Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research

Date: February 03, 2003

From: Lawrence Goldkind MD.

Deputy Division Director

Division of Anti-inflammatory, Analgesic and Ophthalmic Drug Products

HFD-550

To: Lee Simon MD

Division Director

Division of Anti-inflammatory, Analgesic and Ophthalmic Drug Products

HFD-550

Materials reviewed: Submission dated April 4, 2002, April 30, 2002,
September 13, 2002, September 20, 2002, December 20, 2002, and January
13, 2003

Subject:

Advisory Committee Background Document

**Safety Analysis of leflunomide NDA 20-905**

Table of Contents

I. Executive summary

II. Background and introduction

III. Safety Review

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A.  Pooled Analysis from phase II-IV studies

> Background and description of material reviewed

a.  Pooled analysis of monotherapy from clinical trials phase II-IV.

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i.  Definition of database

ii. Events if interest- nonhepatic

iii. Hepatic events

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b.  Hepatotoxicity in phase IV studies of combination therapy

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i.  Study 4001 An evaluation of leflunomide versus placebo for the
    treatment of active Rheumatoid Arthritis receiving a stable doses of
    Methotrexate

ii. Study 4002: Evaluation of the (leflunomide/sulfasalazine)
    combination versus sulfasalazine alone in patients with active
    Rheumatoid Arthritis non responders to leflunomide

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c.  Overall conclusions

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B.  Post-Marketing Cohort studies of leflunomide and other DMARDs

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i.  Aetna/US Healthcare cohort

ii. Pharmetrics and Protocare cohort study

iii. American College of Rheumatology abstract 2002: Abstract 968:
     American College of Rheumatology: Frederick Wolfe MD. Low rates of
     serious Liver Toxicity to Leflunomide (LEF) and Methotrexate (MTX)

###### Post-marketing reports of Acute Liver Failure (ALF)

i.  Definitions

ii. Discussion of causality

iii. Discussion of Office of Drug Safety assessment methodology

iv. Review of post marketing reports of ALF

v.  Summary of external consultation regarding hepatoxicity

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C.  Conclusions

G. Appendices 1-28

Executive Summary:

Leflunomide is a well-studied disease modifying therapy that has been
shown to improve signs and symptoms of rheumatoid arthritis as well as
slowing the x-ray progression of disease. The sponsor has submitted for
review data to support labeling that leflunomide improves physical
function in patients with this debilitating disease.

The Office of Drug Safety (ODS) has identified potential cases of acute
liver failure (ALF) in post-marketing reports and a citizen's petition
to remove leflunomide from the market has been submitted to the FDA
primarily based on such reports. This review documents a reassessment of
available safety data, particularly in the context of comparative safety
to a current standard of care, methotrexate.

A pooled analysis of the clinical trials from the original databases
from NDA 20905 as well as additional controlled studies performed by the
sponsor have been reviewed. This review has not identified new
toxicities that have not been addressed in the current product label.
Comparative safety profile is similar to methotrexate.

In addition, multiple large postmarketing cohort studies have been
reviewed to further explore the comparative safety of leflunomide and
methotrexate and to attempt further assessment of serious
hepatotoxicity. These databases include:

1.  **A 40,000 person Protocare and Pharmetrics claims database**

2.  **A 14,000 Aetna/US Healthcare claims database**

3.  **A 15,000 person cohort followed by the National Database for
    Rheumatic Diseases**

**These databases in addition to the clinical studies include over
16,000 patients treated with leflunomide and over 37,000 subjects
treated with methotrexate. While there are varying comparative rates for
various specific toxicities in the different databases, there was no
consistent signal for higher rates of serious liver injury in
leflunomide treated patients compared to methotrexate treated
patients.**

**In addition, 16 post-marketing reports of possible ALF in the US have
been identified by the Office of Drug Safety. Many of these reports are
highly confounded and have therefore been analyzed by two external
expert hepatologists as well as this reviewer. This reviewer identified
only two cases of *[probable]{.underline}* ALF associated with
leflunomide (one case associated with an unintentional overdose). The
external expert hepatologists identified no definite cases of
leflunomide induced ALF. All three reviewers considered some cases to be
*[possibly]{.underline}* related to leflunomide. In addition, non-US
reports of potential ALF have been identified by the Office of Drug
Safety and reviewed by hepatology consultants as well.**

