# Presentation: 105032

## Alpha-1 Proteinase Inhibitor (Human) Product (A1PI) Safety Reporting

- Tina Khoie, M.D., M.P.H.
- Kathryn O’Connell, M.D., Ph.D.
- Craig E. Zinderman, M.D., M.P.H.
- Robert P. Wise, M.D., M.P.H.

**U.S. Food and Drug Administration**
**Center for Biologics Evaluation and Research**
**Office of Biostatistics and Epidemiology**
**Division of Epidemiology**
**Therapeutics and Blood Safety Branch**

- BPAC, November 2005

## Objective

-    Summarize and describe spontaneously reported adverse events from A1PI post-licensure safety surveillance

## Definitions

- Adverse Event (AE) – any unwanted outcome associated with A1PI *irrespective of causality*
- Report – one patient’s experience, excluding duplicates and follow-ups
- Serious AE – death, life-threatening experience, hospitalization (or prolongation), disability/incapacity, birth defect or other important medical events
- Unlabeled event – AE not listed in professional package insert

## Overview of AEs Listed in Package Insert

- * Anaphylaxis warning for IgA Deficiency

## Adverse Event Reporting System (AERS)/MedWatch

- FDA’s passive postmarketing safety surveillance
- Drugs and therapeutic biologics
- AERS contains the following:
- All direct reports
- All manufacturer reports through 10/1997
- Serious manufacturer reports since 11/1997

## Methods

- Queried AERS for reports with A1PI as suspect product
- Nonserious cases submitted in periodic reports and not entered into AERS were included for time period when all 3 products were marketed, January 2003 – July 2005
- Retrieved the following data from AE reports:
- Demographics
- Adverse reaction MedDRA PTs*
- Lot number(s)

- *MedDRA PTs = Medical Dictionary for Regulatory Activities Preferred Terms

## Results 

- Total number of AE reports identified:
- 806 Prolastin (Since 12/1987)
-   38 Aralast    (Since 12/2002)
-     6 Zemaira  (Since 07/2003)
- 90% of A1PI reports are domestic and 10% are foreign (only Prolastin had foreign reports)
- Demographics of domestic A1PI reports:
- 12% serious, 67% nonserious, 21% unknown severity
- 51% 30-69 year olds, 47% unknown age
- 40% females, 35% males, 25% unknown gender

## Total Number of Domestic A1PI AE Reports From 01/2003 – 07/2005

**Numbers are not adjusted for differences in market share, thus number of reports CANNOT be compared among the 3 products.**

## 10 Most Common MedDRA PTs From Domestic Reports

- 10 Most Common MedDRA PTs From Domestic Reports

**Numbers are not adjusted for differences in market share and time on market, thus number of reports CANNOT be compared among the 3 products.**
- *PTs chest pain, chest tightness, chest discomfort, angina pectoris and cardiac pain

## Selected‡ MedDRA PTs from Domestic Reports

- Selected‡ MedDRA PTs from Domestic Reports

**Numbers are not adjusted for differences in market share and time on market, thus number of reports CANNOT be compared among the 3 products.**
- ‡AE’s judged medically most important and appearing in > 1 domestic report
- *PTs chest pain, chest tightness, chest discomfort, angina pectoris and cardiac pain

## Limitations of Passive Surveillance and Spontaneous Reporting

- Underreporting
- Reporting biases
- Reported events unverified and data often incomplete
- Reported events may be related to concurrent medication or underlying disease
- Causal inferences usually impossible
-    Bottom line: Numerical differences among the 3 A1PI products require cautious interpretation

## Acknowledgements

- Miles Braun
- Basil Golding
- Ewa Marszal
- Ross Pierce
- Michael Scheuermann
- Andrew Shrake
- Toby A. Silverman
- Lise Stevens-Hawkins
- Su Wang

## Questions/Comments

## Reporting Rates

- A reporting rate = # AE / # Doses
- Adjusts for differences in product utilization
- Numerator data is subject to limitations of passive surveillance
- Denominator data represents population exposure estimate
- Today’s presentation has been limited to numerator data
- Note: reporting rate  incidence rate, so still have limitations in interpretation

## Age and Gender Distribution for All Domestic A1PI Product AE Reports*

- * 364 reports with missing age or gender not shown in graph.

