Title: Postmarketing Safety Data
1Post-marketing Safety Data
Anti-Infective Drugs Advisory Committee January
8, 2003 Charles Cooper, M.D. Medical Officer
Division of Anti-Infective Drug Products Center
for Drug Evaluation and Research U.S. Food and
Drug Administration
2Post-marketing data - caveats
- Passive reporting underreporting,
reporting/recall biases may exist - Numerator usually uncertain
- Denominator usually uncertain
- Information frequently incomplete
- Confounds assessment of association
- Confounds assessment of causality
3Post-marketing Safety Data
- Approved in July 2001 by European Union
- Since October 2001, Ketek has been marketed in
several countries including - Germany, France, Spain, Italy, Brazil, and
Mexico - Approved indications CAP, AECB, ABS, T/P
- FDA has reviewed safety data up until October 1,
2002 ( 1 million prescriptions) - One ongoing post-marketing safety survey being
conducted in Germany
4Post-marketing Safety Data
- FDA has received data on 406 patients with AEs
- Spontaneous reporting 347 patients
- Post-marketing safety survey 30 patients
- Sponsored studies 29 patients
These have been excluded from this presentation
5Post-marketing Safety Data
- AEs by country (no. of patients)
- 218 Germany
- 99 Brazil
- 44 Spain
- 16 France
- Distribution of prescriptions by country
- Majority in Germany and Italy
6Post-Marketing Cardiac Adverse Events
- 37 reported Cardiac AEs from 24 patients
Plus 1 additional case not in reporting period
7Post-Marketing Cardiac AE of Interest
- AE torsades de pointes, report by general
practioner. - 44 yo male, no cardiac disorder
- Tx with Ketek for bronchitis beginning on 10/2/02
- Malaise on way to rheumatology visit on 10/12/02
- Patient discovered to be in Torsades
- Counter-measures taken and patient recovered
- Reporter considered causation as highly probable
8Post-Marketing Cardiac AE of Interest
- AE Syncope equivalent, depressed level of
consciousness, torsade de pointes Fatal,
ventricular fibrillation. - Source spontaneous report by general
practitioner via company representative. Patient
59 years, male. - Medical History coronary heart disease, state
after percutaneous transluminal angioplasty with
stent implantation after angina pectoris attack
in 2001, hypertension, transverse lesion of the
cord with paraplegia TH 5/6 (car accident in
1990), spastic vesical paralysis, adiposity,
hypertriglyceridemia, hypercholesterolemia, manic
depressive disease.
9Post-Marketing Cardiac AE of Interest
- Concomitant medications methionin, triamterene,
baclofen, isosorbide mononitrate, diazepam,
atorvastatin, mirtazapin, metoprolol, amlodipine. - Course The patient started treatment on 5/23/02
with Ketek for sinusitis and tracheobronchitis
and on 5/28/02 he experienced an episode of
confusion, retrospectively considered an
equivalent of syncope. ECG at that time was
normal as was blood pressure. Ketek was
discontinued.
10Post-Marketing Cardiac AE of Interest
- On 5/30/02, the patient lost control while
driving his car. He was hospitalized and ECG
showed no abnormalities. According to patients
wife, Ketek was re-administered. The patient was
without symptoms until the next afternoon when
the patients telemetry monitor revealed classic
torsade, persisting, finally changing to
ventricular fibrillation that results in a zero
line.
11Rhythm Strips for Possible Torsades Patient
(Study 3014)
Strip 1
Strip 2
Strip 3
Strip 4
12Strip 1 - Poss. Torsades May 31, 2002 Time -
1452
13Strip 4 - Poss. Torsades May 31, 2002 Time -
1457
14Strip 3 - Poss. Torsades May 31, 2002 Time -
1524
15Strip 2 - Poss. Torsades May 31, 2002 Time -
1533
16Case of Interest (cont.)
- Echocardiography left venticle at the end of
diastole 5.9 cm, posterior wall moderately
hypokinetic, ejection fraction 50, aortic sail
closes relatively tight, opening amplitude
reduced but sufficiently large. Satisfactory left
ventricular function. - Labs at admission
- Laboratory CK 530 U/l, CKMB 11 U/l, creatinine
1.4 mg/dl, potassium 3.6 mmol/l, other values
within normal ranges
17Hepatic Adverse Events
- 42 reported AEs from 18 patients
- All from Germany
18Hepatic Post-Marketing Events
- No deaths
- 2 liver biopsies
- Many reports lack detailed information or
narratives
19Case of Interest 1
- 61 yo female, history of IE, on long term
prophylaxis - 2 wk. tx with Ketek for sinusitis/ tonsilitis
- Continued fever work up
- Negative except for incr. LFTs.