**The overall conclusion of this reviewer is that definite/probable
cases of ALF have been reported both in the US as well as the
international post marketing databases of leflunomide.**

**These rare cases while important to the characterization of drug
toxicity profile do not outweigh the potential benefit of this product.
Life threatening toxicity is associated with the alternate disease
modifying therapies for Rheumatoid Arthritis, as evidenced by the high
degree of warning and caution in the label of such products. While each
drug or biologic therapy has a unique "fingerprint" of toxicity, the
case reports in the context of post marketing reporting do not appear to
identify a frequency of life threatening toxicity higher than other
comparably efficacious agents. Furthermore, large cohort studies have
not identified an excess of risk overall (or hepatotoxicity
specifically) with leflunomide compared to methotrexate.**

**A. Specific findings relate to liver toxicity**

1.  **In the submitted pooled analysis of controlled clinical trials
    database of 2700 (2533 pt. yr and median exposure approximately 12
    months) patients on leflunomide and 700 (1340 pt. yr and median
    exposure 24 months) on methotrexate:**

-   **There were no cases of ALF or jaundice associated with hepatic
    necrosis (as defined by ALT over 8XULN).**

-   **There was a single case of clinically serious hepatocellular
    necrosis with ALT peak of 2710 without associated jaundice.**

-   **Crude rates of ALT elevation above 3 XULN range from 2-5% within
    clinical trials of leflunomide compared to 3-19% for methotrexate
    (depending on the presence of folate supplementation).**

-   **Cumulative rates of ALT elevations of 3 XULN at 1 year in the
    controlled clinical trials database was 5 per 100 pt years for
    leflunomide and 18 per 100 pt years for methotrexate. Thus, there
    was no clear signal for a higher overall rate of hepatotoxicity in
    association with leflunomide compared to methotrexate.**

2.  **In the Protocare and Pharmetrics databases (total of over 40,00
    patients: 2800 patients exposed to leflunomide with mean follow-up
    of 430-500 days):**

-   **The relative rate for hospitalization associated with hepatic
    events (without causality assessment) was 1.1 for leflunomide
    compared to methotrexate with mean follow-up of 430-500 days in the
    Protocare and Pharmetrics databases (total of over 40,000 patients:
    2800 patients exposed to leflunomide).**

-   **There were no cases of hospitalization for acute or subacute
    hepatic necrosis or hepatic coma in-patients on leflunomide
    monotherapy.**

3.  **In the database from the National Data Bank for Rheumatic Diseases
    (5437 patients on leflunomide and 10,527 patients on
    methotrexate):**

-   **There was one hospitalization attributed to acute hepatic necrosis
    in each of the leflunomide and methotrexate groups.**

-   **The overall rates of hospitalization for liver related events
    (without causality assessment) was 2.0 and 2.7/1000 patient years
    for leflunomide and methotrexate treated cohorts respectively.**

-   **There were no deaths caused by liver disease in this entire
    database.**

-   **The total time on methotrexate prior to enrollment into the cohort
    was longer than the leflunomide cohort. Following adjustment for
    duration on therapy, age, sex and HAQ, the rates for "patient
    reported liver side effects" per 100 patients were 0.4 in both
    groups.**

4.  **In the Aetna US Healthcare cohort of 4478 patients on leflunomide
    and 9842 subjects on methotrexate:**

-   **the rate per 100pt/yr of exposure for "severe hepatic events"
    (defined as cirrhosis, hepatic failure, hepatic necrosis, biliary
    cirrhosis and hepatitis) was 0.28 and 0.48 respectively for
    leflunomide and methotrexate.**

-   **There were no cases of hepatic coma or jaundice in the entire
    leflunomide database.**

5.  **Post marketing cases of possible ALF identified by ODS have been
    reviewed by a gastroenterologist within the division as well as two
    external hepatology consultants.**

-   **Although individual cases were variably adjudicated as unlikely,
    possible or probable, all three reviewers concluded that many of the
    16 case database in the ODS review dated November 7, 2002 were not
    likely to be causally related to leflunomide.**