## A1PI Lot Number Clusters

- 421 (55%) reports had lot number data available; 329 different lot numbers identified.
- Two lot numbers were associated with more than 10 reports.
- One lot number from 1989-1990 was associated with chest pain (9 reports), dyspnea (6 reports) and back pain (5 reports).
- One lot number from 1989 was associated with chills (10 reports), headache (7 reports) and fever (6 reports).

## Serious, Unlabeled AE possibly Related to A1PI

- Prolastin:
- Anaphylaxis (in non-IgA deficient)
- Tongue edema
- Aralast: Tongue edema
- Zemaira: None

## Prolastin: Lot Numbers Associated with More Than 4 Adverse Event Reports

- Includes Domestic AERS and Periodic Reports (n=808)
- Lot Numbers are not mutually exclusive

## Aralast: Lot Numbers Associated with More Than 1 Adverse Event Report

- Includes AERS and Periodic Reports (n=37)
- Lot Numbers are not mutually exclusive

## Zemaira: Lot Numbers Associated with More Than 1 Adverse Event Report

- Includes AERS and Periodic Reports (n=6)
- Lot Numbers are not mutually exclusive

## Distribution of Domestic A1PI Reports by AE (Does not include Periodic Reports)

## All A1PI Products: Number AERS AE Reports by FDA Receipt Year*

- *Excludes Non-serious Reports Received in Periodic Submissions since November 1997

## Chest Pain

**There were no cases which provided information on cardiac workup (i.e. cardiac enzymes, EKG).**
**There were no diagnosed myocardial infarctions reported.**

## Dypsnea

## Anaphylactic Reaction

- 4 Domestic Prolastin reports
- 54 y/o male developed anaphylactoid reaction, chest pain and dyspnea (’89).
- 30 y/o male developed anaphylaxis 10 minutes into first infusion. IgA status unknown (’91).
- Male patient developed anaphylactoid reaction, hypotension and tachycardia (’93).
- 46 y/o male developed anaphylactoid reaction and hypotension (’95).
- 2 Foreign Prolastin reports
- 44 y/o female developed anaphylaxis after 3rd infusion; *normal serum IgA concentrations*. Anti-Prolastin IgE positive. Prolastin therapy discontinued* *(’96).
- 49 y/o male developed anaphylactoid reaction, angina pectoris, dermatitis and hypotension (‘93).

## Convulsion

- 4 Domestic Prolastin reports
- 34 y/o male with *history of seizure disorder*, ESRD on HD, hypertension and on Prolastin therapy 4-5 wks, developed nausea, chills, numbness and suspected grand mal seizure 10 min into infusion; 1 wk later rechallenge resulted in nausea, chills, numbness and chest pain; weekly Prolastin infusions have resumed;  only one lot number noted in report (’02).
- 71 y/o male developed fever, malaise and convulsion (’89).
- 41 y/o female on occasion develops hypotension, shivering, lightheadedness, nausea and suspected petit mal seizure; temporal onset of symptoms not specified and may have started prior to Prolastin therapy in 1989 (’93).
- 49 y/o female with no history of neuropathology experienced suspected clonic convulsion, involuntary myoclonic jerks and sudden inhibition of muscle tone.  “Neurologic work-up unremarkable” (’97).
- 1 Foreign Prolastin report (Canadian clinical study)
- Premature neonate male with grade 3 intraventricular hemorrhage experienced seizures,  hemoglobin and died; event unrelated to product per study investigator and manufacturer (’96).

