Post on 15-Dec-2015
Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
TysabriTysabri®® (natalizumab) Risk (natalizumab) Risk Minimization Action Plan (RiskMAP)Minimization Action Plan (RiskMAP)TysabriTysabri®® (natalizumab) Risk (natalizumab) Risk Minimization Action Plan (RiskMAP)Minimization Action Plan (RiskMAP)
Joint Meeting of the Gastrointestinal Drugs Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeManagement Advisory Committee
Claudia B. Karwoski, Pharm.D.,Claudia B. Karwoski, Pharm.D.,Risk Management Team LeaderRisk Management Team Leader
Office of Surveillance and EpidemiologyOffice of Surveillance and EpidemiologyJuly 31, 2007July 31, 2007
Joint Meeting of the Gastrointestinal Drugs Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeManagement Advisory Committee
Claudia B. Karwoski, Pharm.D.,Claudia B. Karwoski, Pharm.D.,Risk Management Team LeaderRisk Management Team Leader
Office of Surveillance and EpidemiologyOffice of Surveillance and EpidemiologyJuly 31, 2007July 31, 2007
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
OverviewOverviewOverviewOverview
• TOUCH Prescribing Program– Key Elements of MS-TOUCH – Experience with TOUCH in multiple
sclerosis (MS) patients – Proposed features of CD-TOUCH – Additional considerations in Crohn’s
disease (CD) patients• Postmarketing Safety Update
• TOUCH Prescribing Program– Key Elements of MS-TOUCH – Experience with TOUCH in multiple
sclerosis (MS) patients – Proposed features of CD-TOUCH – Additional considerations in Crohn’s
disease (CD) patients• Postmarketing Safety Update
3Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Reintroduction to US MarketReintroduction to US MarketReintroduction to US MarketReintroduction to US Market
• PCNS AC recommended return to market based on magnitude of efficacy– Treatment effect as monotherapy at 2 years*
• Progression of disability: absolute reduction in risk of 12%%; relative reduction in risk of 42%
• Annualized relapse rate: absolute reduction of 49%; relative reduction of 67%
• PCNS AC also recommended a RiskMAP that includes mandatory registration and restricted distribution
• PCNS AC recommended return to market based on magnitude of efficacy– Treatment effect as monotherapy at 2 years*
• Progression of disability: absolute reduction in risk of 12%%; relative reduction in risk of 42%
• Annualized relapse rate: absolute reduction of 49%; relative reduction of 67%
• PCNS AC also recommended a RiskMAP that includes mandatory registration and restricted distribution
*PCNS AC FDA Briefing Document, February 9, 2006
4Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
TOUCH Prescribing ProgramTOUCH Prescribing ProgramTOUCH Prescribing ProgramTOUCH Prescribing Program
• Performance-linked Access System RiskMAP– Requires documentation of safe use before
the patient can be treated with the product – Often requires participation of all parties
involved in the prescribing, dispensing, or administration of the product
– It is the rigorous of the 3 categories of RiskMAPs
– Has some disadvantages but also has some evidence of effectiveness in minimizing risk
• Performance-linked Access System RiskMAP– Requires documentation of safe use before
the patient can be treated with the product – Often requires participation of all parties
involved in the prescribing, dispensing, or administration of the product
– It is the rigorous of the 3 categories of RiskMAPs
– Has some disadvantages but also has some evidence of effectiveness in minimizing risk
5Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
TOUCH GoalsTOUCH GoalsTOUCH GoalsTOUCH Goals
• Risk minimization goals:– To promote informed risk-benefit decisions
regarding natalizumab use – To minimize the health consequences of PML
(e.g., death, disability)– To minimize the risk of PML
• Risk minimization goals:– To promote informed risk-benefit decisions
regarding natalizumab use – To minimize the health consequences of PML
(e.g., death, disability)– To minimize the risk of PML
6Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
TOUCH Goals TOUCH Goals TOUCH Goals TOUCH Goals
• Risk assessment goals:– To determine the incidence and risk factors
for PML and other serious opportunistic infections (OI) with natalizumab treatment
– To assess further the overall safety profile of natalizumab
• Risk assessment goals:– To determine the incidence and risk factors
for PML and other serious opportunistic infections (OI) with natalizumab treatment
– To assess further the overall safety profile of natalizumab
7Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Key Elements of MS-TOUCHKey Elements of MS-TOUCHKey Elements of MS-TOUCHKey Elements of MS-TOUCH
• Mandatory enrollment of prescribers, patients, infusion sites, and afflilated central pharmacies
• Controlled distribution to authorized infusion sites and pharmacies
• Education program for health care providers and patients
• Safety surveillance of PML, serious OI, and deaths
• Program evaluation of health outcomes, process compliance, and assessment of knowledge
• Mandatory enrollment of prescribers, patients, infusion sites, and afflilated central pharmacies
• Controlled distribution to authorized infusion sites and pharmacies
• Education program for health care providers and patients
• Safety surveillance of PML, serious OI, and deaths
• Program evaluation of health outcomes, process compliance, and assessment of knowledge
Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
How Does MS-TOUCH Work to How Does MS-TOUCH Work to Meet Its Risk Minimization Goals?Meet Its Risk Minimization Goals?