-   **The analysis in this review identified two cases of probable
    leflunomide related ALF (one of which was an unintentional chronic
    overdose). Three cases were possible although there were other more
    compelling and likely causes than leflunomide. Three cases were
    highly unlikely based on time course of ALF and or the compelling
    nature of other causes. Five cases did not meet the definition of
    ALF. Three cases had inadequate data to assess.**

-   **The paucity of cases of probable leflunomide related ALF in the US
    are inadequate for the statistical analyses performed by the ODS
    reviewer.**

-   **There were several cases of ALF in the post marketing database
    outside the US that were probable cases of leflunomide related
    ALF.**

-   **The probable cases of hepatotoxicity in the US and international
    postmarketing databases are adequate evidence that very rare life
    threatening hepatotoxicity has been associated with leflunomide.**

6.  **Methodologically, this reviewer has concerns over the use of
    "possible" cases, undocumented cases of drug toxicity and cases
    without adequate information for the generation of absolute hazard
    rates as proposed by the ODS review of November 7, 2002. The
    analysis of benefit in the ODS review does not adequately address
    the therapeutic impact of therapy with leflunomide. There is an
    extensive medical literature on the morbidity and mortality
    associated with rheumatoid arthritis (RA) as well as the impact that
    disease-modifying agents such as leflunomide have on the morbidity
    associated with RA.**

7.  **This reviewer concludes that given the severity of the rare cases
    of serious hepatotoxicity including ALF reported to date risk
    communication should be expanded to characterize the risks of
    hepatotoxicity based on the findings of post- marketing reports of
    ALF.**

**Conclusions regarding non-hepatic safety assessment following review
of the pooled controlled clinical trials database:**

1.  **The occurrence of hypertension on therapy does not appear to be
    different between leflunomide and methotrexate when assessed as new
    onset hypertension. Imbalances in the baseline rates of hypertension
    in the original clinical trial database may limit the value of
    "rates of hypertension on therapy" in this database. The rates for
    hypertension as a serious adverse event and withdrawals due to
    adverse events were low in all groups although there was a trend for
    higher rates in leflunomide treated subjects.**

2.  **Cumulative rate for weight loss was slightly higher in the
    leflunomide treated subjects compared to methotrexate treated
    subjects. The significance and cause for this finding is unclear.**

**II: Background and introduction:**

Aventis received marketing approval for leflunomide in 1998 for the
treatment of rheumatoid arthritis. The basis of approval included
multiple efficacy studies including placebo and active control studies
of up to 12 months. The efficacy of leflunomide in controlled clinical
trials was similar to that of methotrexate and sulfasalazine (SSZ), two
agents currently approved for the treatment of rheumatoid arthritis. In
addition, leflunomide is the only nonbiologic therapy approved "to
retard structural damage" associated with rheumatoid arthritis.
Supplemental NDA 20905/ S006 is currently under review. This supplement
includes clinical trials data to support the indication of "improvement
in physical function".

The mechanism of action as an immunomodulatory agent is thought to be
through inhibition of dihydroorotate dehydrogenase, an enzyme involved
in de novo pyrimidine synthesis. Thus anti-proliferative effects are
anticipated in organs with high cell turnover such as intestinal tract,
myeloid system and integument including hair. These organ systems are in
fact prominent in the adverse event profile of leflunomide.

The safety database as reflected in the approved label identifies
multiple adverse events associated with the use of leflunomide at rates
that are higher than placebo associated rates. These include
hypertension, elevated liver function tests, alopecia, rash, pneumonia,
and diarrhea. The currently approved label informs prescribers of the
potential for hepatotoxicity and cautions use in patients who may be at
risk for hepatotoxicity such as those with underlying liver disease or
on other hepatotoxic agents. The warning and precaution section of the
label includes information on immune suppression, malignancy,
hepatotoxicity, skin reactions and teratogenicity. The current label
includes prominent reference to toxicity as noted in excerpts from the
label noted below.

*[Begin label excerpts]{.underline}*

***[Warnings:]{.underline}***

[Immunosuppression Potential]{.underline}

ARAVA is not recommended for patients with severe immunodeficiency, bone
marrow dysplasia, or severe, uncontrolled infections.

