# Presentation: 096019

## Clarithromycin Subject 4003/3212/003with 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 (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.

## 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%)

- TEL	COMP

- 	5 d	7–10 d	7–10 d	N=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 3014/2004/00202-HS-598-Live-4x-2

**LB-2**

## Subject 3014/2004/00202-HS-598-Live-4x-T

**LB-3**

## Subject 3014/2004/00202-HS-598-Live-40x-4

**LB-4**

## Subject 3014/2004/00202-HS-598-Live-40x-2

**LB-5**

## Subject 3014/2004/00202-HS-598-Live-10x-2

**LB-7**

## Subject 3000/502/10692758470-99-4879-4x001

**LB-9**

## Subject 3000/502/10692758470-99-4879-10x001

**LB-10**

## Subject 3000/502/10692758470-99-4879-20x002

**LB-11**

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

**LB-12**

## Subject 3000/502/10692758470-99-4879-40x003

**LB-14**

## Subject 3000/502/10692758470-liver-4x-T001

**LB-16**

## Subject 3000/502/10692758470-liver-20x001

**LB-17**

## Subject 3000/502/10692758470-liver-40x001

**LB-18**

## 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 *erm*B
- 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**

## QTc vs Telithromycin Plasma Concentration in Phase III Studies 

**Concentration (μg/mL)**

******QTc  (ms)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**-160**

**-120**

**-80**

**-40**

**0**

**40**

**80**

**120**

- Concs  5μg/mL

- 	Conc	QTc	QTc
- 	5.2	410	-7.4
- 	5.2	364	-24.5
- 	5.2	411	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

**N=1512 patients**
**Slope=0.88 ms/μg/mL**
**r****2****=0.0025, p********0.05**

**CK-12**

**Notes:**
Phase III QT analytical report  (Shashank Rohatagi)

## 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-arrhythmics
- TEL = 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**

**Notes:**
Source: Section 7.2.1.1 of NDA Amendment 2

## 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**

**Notes:**
Source: Section 7.2.1.1 of NDA Amendment 2

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

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

**CK-28**

**Notes:**
Source: Section 7.2.1.1 of NDA Amendment 2

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

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

**CK-29**

**Notes:**
Source: Section 7.2.1.1 of NDA Amendment 2

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

- 15:33: ventricular fibrillation

**CK-30**

**Notes:**
Source: Section 7.2.1.1 of NDA Amendment 2