# Presentation: 890075

## 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**

## 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 **

## 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**

## 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**

## 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**

## Post-Marketing Cardiac Adverse Events

- 37 reported Cardiac AEs from 24 patients

| Adverse Event | Total # | Serious |
| --- | --- | --- |
| Tachycardia NOS | 8 | 2 |
| Palpitations | 6 | 1 |
| Cardiovasc d/o NOS | 4 | 2 |
| Atrial fibrillation | 1 | 1 |
| Supraventricular arrhythmia NOS | 1 | 1 |
| Torsades de Pointes | 1* | 1 |

*** Plus 1 additional case not in reporting period**

## 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”

## 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.

## 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.

## 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 patient’s wife, Ketek was re-administered.  The patient was without symptoms until the next afternoon when the patient’s telemetry monitor revealed “classic torsade, persisting, finally changing to ventricular fibrillation that results in a zero line.”

## Rhythm Strips for Possible Torsades Patient (Study 3014)

**Strip #2**

**Strip #1**

**Strip #3**

**Strip #4**

## Strip #1 - Poss. Torsades : May 31, 2002 Time -  14:52

## Strip #4 - Poss. Torsades : May 31, 2002 

**Strip #4 - Poss. Torsades : May 31, 2002 **
**Time -  14:57**

## Strip #3 - Poss. Torsades : May 31, 2002 Time -  15:24

## Strip #2 - Poss. Torsades : May 31, 2002 Time -  15:33

## 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

## Hepatic Adverse Events

**42 reported AEs from 18 patients**
**All from Germany**

| Preferred Term | Total # |
| --- | --- |
| LFT NOS abnormal | 6 |
| Transaminase Incr | 5 |
| Jaundiced | 4 |
| Hepatitis NOS | 4 |
| Bilirubin Incr | 4 |
| ALT Incr | 3 |
| Hepatocellular damage | 2 |

## Hepatic Post-Marketing Events

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

## 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. LFT’s. **
**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**

## 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****”**

## 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”**

## 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.”**

## 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 ****μ****mol/L (nl<21)**
**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”**

## 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

## 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”

## 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. LFT’s 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 <10). 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.

## 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 (nl<10)
- Hepatitis B, C serology neg, Hep A IgM strongly positive

- (cont.)

## 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

## Visual Post-Marketing Adverse Events 

- 168 reported visual AEs from 124 patients*

| Adverse Event | Total # |
| --- | --- |
| Vision blurred | 82 |
| Visual disturbance | 42 |
| Accommodation d/o | 12 |
| Diplopia | 9 |
| Visual acuity reduced | 3 |
| Photophobia | 2 |
| Blindness/visual loss | 1 |

*** 36 total serious, 24 not reported 108 not serious**

## 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)

## 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.

## 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 husband’s help. The event resolved after 9 hours. The physician assessed the causal relationship between event and treatment with Ketek as “highly probable.”  Serious: Yes.”

## 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.”

## 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.”

## 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.

## Selected Narratives (cont.)

- 	The patient was alone when the event started. The patient’s 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.

## END