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Postmarketing Safety Data

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Title: Postmarketing Safety Data


1
Post-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
2
Post-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

3
Post-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

4
Post-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
5
Post-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

6
Post-Marketing Cardiac Adverse Events
  • 37 reported Cardiac AEs from 24 patients

Plus 1 additional case not in reporting period
7
Post-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

8
Post-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.

9
Post-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.

10
Post-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.

11
Rhythm Strips for Possible Torsades Patient
(Study 3014)
Strip 1
Strip 2
Strip 3
Strip 4
12
Strip 1 - Poss. Torsades May 31, 2002 Time -
1452
13
Strip 4 - Poss. Torsades May 31, 2002 Time -
1457
14
Strip 3 - Poss. Torsades May 31, 2002 Time -
1524
15
Strip 2 - Poss. Torsades May 31, 2002 Time -
1533
16
Case 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

17
Hepatic Adverse Events
  • 42 reported AEs from 18 patients
  • All from Germany

18
Hepatic Post-Marketing Events
  • No deaths
  • 2 liver biopsies
  • Many reports lack detailed information or
    narratives

19
Case 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

20
Case 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

21
Case 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

22
Case 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.

23
Case 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

24
Case 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

25
Case 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

26
Case 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.
27
Case 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.)
28
Case 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

29
Visual Post-Marketing Adverse Events
  • 168 reported visual AEs from 124 patients

36 total serious, 24 not reported 108 not
serious
30
Visual 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)

31
Selected 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.
32
Selected 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.

33
Selected 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.

34
Selected 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.

35
Selected 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.
36
Selected 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.

37
END
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