR, 55-57 bpm, no QTc prolongation
• 1524 ventricular fibrillation
• 1533 ventricular fibrillation
• No torsades de pointes documented.

CK-27
29
Subject 200214256DE Spontaneous Report Fatal
Ventricular Arrhythmia (3)

• 1457 normal sinus rhythm, 55-57 bpm, no QTc
  prolongation

CK-28
30
Subject 200214256DE Spontaneous Report Fatal
Ventricular Arrhythmia (4)

• 1524 reported as torsades de pointes
• Considered ventricular fibrillation on expert
  read

CK-29
31
Subject 200214256DE Spontaneous Report Fatal
Ventricular Arrhythmia (5)

• 1533 ventricular fibrillation

CK-30