There have been rare reports of pancytopenia in patients receiving
ARAVA. In most of these cases, patients received concomitant treatment
with methotrexate or other immunosuppressive agents, or they had
recently discontinued these therapies; in some cases, patients had a
prior history of a significant hematologic abnormality. If ARAVA is used
in such patients, it should be administered with caution and with
frequent clinical and hematologic monitoring. The use of ARAVA in
combination therapy with methotrexate has not been adequately studied in
a controlled setting.

If evidence of bone marrow suppression occurs in a patient taking ARAVA,
treatment with ARAVA should be stopped, and cholestyramine or charcoal
should be used to reduce the plasma concentration of leflunomide active
metabolite (see [PRECAUTIONS](#C05) \-- [General \-- Need for Drug
Elimination](#C05S05.5) ).

In any situation in which the decision is made to switch from ARAVA to
another anti-rheumatic agent with a known potential for hematologic
suppression, it would be prudent to monitor for hematologic toxicity,
because there will be overlap of systemic exposure to both compounds.
ARAVA washout with cholestyramine or charcoal may decrease this risk,
but also may induce disease worsening if the patient had been responding
to ARAVA treatment.

[Skin Reactions]{.underline}

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis
have been reported in patients receiving ARAVA. If a patient taking
ARAVA develops any of these conditions, ARAVA therapy should be stopped,
and a drug elimination procedure is recommended (see [PRECAUTIONS](#C05)
\-- [General \-- Need for Drug Elimination](#C05S05.5) ).

[Hepatotoxicity]{.underline}

In clinical trials, ARAVA treatment was associated with elevations of
liver enzymes, primarily ALT and AST, in a significant number of
patients; these effects were generally reversible. Most transaminase
elevations were mild (\</=2-fold ULN) and usually resolved while
continuing treatment. Marked elevations (\>3-fold ULN) occurred
infrequently and reversed with dose reduction or discontinuation of
treatment. The following table shows liver enzyme elevations seen with
monthly monitoring in clinical trials US301 and MN301. It was notable
that the absence of folate use in MN302 was associated with a
considerably greater incidence of liver enzyme elevation on
methotrexate.

  ---------------------------------- ----------- -------- --------- ----------- -------- --------- -------------- --------- --
  **Table 4. Liver Enzyme Elevations                                                                                        
  \>3-fold Upper Limits of Normal                                                                                           
  (ULN)**                                                                                                                   

                                     **US301**                      **MN301**                      **MN302                  
                                                                                                   [\*](#F10)**             

                                     **LEF**     **PL**   **MTX**   **LEF**     **PL**   **SSZ**   **LEF**        **MTX**   

  ALT (SGPT)                                                                                                                

  \>3-fold ULN                       8           3        5         2           1        2         13             83        

  (n %)                              (4.4)       (2.5)    (2.7)     (1.5)       (1.1)    (1.5)     (2.6)          (16.7)    

  Reversed to \</=2-fold ULN:        8           3        5         2           1        2         12             82        

  Timing of Elevation                                                                                                       

  0\--3 Months                       6           1        1         2           1        2         7              27        

  4-6 Months                         1           1        3         \--         \--      \--       1              34        

  7-9 Months                         1           1        1         \--         \--      \--       \--            16        

  10-12 Months                       \--         \--      \--       \--         \--      \--       5              6         

  AST (SGOT)                                                                                                                

  \>3-fold ULN                       4           2        1         2           0        5         7              29        

  (n %)                              (2.2)       (1.7)    (0.6)     (1.5)       \--      (3.8)     (1.4)          (5.8)     

  Reversed to \</=2-fold ULN:        4           2        1         2           \--      4         5              29        

  Timing of Elevation                                                                                                       

  0\--3 Months                       2           1        \--       2           \--      4         3              10        

  4-6 Months                         1           1        1         \--         \--      1         1              11        

  7-9 Months                         1           \--      \--       \--         \--      \--       \--            8         

  10-12 Months                       \--         \--      \--       \--         \--      \--       3              \--       

  \*Only 10% of patients in MN302                                                                                           
  received folate. All patients in                                                                                          
  US301 received folate.                                                                                                    

                                                                                                                            
  ---------------------------------- ----------- -------- --------- ----------- -------- --------- -------------- --------- --

At minimum, ALT (SGPT) should be performed at baseline and monitored
initially at monthly intervals then, if stable, at intervals determined
by the individual clinical situation.