- Hospital physician suspected liver reaction
caused by Ketek - Hosp adm. for liver biopsy
- Date of liver biopsy in relation to Ketek
administration was not reported
20Case of Interest 1- Biopsy
- No info on ETOH use or U/S results
- Biopsy results focal fatty (mixed drop size of
vacuoles) degeneration of hepatic tissue with
moderate intrahepatic cholestasis as well as mild
inflammatory mesenchymal activity (lymphocytes).
No signs of malignancy or specificity. No typical
histologic aspect of chronic viral hepatitis, the
findings could indicate a nutritive-toxic genesis
21Case of Interest 2
- 70 yo male, history of COPD, DM, s/p Bilroth
surgery (no hx of liver dx or ETOH) - Admitted 12/13/01 with flu sxs, prod
cough/hemopt. - Ketek course completed Dec. 15 and pt. d/c on
prednisolone - Readmitted Jan 28, 2002 with Cholestatic
hepatosis, likely drug-induced by telithromycin - U/S liver homogenous, size normal, ductus
hepchol 2 mm (enlarged), gall bladder with
suspected polyp, pancreas normal, aorta 18mm,
spleen size normal, kidneys normal
22Case of Interest 2 - Biopsy
- Liver biopsy performed 2/2/2002
- marked cholestatic hepatopathy with mononuclear
inflammatory infiltration in the periportal
triangle with singular cell necrosis and
surrounding granulocytic reaction. Comment
morphol picture compatible with a cholestatic
drug--toxic hepatitis such as can occur after
antibiotics.
23Case of Interest 3
- 33 yo female with history of pyeloplasty, on OC
- No other past medical history
- Treated with Ketek 3/10/02-3/14/02 for
ABS/Bronchitis (unclear if first exposure) - 3/12/02, pt developed n/v/f/s/RUQ pain
- ALT incr. to 823 and Tbili incr to 33 µmol/L
(nllt21) - Viral serologies negative, U/S unremarkable
- Enzymes normalized after 5 weeks. anti-sm Ab not
reported - Increased eosinophils at 7 (not repeated)
- Physician reported causation as probable
24Case of Interest 4
- Report 2/14/02 - 44 yo female with COPD on
beta-stimulant, budesonide, corticosteroids - Tx with Ketek for 6-7 days for febrile
infection - After 2-3 days of tx, she developed severe
tiredness, RUQ pain, fever, icterus - F/u report 3/26/02 clarified no icterus.
Reporter listed with no doubt the diagnosis as
allergic hepatopathy and Ketek causation as
highly probable - Disorder lasted 2/13/02-2/25/02 and resolved 15
days after withdrawal of Ketek
25Case of Interest 4 (cont.)
- Other info/tests
- ALT, AST 200-300
- AMA, ANA and ANCA were negative. No report of
eosinophil count or anti-sm Ab - The patient was hospitalised from 13-Feb to
16-Feb-2002 - Hepatitis A, B and C were negative test for
Epstein-Barr virus was slightly positive - Sonography there were no congested bile ducts
and the liver was morphological without findings - F/u report 4/3/02 reporting physician changed
cause to idiopathic
26Case of Interest 5
- 75 yo male patient with a past history of chronic
bronchitis with chronic stable resp.
insufficiency. No alcoholism, familial history of
hepatitis. Concomitant medications included
paracetmol prn. LFTs were normal 6 mos prior to
event. On 11/27/02, the patient was treated with
Ketek 800 mg qd x 5 d for AECB exacerbation. He
was also treated with prednisolone, paracetamol 4
gr/day, formoterol. - On 12/3/02, the patient experienced fatigue,
jaundice and fever. Lab tests revealed ALT 2810,
AST 1490, total bilirubin 133 (nl lt10). U/S
revealed liver normal for size and for contour
with homogenous echostructure. There was no
dilatation of intra and extrahepatic biliary
ducts
AE occurred after the reporting period.
27Case of Interest 5 (cont.)