How Does MS-TOUCH Work to How Does MS-TOUCH Work to Meet Its Risk Minimization Goals?Meet Its Risk Minimization Goals?
9Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Challenges in Minimizing Challenges in Minimizing Risk of PMLRisk of PML
Challenges in Minimizing Challenges in Minimizing Risk of PMLRisk of PML
• Risk factors for natalizumab-associated PML are not known
• No known effective non-invasive laboratory test to monitor for PML
• May not be preventable • No known effective treatment
• Risk factors for natalizumab-associated PML are not known
• No known effective non-invasive laboratory test to monitor for PML
• May not be preventable • No known effective treatment
10Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
MS-TOUCH Methods to MinimizeMS-TOUCH Methods to Minimizethe Risk of PMLthe Risk of PML
MS-TOUCH Methods to MinimizeMS-TOUCH Methods to Minimizethe Risk of PMLthe Risk of PML
• Program reinforces:– Appropriate patient selection– Risk communication to HCPs and
patients – Close patient monitoring
• Program reinforces:– Appropriate patient selection– Risk communication to HCPs and
patients – Close patient monitoring
11Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Prescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing Risk
• Appropriate Patient Selection – At enrollment prescribers indicate that they
acknowledge: • Their patient has relapsing form of MS based
upon clinical and radiological evidence • Indicated as monotherapy• Generally recommended for patients who have
had an inadequate response to, or are unable to tolerate alternative MS therapies
• Appropriate Patient Selection – At enrollment prescribers indicate that they
acknowledge: • Their patient has relapsing form of MS based
upon clinical and radiological evidence • Indicated as monotherapy• Generally recommended for patients who have
had an inadequate response to, or are unable to tolerate alternative MS therapies
12Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Prescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing Risk
• Every 6 months• Prescriber determines whether patient is
still appropriate for natalizumab treatment
• An interim history is collected as part of the re-authorization process
• Every 6 months• Prescriber determines whether patient is
still appropriate for natalizumab treatment
• An interim history is collected as part of the re-authorization process
13Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Prescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing Risk
• MS-TOUCH recommends close monitoring– Routine evaluation of patient at 3 and 6
months after the first dose and every 6 months thereafter
– More frequent evaluation if contacted by the infusion site and/or patient
– For symptoms suggestive of PML• Suspension of natalizumab dosing and further
evaluation• If clinically indicated, obtain MRI of the brain and
cerebrospinal fluid for JC viral DNA
• MS-TOUCH recommends close monitoring– Routine evaluation of patient at 3 and 6
months after the first dose and every 6 months thereafter
– More frequent evaluation if contacted by the infusion site and/or patient
– For symptoms suggestive of PML• Suspension of natalizumab dosing and further
evaluation• If clinically indicated, obtain MRI of the brain and
cerebrospinal fluid for JC viral DNA
14Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Infusion Site StaffInfusion Site Staff Role in Minimizing Risk Role in Minimizing Risk
Infusion Site StaffInfusion Site Staff Role in Minimizing Risk Role in Minimizing Risk
• Before every infusion, staff determine if patient:– is authorized to receive natalizumab– has received and read the Medication
Guide
• Before every infusion, staff determine if patient:– is authorized to receive natalizumab– has received and read the Medication
Guide
15Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Infusion Site StaffInfusion Site Staff Role in Minimizing Risk Role in Minimizing Risk
Infusion Site StaffInfusion Site Staff Role in Minimizing Risk Role in Minimizing Risk
• Screening for possible symptoms indicative of PML and inappropriate use – Have you experienced any new or worsening
medical problems (change in thinking, eyesight, balance, strength or other problems)?
– Do you have a medical condition that can weaken the immune system?
– Have you taken any medicines that weaken the immune system?
– Have you taken any systemic steroids (other than for recent MS relapse)?