## Hepatitis

- 6 Domestic Prolastin reports
- 51 y/o female diagnosed with HCV by liver biopsy 8/03; Prolastin infusions 8/01 to 1/02; serologic status prior to A1PI therapy unknown (’03).
- 41 y/o female with history of IVDA developed acute hepatitis (biopsy confirmed) (’93).
- Patient experienced “bacteremic hepatitis” unrelated to A1PI product per attending assessment (’93).
- Male patient receiving A1PI since 1994 tested HCV Ab positive in routine screening for lung transplant (’99).
- 2 males listed with HCV (’95).
- 1 Foreign Prolastin report
- 50 y/o female listed with HBV MedDRA PT (’03).

## Sepsis

- 2 Domestic Prolastin reports
- Adult female with contaminated IV port developed sepsis (MedDRA PT medication error) (’95).
- 67 y/o old female developed bacteremia (’97).
- 5 Foreign Prolastin reports (Canadian clinical study)
- 2 premature male neonates developed *Staphylococcus epidermidis* sepsis; considered nosocomial (’98).
- 2 premature neonates (1 male,  1 female) developed CONS sepsis; unlikely association with study drug per product manufacturer physician assessment (’99).
- Female neonate with bilateral grade 3 intraventricular hemorrhage, GI bleed, presumed sepsis and died (’95).

## Tongue edema

- 5 Domestic Prolastin reports
- 30 y/o male experienced thick tongue, SOB, lightheadedness and slurred speech 30 min after infusion (’99).
- 35 y/o female experienced tongue swelling, SOB, erythema, tachycardia and dysgeusia 10 min after infusion; symptoms normal 30 min after infusion discontinued and treated with proventil, solumedrol (125mg IV), benadryl and tagamet (’94).
- 55 y/o male hospitalized for tongue and neck swelling 8 days after infusion (experienced mucocuntaenous blistering of tongue and lips, chest tightness and rihinorrhea within 24 hours after infusion) (’94).
- 46 y/o female experienced dyspnea, tongue and throat swelling; treated with epinephrine (’94).
- 35 y/o, gender unknown experienced tongue edema, dyspnea, dysgeusia and dermatitis (’95).
- 1 Domestic Aralast report
- Female patient experienced tongue edema and pruritus at infusion site; treated with epi-pen, prednisone and benadryl (’05)

## Death

- Domestic Prolastin reports
- 71 y/o male experienced convulsion, malaise and fever (’89)
- 60 y/o male experienced hallucinations; death secondary to emphysema (’94)
- Foreign Prolastin reports (Both from clinical trial for off-label use in neonate bronchopulmonary dysplasia prevention)
- Female neonate with bilateral grade 3 intraventricular hemorrhage died of GI bleed and presumed sepsis (’95)
- Premature male neonate experienced seizures and  Hg; died of bilateral grade 3 intraventricular hemorrhage (’95)

## Prolastin Serious AERS Reports Received From 2003 - 2005

- 2003, Prolastin
- 41 y/o female developed severe back pain 3 days after infusion.  ER lab tests revealed elevated CPK.  LFTs and serum Cr were normal. Assessment of causal relationship confounded by concomitant meds effexor, remeron, combivent, serevent, ambien and multivitamin.
- 51 y/o female diagnosed with HCV by liver biopsy 8/03; Prolastin infusions 8/01 to 1/02; serologic status prior to A1PI therapy unknown.  Assessment of causal relationship cannot be made because report lacks sufficient medical/social history and serologic status prior to initiation of A1PI therapy.

## 2003, Prolastin
38 y/o female developed rigors, nausea, vomiting, HA and fatigue (foreign)
2004, Prolastin
Adult male hospitalized for dyspnea, fever and abnormal blood gases. Negative rechallenge 2 weeks later. No information on past medical history or concomitant medications. 
57 y/o female with a family history of psoriasis  developed psoriasis during first week of treatment.  Dermatologist found it unlikely that A1PI was related to event.