- but there was at least one lithiasis in
gallbladder with aspect of cholecystitis. - During the night of admission, the patient
aggravated with coma, was transferred in ICU and
intubated. - 12/4/02 ALT - 595, AST 255. Patient underwent
expl. Lap which did not confirm cholecystitis but
did show hard and nodular liver. Post-op, the
patient experienced hemorrhage and multivisceral
failure with anuria and metabolic acidosis. - 12/5/02 Total bilirubin increased to 282
(nllt10) - Hepatitis B, C serology neg, Hep A IgM strongly
positive
(cont.)
28Case of Interest 5 (cont.)
- Patient also found to have positive acute
serology for C. burnetti - Measurement of paracetamol two days after
admission was low. - Patient died on 12/8/02
- No post-mortem was performed as family refused
29Visual Post-Marketing Adverse Events
- 168 reported visual AEs from 124 patients
36 total serious, 24 not reported 108 not
serious
30Visual Post-Marketing Adverse Events
- Visual Disturbance included the following
- Could not see anything
- Severe dimming of sight
- black before eyes
- Temporary total loss of vision repeated x 5
- Extreme visual disturbance
- Seeing abnormal color (orange/red)
31Selected Narratives
- AE Visual Lost sic
- This spontaneous report from Brazil involves a
39 yo female patient who received therapy with
Ketek 800mg daily from 10/25/02-10/26/02 for the
treatment of sinusitis. There was no mention of
relevant history or concommittant drugs. On
10/25/02 the patient experienced vision loss and
cephalgia. She had partial recovery of vision on
10/29/02. The events are ongoing at the time of
this report. The reporter assessed the events as
highly probable and medically important. Serious
Yes.
AE occurred after the reporting period.
32Selected Narratives
- AE Severe Visual Disturbance
- Source spontaneous report by physician
(internal medicine). Patient female, 36 years.
No information on medical history and concomitant
medication. The patient was treated with Ketek
orally (indication unknown), first intake on
10/1/02. One hour later the patient developed
severe visual disturbance so that she had to
rely on her husbands help. The event resolved
after 9 hours. The physician assessed the causal
relationship between event and treatment with
Ketek as highly probable. Serious Yes.
33Selected Narratives
- AE Massive visual disturbance (could not see
anything) - Source spontaneous report. Patient male, 33
years. The patient was treated with Ketek 1 x 400
mg/day orally from 1/13/02 till 1/15/02 for
sinusitis and tracheitis no information on
further medication. The patient had no medical
history of visual disorders. On 1/15/02 the
patient developed visual disturbance (blurred
vision, affecting near and far sight) he was
considerably impaired in his activities. The
symptoms started increasingly within hours after
intake of Ketek and resolved hours after stop of
treatment with Ketek (end of event 1/16/02). The
patient was not seen by a specialist. According
to physician there was no alternative explanation
for the event. He assessed the causal
relationship between event and treatment with
Ketek as highly probable. Serious Yes.
34Selected Narratives
- AE Visual Disorder, Visual Loss
- Narrative This spontaneous report from a
physician involves a 27 year old female patient
who received therapy with telithromycin 800mg
daily from 5/31/02 until 6/2/02 for the treatment
of probably mycoplasm cough and expectoration.
Relevant medical history includes hypothyroidism
and dysrhythmia. Concomitant drugs include
salbutamol, betamethasone and thyroxine sodium.
On 6/2/02 the patient experienced visual disorder
with visual loss. She discontinued the treatment
with telithromycin. She underwent CAT scan and
visual field studies, both were reported to be
normal. The patient experienced a complete
recovery upon discontinuing drug. The physician
assessed the event as highly probable (for
causality). Serious Yes.
35Selected Narratives
- Excerpts from one additional case. AE Visual
Disorder, Visual Loss - 17 yo female who received Ketek 800 mg orally on
11/11/02 for the treatment of lung infection.
The patient experienced blurred vision 30 min
after intake of Ketek. The visual loss was a
severe blurred vision. It was severe enough to
make the patient unable to distinguish her face
in a mirror, walk, or eat by herself. It is
presumed that the problem was an accommodation
problem. (continued next slide)
AE occurred after the reporting period.
36Selected Narratives (cont.)
- The patient was alone when the event started.
The patients mother arrived 5 hours later and
found the patient in bed due to the event. The
patient has no history of visual abnormalities.
She complained of blurred vision in both distance
and near vision. The event lasted 12 hours after
the Ketek dose was received. The patient was not
only unable to read but was also unable to walk
due to the visual abnormality. She had to remain
in bed and needed assistance with eating.
37END