• A “yes” response prompts a call to the prescriber for authorization to infuse natalizumab
• Screening for possible symptoms indicative of PML and inappropriate use – Have you experienced any new or worsening
medical problems (change in thinking, eyesight, balance, strength or other problems)?
– Do you have a medical condition that can weaken the immune system?
– Have you taken any medicines that weaken the immune system?
– Have you taken any systemic steroids (other than for recent MS relapse)?
• A “yes” response prompts a call to the prescriber for authorization to infuse natalizumab
16Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Patient’s Role in Minimizing RiskPatient’s Role in Minimizing RiskPatient’s Role in Minimizing RiskPatient’s Role in Minimizing Risk
• Acknowledge their awareness of risks• Understand the required monitoring • Report new or worsening symptoms• Provide a list of all medicines and treatments
to each scheduled infusion appointment
• Acknowledge their awareness of risks• Understand the required monitoring • Report new or worsening symptoms• Provide a list of all medicines and treatments
to each scheduled infusion appointment
Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Postmarketing Experience with Postmarketing Experience with MS-TOUCHMS-TOUCH
Postmarketing Experience with Postmarketing Experience with MS-TOUCHMS-TOUCH
18Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Post-Marketing ExposurePost-Marketing ExposurePost-Marketing ExposurePost-Marketing Exposure
• 16,900 patients worldwide• 13,745 US patients
– ~7,500 during initial marketing period– 8,313 TOUCH patients infused Tysabri
• 6,245 treated for the first time• 38,898 total infusions; median of 4
infusions/patient• 2,100 exposed for 6-12 months • None > 1 year of continuous use
• 16,900 patients worldwide• 13,745 US patients
– ~7,500 during initial marketing period– 8,313 TOUCH patients infused Tysabri
• 6,245 treated for the first time• 38,898 total infusions; median of 4
infusions/patient• 2,100 exposed for 6-12 months • None > 1 year of continuous use
Data derived from Biogen Idec; exposure as of May 23, 2007
19Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
MS-TOUCH Safety Surveillance MS-TOUCH Safety Surveillance MS-TOUCH Safety Surveillance MS-TOUCH Safety Surveillance
• There were no reports of PML in the postmarketing period
• Two reports of other serious opportunistic infections:
• There were no reports of PML in the postmarketing period
• Two reports of other serious opportunistic infections:
Source Age/Gender
Diagnosis # of infusions
Outcome
ForeignSpontaneous
26Female
Herpes Zoster
7 Hospitalized, treated and discharged
USSpontaneous
26 Male
Herpes esophagitis
~6 Hospitalized, treated and discharged
20Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Baseline Patient DataBaseline Patient DataBaseline Patient DataBaseline Patient Data
• Demographics – Gender:
• Women 5,925• Men 2,381• Unspecified 7
– Median age 46 years
• Demographics – Gender:
• Women 5,925• Men 2,381• Unspecified 7
– Median age 46 years
21Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Baseline Patient DataBaseline Patient DataBaseline Patient DataBaseline Patient Data
• Prior MS therapy – 2.63% were naïve to MS therapy– Recent therapies
• Avonex (interferon beta 1a) 29%• Copaxone (glatiramer acetate) 27%• Rebif (interferon beta 1a) 18%• Natalizumab 6.4%, ~25% had received
natalizumab sometime in the past• ~25% had received combination therapy• ~12% indicate recent immunosuppressant use
• Prior MS therapy – 2.63% were naïve to MS therapy– Recent therapies
• Avonex (interferon beta 1a) 29%• Copaxone (glatiramer acetate) 27%• Rebif (interferon beta 1a) 18%• Natalizumab 6.4%, ~25% had received
natalizumab sometime in the past• ~25% had received combination therapy• ~12% indicate recent immunosuppressant use
22Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Pre-infusion Patient ChecklistPre-infusion Patient ChecklistPre-infusion Patient ChecklistPre-infusion Patient Checklist
• About 8% (3,123) of all checklists required prescriber contact and authorization – Overall good compliance, only 3 infusions
occurred when authorization was not granted • “Yes” responses to questions
• About 8% (3,123) of all checklists required prescriber contact and authorization – Overall good compliance, only 3 infusions
occurred when authorization was not granted • “Yes” responses to questions
Changes in medical problems 5.4%
Concurrent immunosuppressant or immunomodulatory agents
1.5%
Concurrent systemic corticosteroid 2.3%
Concomitant condition that may weaken the immune system
0%
23Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Prescriber ReauthorizationPrescriber Reauthorization Prescriber ReauthorizationPrescriber Reauthorization
• Prescriber is required to complete the Patient Status and Reauthorization Form every 6 months
