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
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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

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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

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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
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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

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Post-Marketing Cardiac Adverse Events

• 37 reported Cardiac AEs from 24 patients

Plus 1 additional case not in reporting period
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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

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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.

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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.

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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.

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Rhythm Strips for Possible Torsades Patient
(Study 3014)
Strip 1
Strip 2
Strip 3
Strip 4
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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
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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

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Hepatic Adverse Events

• 42 reported AEs from 18 patients
• All from Germany

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Hepatic Post-Marketing Events

• No deaths
• 2 liver biopsies
• Many reports lack detailed information or
  narratives

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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

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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

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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

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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.

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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

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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

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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

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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.
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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.)
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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

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Visual Post-Marketing Adverse Events

• 168 reported visual AEs from 124 patients

36 total serious, 24 not reported 108 not
serious
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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)

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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.
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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.

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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.

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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.

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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.
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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.

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END