Guidelines for dose adjustment or discontinuation based on the severity
and persistence of ALT elevation are recommended as follows: For
confirmed ALT elevations \>2-fold ULN, dose reduction to 10 mg/day may
allow continued administration of ARAVA. If elevations \>2 but
\</=3-fold ULN persist despite dose reduction, liver biopsy is
recommended if continued treatment is desired. If elevations \>3-fold
ULN persist despite dose reduction, ARAVA should be discontinued and
cholestyramine should be administered (see [PRECAUTIONS](#C05) \--
[General \-- Need for Drug Elimination](#C05S05.5) ) with close
monitoring, including retreatment with cholestyramine as indicated.

Rare elevations of alkaline phosphatase and bilirubin have been
observed. Trial US301 used ACR Methotrexate Liver Biopsy Guidelines for
monitoring therapy. One of 182 patients receiving leflunomide and 1 of
182 patients receiving methotrexate underwent liver biopsy at 106 and 50
weeks respectively. The biopsy for the leflunomide subject was Roegnik
Grade IIIA and for the methotrexate subject, Roegnik Grade I.

[Pre-existing Hepatic Disease]{.underline}

Given the possible risk of increased hepatotoxicity, and the role of the
liver in drug activation, elimination and recycling, the use of ARAVA is
not recommended in patients with significant hepatic impairment or
evidence of infection with hepatitis B or C viruses.

[Malignancy]{.underline}

The risk of malignancy, particularly lymphoproliferative disorders, is
increased with the use of some immunosuppression medications. There is a
potential for immunosuppression with ARAVA. No apparent increase in the
incidence of malignancies and lymphoproliferative disorders was reported
in the clinical trials of ARAVA, but larger and longer-term studies
would be needed to determine whether there is an increased risk of
malignancy or lympho-proliferative disorders with ARAVA.

[Use in Women of Childbearing Potential]{.underline}

There are no adequate and well-controlled studies evaluating ARAVA in
pregnant women. However, based on animal studies, leflunomide may
increase the risk of fetal death or teratogenic effects when
administered to a pregnant woman (see [CONTRAINDICATIONS](#T05) ). Women
of childbearing potential must not be started on ARAVA until pregnancy
is excluded and it has been confirmed that they are using reliable
contraception. Before starting treatment with ARAVA, patients must be
fully counseled on the potential for serious risk to the fetus.

The patient must be advised that if there is any delay in onset of
menses or any other reason to suspect pregnancy, they must notify the
physician immediately for pregnancy testing and, if positive, the
physician and patient must discuss the risk to the pregnancy. It is
possible that rapidly lowering the blood level of the active metabolite
by instituting the drug elimination procedure described below at the
first delay of menses may decrease the risk to the fetus from ARAVA.

Upon discontinuing ARAVA, it is recommended that all women of
childbearing potential undergo the drug elimination procedure described
below. Women receiving ARAVA treatment who wish to become pregnant must
discontinue ARAVA and undergo the drug elimination procedure described
below which includes verification of M1 metabolite plasma levels less
than 0.02 mg/L (0.02 µg/mL). Human plasma levels of the active
metabolite (M1) less than 0.02 mg/L (0.02 µg/mL) are expected to have
minimal risk based on available animal data.

*[Precautions]{.underline}*

[Laboratory tests]{.underline}

At minimum, ALT (SGPT) should be performed at baseline and monitored
initially at monthly intervals then, if stable, at intervals determined
by the individual clinical situation. In patients who are at an
increased risk of hematologic toxicity (see [WARNINGS](#W10) \--
[Immunosuppression Potential](#W10S05) ), more vigilant monitoring,
including hematologic monitoring, is warranted.