• Prescriber is required to complete the Patient Status and Reauthorization Form every 6 months
Percent of Patient Status and Re-authorization questionnaires completed
99.6%
Percent of patient reauthorized to continue natalizumab
96.1%
Concurrent immunosuppressant, immuno-modulatory agents, or chronic corticosteroids
~3%
Intermittent courses of corticosteroids (allowed in TOUCH)
9.4%
24Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Other RiskMAP Evaluation Other RiskMAP Evaluation ComponentsComponents
Other RiskMAP Evaluation Other RiskMAP Evaluation ComponentsComponents
• HCP (prescriber and nurse) survey – High percentages of correct responses to
questions:• Knowledge of the key risk management
messages • Actions taken to minimize the risk of PML
• Distribution data– Only 10 of >10,000 shipments were
unauthorized (sent to patients or prescribers address)
• HCP (prescriber and nurse) survey – High percentages of correct responses to
questions:• Knowledge of the key risk management
messages • Actions taken to minimize the risk of PML
• Distribution data– Only 10 of >10,000 shipments were
unauthorized (sent to patients or prescribers address)
25Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Summary of MS-TOUCH Summary of MS-TOUCH ExperienceExperience
Summary of MS-TOUCH Summary of MS-TOUCH ExperienceExperience
• At this time the TOUCH program appears to be working satisfactorily in the MS population– No additional cases of PML since
reintroduction– Primarily used as monotherapy – Good compliance with RiskMAP processes – Surveys indicate a high level of understanding
of the risks and requirements of the RiskMAP– The postmarketing experience is relatively
short
• At this time the TOUCH program appears to be working satisfactorily in the MS population– No additional cases of PML since
reintroduction– Primarily used as monotherapy – Good compliance with RiskMAP processes – Surveys indicate a high level of understanding
of the risks and requirements of the RiskMAP– The postmarketing experience is relatively
short
26Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Proposed CD-TOUCHProposed CD-TOUCHProposed CD-TOUCHProposed CD-TOUCH
• Process for enrollment, reauthorization, and follow-up are the same
• Minor Differences:– MS patients are enrolled in MS-TOUCH,
CD patients are enrolled in CD-TOUCH – Educational materials will be updated to
include use in CD
• Process for enrollment, reauthorization, and follow-up are the same
• Minor Differences:– MS patients are enrolled in MS-TOUCH,
CD patients are enrolled in CD-TOUCH – Educational materials will be updated to
include use in CD
27Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
DifferencesDifferencesDifferencesDifferences
• CD-TOUCH does not emphasize monotherapy to same extent as MS-TOUCH
The prescriber acknowledgement section includes the following statement for each program:
• CD-TOUCH does not emphasize monotherapy to same extent as MS-TOUCH
The prescriber acknowledgement section includes the following statement for each program:
MS-TOUCH CD-TOUCH
TYSABRI is indicated as monotherapy for relapsing forms of MS
TYSABRI is indicated for the treatment of moderately to severely active CD
28Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
DifferencesDifferencesDifferencesDifferences• CD-TOUCH allows for concomitant use of
chronic steroids. CD-TOUCH prescriber acknowledgement includes the following statement:
“Patients receiving steroid therapy at the time of Tysabri initiation should undergo a steroid taper regimen once a clinical response is achieved. Steroids should be discontinued no later than 6 months after Tysabri initiation. If this is not possible, Tysabri therapy should be discontinued. Intermittent short courses of steroids are permissible to treat acute disease flares.”
• CD-TOUCH allows for concomitant use of chronic steroids. CD-TOUCH prescriber acknowledgement includes the following statement:
“Patients receiving steroid therapy at the time of Tysabri initiation should undergo a steroid taper regimen once a clinical response is achieved. Steroids should be discontinued no later than 6 months after Tysabri initiation. If this is not possible, Tysabri therapy should be discontinued. Intermittent short courses of steroids are permissible to treat acute disease flares.”
29Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
DifferencesDifferencesDifferencesDifferences
• Questions 3 and 4 on the Pre-infusion Patient Checklist have minor differences– In the past month, have you taken medicines
to treat cancer or MS [or CD] or any other medicines that weaken your immune system?
– In the past month, other than for the treatment of a recent relapse [flare], have you taken any of the following medicines (common medicines for each disease listed)?