- 38 y/o female developed rigors, nausea, vomiting, HA and fatigue (foreign)
- 2004, Prolastin
- Adult male hospitalized for dyspnea, fever and abnormal blood gases. Negative rechallenge 2 weeks later. No information on past medical history or concomitant medications.
- 57 y/o female with a family history of psoriasis  developed psoriasis during first week of treatment.  Dermatologist found it unlikely that A1PI was related to event.

- Prolastin Serious AERS Reports Received From 2003 - 2005

## 2004, Prolastin
45 y/o male s/p bronchoscopy, which revealed a granuloma and foreign body, developed bilateral lower lobe pneumonia 3 days post-infusion with fever, cough and bloody, purulent sputum.  Hives developed when infusion rate was increased, but resolved spontaneously.  Pneumonia unrelated to Prolastin per study investigator.
64 y/o female developed wheezing, bronchospasm and facial flushing.
2005, Prolastin
51 y/o female developed injection site irritation and burning.

- 45 y/o male s/p bronchoscopy, which revealed a granuloma and foreign body, developed bilateral lower lobe pneumonia 3 days post-infusion with fever, cough and bloody, purulent sputum.  Hives developed when infusion rate was increased, but resolved spontaneously.  Pneumonia unrelated to Prolastin per study investigator.
- 64 y/o female developed wheezing, bronchospasm and facial flushing.
- 2005, Prolastin
- 51 y/o female developed injection site irritation and burning.

- Prolastin Serious AERS Reports Received From 2003 - 2005

## 2004, Aralast
58 y/o female developed hives on back and right arm, which had an IV.  Good response with epinephrine and benadryl. 
39 y/o female developed SOB and puffy eyes.
47 y/o female developed increased cough with 2 infusions noted to be brownish in color instead of yellow-green.
53 y/o female developed DVT in left arm.
2005, Aralast
Adult female developed infusion-site itching at end of infusion and later that day a swollen tongue.  Treated with Epi pen, prednisone and benadryl.  History of hypersensitivity to synthetics.
31 y/o female developed diarrhea 2 hours post-infusion, lasting 24 hours, and an infusion related reaction.

- 58 y/o female developed hives on back and right arm, which had an IV.  Good response with epinephrine and benadryl.
- 39 y/o female developed SOB and puffy eyes.
- 47 y/o female developed increased cough with 2 infusions noted to be brownish in color instead of yellow-green.
- 53 y/o female developed DVT in left arm.
- 2005, Aralast
- Adult female developed infusion-site itching at end of infusion and later that day a swollen tongue.  Treated with Epi pen, prednisone and benadryl.  History of hypersensitivity to synthetics.
- 31 y/o female developed diarrhea 2 hours post-infusion, lasting 24 hours, and an infusion related reaction.

- Aralast Serious AERS Reports Received From 2003 - 2005

## 2004, Zemaira
43 y/o female received infusion without 5 micron filter during first 2 minutes of infusion.  Patient developed fever 2-3 hrs after infusion. Pt also developed severe HA and body aches.  Symptoms resolved spontaneously within 2 days.
2005, Zemaira
43 y/o male with prior adverse reactions to Zemaira including hangover-post infusion, HA and peripheral edema, was hospitalized with COPD and CHF.  CHF more likely related to underlying COPD rather than A1PI.

- 43 y/o female received infusion without 5 micron filter during first 2 minutes of infusion.  Patient developed fever 2-3 hrs after infusion. Pt also developed severe HA and body aches.  Symptoms resolved spontaneously within 2 days.
- 2005, Zemaira
- 43 y/o male with prior adverse reactions to Zemaira including hangover-post infusion, HA and peripheral edema, was hospitalized with COPD and CHF.  CHF more likely related to underlying COPD rather than A1PI.

- Zemaira Serious AERS Reports Received From 2003 - 2005