Due to a specific effect on the brush border of the renal proximal
tubule, ARAVA has a uricosuric effect. A separate effect of
hypophosphaturia is seen in some patients. These effects have not been
seen together, nor have there been alterations in renal function.

*[End Label excerpts]{.underline}*

Top of Form 1

Bottom of Form 2

HFD-430, Division of Drug Risk Evaluation, Office of Drug Safety has
identified reports of serious hepatitis and liver failure in the
post-marketing adverse event reporting system (AERS) that are currently
under review. The Department of Health and Human Services received a
citizens petition (CP) on March 28, 2002 form the consumer advocacy
group, Public Citizen, requesting that leflunomide be removed from the
market based on safety concerns including hepatotoxicity as the most
prominent concern. The petitioner claimed that there are equally
efficacious drugs with less toxicity as a basis for withdrawal.

## Brief review of Efficacy

Active comparator studies were included in the NDA 20,904 submission in
addition to placebo control. The results of these studies appear in the
approved label and suggest similar efficacy based on ACR 20 response
rate criterion as well as retardation of structural damage associated
with RA. The petitioner cited the apparent superiority of methotrexate
over leflunomide in study MN302, a 12-month international study of
approximately 500 subjects per arm. In this study only 10% of subjects
received folate supplementation. Folate supplementation is common in the
US and was protocol mandated in the US studies of leflunomide for that
reason. It has been proposed that folate supplementation decreases the
toxicity of methotrexate at the "price" of lessening efficacy. The data
from the submitted studies of leflunomide corroborate this clinical
observation. Elevated liver function tests (ALT\>3ULN) were
substantially higher in MN 302 (17%) compared to US 301 (3%) for
methotrexate treated subjects. The efficacy of leflunomide and
methotrexate appears to be similar under conditions of routine use
employed in the US.

The differences in relative efficacy seen in the US and MN studies may
reflect the differences in folate supplementation although one could not
rule out a true difference in relative efficacy. In fact the studies
submitted by the sponsors of leflunomide provided the most robust data
on the efficacy of methotrexate to date. The results of MN301 do not
suggest that sulfasalazine is superior to leflunomide.

In RA as with most medical conditions failure of one therapy does not
predict failure of other therapies. Given the relatively low ACR 50 and
70 response rates for all currently approved therapies it is anticipated
that many patients will not be adequately treated with methotrexate and
will require other treatment options. Likewise a significant number of
patients do not tolerate methotrexate. Therefore, the presence of an
effective therapy as defined in clinical trials does not obviate the
need for other therapies. The therapeutic needs of patients and the
potential toxicity of other available therapies must be considered in
assessing the role of a therapy with identified serious toxicity.

**III: Safety review**

######### A. Background and description of material reviewed

The issue of comparative safety is appropriately raised at this point.
Although organ specific adverse event rates in clinical trials are easy
to compare, overall or "global" safety comparisons are difficult to
calculate and compare. Deaths, hospitalization, serious adverse events
are definable and therefore measurable. The infrequency of drug
attributable deaths and hospitalizations is such that they are generally
statistically not evaluable in clinical trial databases submitted for
drug approval in all but the most toxic of therapies. The term *serious
adverse event suggests high morbidity and therefore a good metric for
the assessment of overall safety.* The definition of serious adverse
events (SAE) is quite broad however. Events generally defined as serious
include:

1.  An event that results in death

2.  A life-threatening event

3.  An event that results in a persistent or significant
    disability/incapacity

4.  An event that results in or prolongs hospitalization

5.  An event that is a congenital anomaly

6.  Cancer

7.  Result of an overdose

8.  An important medial event that may not result in death, not be
    life-threatening or not require hospitalization may be considered a
    serious adverse event when based upon appropriate medical judgement
    the event may jeopardize the patient and may require medical or
    surgical intervention to prevent an outcome listed above

Although hospitalization is a clinically important event, the reason for
hospitalization is critical to an assessment of toxicity.
Hospitalization for the evaluation of chest pain is considered an SAE
regardless of whether esophageal reflux or a myocardial infarction is
diagnosed. Thus, while of value, the term "hospitalization" is less
pivotal as a global metric of serious events than the name suggests.

