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TNF Blocker Safety:Lymphoma and

Liver Failure

Tim Coté MD MPH, Chief, Therapeutics & Blood Safety Branch, DE/OBE/CBER/FDA

March 4, 2003

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Postmarketing Surveillance Clinicians and others can report

adverse events associated with drugs

Passive surveillance Greatest strength is as a means of

signal generation

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Characteristics of Postmarketing Reports:

Voluntary for clinicians but mandatory for companies

Often incomplete-Unreported cases and-Sketchy narratives

Coded into MedDRA terminology with high sensitivity

Causality assessments are tenuous by design Cannot generate incidence rates

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Lymphomas with TNF Blockers Rich body of medical literature associating

immunodisregulation and lymphoma; biologically plausible that TNF blockers might cause lymphoma

Hundreds of thousands of patients on these drugs, increasing the public health importance of this Committee’s consideration.

We have published a series of 26 lymphomas arising among people on TNF Blockers, but causality unclear.

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Lymphomas and TNF Blockers: Current Understanding

RA and NHL are associated; this complicates the problem.

Placebo-controlled studies have been small.

Manufacturer’s pre- and post-marketing cohort studies have short follow-up times relative to carcinogenesis.

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Update: Lymphomas Reported to FDA following TNF blockers, 1/99-12/02

95 reports o fbx-proven Lymphom adx'ed subsequent to

Infliximab Tx

368 not lym phomas8 had no biopsy

1 lacked temporality

473 reports with MedDR Aterms coding for Lym phom a

and Infliximab tx

63 reports with bx-provenLym phoma dx'ed

subsequent toE tanercept T x

324 not lym phomas2 had no bx

1 lacked temporality

390 reports w ith MedDR A Codingfor Lym phoma and E tanercept tx

863 reports w ithMedDRA terms (specific and non-specific) fo r

Lym phom a and TN F blockers

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Reports of 158 Lymphomas Reported Among Persons Taking TNF Blockers,

1/99-12/02

0

5

10

15

2025

30

35

4045

1-6'99

7-12'99

1-6'00

7-12'00

1-6'01

7-12'01

1-6'02

7-12'02

Date Diagnosed

Cases R

ep

ort

ed

Source: Reports to FDA MedWatch program

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Patient Characteristics: Lymphoma among patients treated with TNF blockers

Infliximab Etanercept Both

Age: Median Range

6624-85

6229-85

6424-85

% Female 55% 63% 59%

Indication RA Crohn’s Other

73%21%6%

86%0%14%

79%12%11%

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Histology of 158 Lymphomasamong Patients with TNF Blockers, Reported to FDA 1/99-12/02

78 (49%) Lymphoma NOS 26 (16%) non-Hodgkin’s Lymphoma, NOS 23 (15%) B-cell lymphoma, NOS 20 (13%) Hodgkin’s Disease 6 (4%) T-cell Lymphoma 3 (2%) Mantle cell lymphoma 1 (1%) Plasmacytoma 1 (1%) Burkitt’s Lymphoma

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Conclusions: Lymphoma among TNF blocker recipients

They are poorly characterized. It has not been established if they are the same grade as the general population. Histologically, they may be consistent with lymphoma secondary to immunodeficiency.

Clinical trials found increased NHL risk, but based on few observations.

Assessment is complicated by RA-confounded increases.

The number of cases of lymphoma among persons taking TNF Blockers is growing.

FDA needs input from the AAC to assess causality and/or propose means to better evaluate causality.

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Liver Failure Signal for Leflunomide, thus of

interest for TNF Blockers In clinical trials, some patients on

Infliximab showed elevated increased liver enzymes.

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Infliximab-mediated ALT Increases

Placebo Infliximab

RA Patients on MTX

25/85 (29%)

127/342 (37%)

CD Patients w/o MTX

68/187 (36%) 160/385 (42%)

-Increased ALT was predominately <2x ULN

--No clinical sequelae

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Analysis of Liver Failure Reports to FDA

4 3 R e po rts fou ndto ha ve o the r p ro xim a lca u ses o f live r fa ilu re

(se e p ie ch a rt)

7 R e p orts (I=5 ,E = 2)M a y B e asso cia ted

w ith a n ti-T N F Tx (fu rth e r in fo p e n d in g)

5 0 R e p o rts w ith w e ll d ocu m e n tedlive r fa ilu re fo llow in g a n ti-T N F tx

(I= 3 1 ; E = 1 9)

1 3 4 R e po rts to M e d W a tchc it in g E ta ne rcep t o r In f lix im ab a n d M ed D R A

te rm s fo r live r fa ilu re

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Extraneous causes of hepatic impairment among 43 pts on TNF

Blockers.

Sepsis, 13

TB/ I NH, 8

ETOH, 5

GVH, 2

Viral hep, 3

Other drug, 6

Other Causes, 6

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Conclusion: Liver Failure with TNF blockers Liver Failure with TNF Blockers appears to

be a rare event While there are a large number of people

on TNF blockers, chance occurrence is unlikely (1/106 in general pop); causality cannot be ruled out. Some concern remains warranted

Further clinical data on remaining cases are pending.