• May need further customization if concomitant therapy permitted
• Questions 3 and 4 on the Pre-infusion Patient Checklist have minor differences– In the past month, have you taken medicines
to treat cancer or MS [or CD] or any other medicines that weaken your immune system?
– In the past month, other than for the treatment of a recent relapse [flare], have you taken any of the following medicines (common medicines for each disease listed)?
• May need further customization if concomitant therapy permitted
30Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Special Considerations in Crohn’s Special Considerations in Crohn’s Disease PatientsDisease Patients
Special Considerations in Crohn’s Special Considerations in Crohn’s Disease PatientsDisease Patients
• The appropriate patient and how these patients would be identified in clinical practice
• The best way to monitor the CD population for PML
• Whether concomitant immunosuppressive and immunomodulatory therapy will be permitted
• Whether the concurrent use of chronic steroids for 6 months is acceptable
• How flares of CD will be treated
• The appropriate patient and how these patients would be identified in clinical practice
• The best way to monitor the CD population for PML
• Whether concomitant immunosuppressive and immunomodulatory therapy will be permitted
• Whether the concurrent use of chronic steroids for 6 months is acceptable
• How flares of CD will be treated
Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Postmarketing Safety UpdatePostmarketing Safety UpdatePostmarketing Safety UpdatePostmarketing Safety Update
32Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Postmarketing Adverse Event Postmarketing Adverse Event ExperienceExperience
Postmarketing Adverse Event Postmarketing Adverse Event ExperienceExperience
• Sponsor’s Periodic Safety Update Report – Types and frequency of postmarketing adverse
events are consistent with known safety profile– Possible higher risk of hypersensitivity with
extended gap in treatment • Labeling changes proposed
• Adverse Event Reporting System– > 1,700 reports, 65% from clinical trials– Most events appear consistent with product labeling– Proposed hypersensitivity labeling changes under
review
• Sponsor’s Periodic Safety Update Report – Types and frequency of postmarketing adverse
events are consistent with known safety profile– Possible higher risk of hypersensitivity with
extended gap in treatment • Labeling changes proposed
• Adverse Event Reporting System– > 1,700 reports, 65% from clinical trials– Most events appear consistent with product labeling– Proposed hypersensitivity labeling changes under
review
33Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Spontaneous Reports of Spontaneous Reports of Natalizumab-associated Liver InjuryNatalizumab-associated Liver Injury
Adverse Event Reporting System (AERS)Adverse Event Reporting System (AERS)
Spontaneous Reports of Spontaneous Reports of Natalizumab-associated Liver InjuryNatalizumab-associated Liver Injury
Adverse Event Reporting System (AERS)Adverse Event Reporting System (AERS) • 28 recently identified unduplicated cases
(reported 11/04 - 6/22/07)• 4 cases of potentially serious hepatocellular
injury; 3/4 cases in US• Remaining 24 reports of mild liver
abnormalities e.g. “increased liver enzymes,” “increased LFTs”
• No deaths or liver transplants• Liver injury ‘signal’ not identified in clinical
trials
• 28 recently identified unduplicated cases (reported 11/04 - 6/22/07)
• 4 cases of potentially serious hepatocellular injury; 3/4 cases in US
• Remaining 24 reports of mild liver abnormalities e.g. “increased liver enzymes,” “increased LFTs”
• No deaths or liver transplants• Liver injury ‘signal’ not identified in clinical
trials
34Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007
Cases of Serious Natalizumab-associated Cases of Serious Natalizumab-associated Liver Injury (n = 4)Liver Injury (n = 4)
Cases of Serious Natalizumab-associated Cases of Serious Natalizumab-associated Liver Injury (n = 4)Liver Injury (n = 4)
• Liver injury occurred within 18 days after 1st dose in 3/4 cases; after 5 doses in 1/4 cases
• Range of peak serum ALT: – 521 u/L - 2,427 u/L*
• Range of peak serum total bilirubin: Normal – 15.7 mg/dLtt
• Diagnostic workups did not identify another obvious cause of liver injury
• Further evaluation of cases is in progress
• Liver injury occurred within 18 days after 1st dose in 3/4 cases; after 5 doses in 1/4 cases
• Range of peak serum ALT: – 521 u/L - 2,427 u/L*
• Range of peak serum total bilirubin: Normal – 15.7 mg/dLtt
• Diagnostic workups did not identify another obvious cause of liver injury
• Further evaluation of cases is in progress
*upper limit of normal: 44 u/Ltt upper limit of normal: 1 mg/dL