Furthermore many SAEs are not causally related to therapy, further
confusing the interpretation of this endpoint. For example, in the
product label for leflunomide, methotrexate has a higher rate of
injury/accident than leflunomide. This is not generally interpreted as a
drug related adverse event associated with methotrexate. In summary, it
is difficult to define an overall or global comparison of safety between
two drugs in NDA databases.

When a particular life-threatening or highly morbid event is identified
through post-marketing reports in association with a drug however,
decisions regarding continued marketing must be addressed frequently
based on *qualitative* data. Post-marketing reports represent a critical
source of information for:

1.  Identifying rare but serious drug related toxicity

2.  Identifying populations at higher risk for serious toxicity such as
    co-morbidities or co-medications that may change the apparent safety
    profile established in clinical trials

***Quantitation*** of risk however is difficult to establish from
post-marketing reports. This is particularly true for events with high
background rates such as myocardial infarctions or lung cancer. For very
rare events such as acute liver failure in the absence of an
identifiable cause, semi-quantitation is possible since background rates
can be reasonably estimated. Quantitation of ***comparative*** risk
between drugs however is difficult since it depends on identical
reporting patterns, which are not likely. Factors that effect reporting
rates include:

1.  Temporal relationship between marketing approval and reporting.
    Reporting rates are highest soon after approval and fall off
    precipitously (the Weber Effect) (1) thereafter unless a particular
    problem comes to the attention of the medical community. In that
    case reporting rates rise, ironically in response to publicity
    rather than being the basis of public awareness.

2.  Perceptions of risk. This is affected by medical literature and
    promotional material

3.  Perceptions of causality. Events such as myocardial infarction or
    lung cancer that are common are unlikely to be attributed to
    prescribed drugs and are likely to be reported less frequently than
    rare events such as ALF.

4.  Perceptions of the need for reporting

Large cohort studies are therefore potentially valuable in addition to
case reports of rare adverse events to quantitate risk for such rare
events

This memorandum documents the updated assessment of safety data from the
controlled clinical trial database of leflunomide as well as review of
postmarketing case reports of ALF. In addition, several studies
conducted on postmarketing databases and articles and abstracts from the
medical literature appropriate for inclusion have been reviewed.

The sources to be reviewed include:

1.  Meta-analysis of serious hepatic injury in Phase II/IV clinical
    studies of leflunomide in

RA as monotherapy. Information request submitted May 21, 2002. (Response
submitted by sponsor on

September 13, 2002)

2.  Study 4001: A study of combination therapy leflunomide/methotrexate
    submitted as NDA 20,905 supplement 8.

3.  Study 4002: A study of combination leflunomide/sulfasalazine (report
    dated April 30, 2002)

4.  Aetna Cohort Study submitted April 4, 2002

5.  Protocare and Pharmetrics cohort studies of methotrexate and
    leflunomide (preliminary report dated December 13, 2002)

6.  Post-marketing cases of possible Acute Liver Failure (ALF) reported
    to the AERS database

7.  FDA consultant hepatologists opinion on US and international cases
    of ALF and serious hepatic toxicity review

# **B. Pooled analysis of controlled clinical trials of monotherapy: phases II-IV**

######### Original NDA 

Medical Officer review dated 1998 of the original NDA 20904 contained a
section entitled "Liver Function Abnormalities" and a subsection on
"Serious LFT abnormalities"

Page 35 of the MO review includes a table provided by the sponsor of ALT
elevations in the three pivotal studies MN301, MN302 and US 301. The
placebo controlled trial, MN301 and US 301 had rates of ALT elevations
over 3 times the upper limits of normal (ULN) for leflunomide of 1.5%
and 4.4% versus 1.1% and 2.5% for placebo. The rate for the active
control, methotrexate in US 301 was 2.7%. Thus, while the differences
were not "significantly different" they trended higher in the
leflunomide treated arms of these studies.

Sponsor tables 36 and 37 as reproduced in the MO review reveal that with
reduction of dose or discontinuation the vast majority of cases
resolved. These data are reflected in the current label.

######### i. Description of pooled analysis of expanded controlled clinical trials database: 

In light of the current reassessment of safety, the division submitted
an information request to the sponsor on May 21, 2002 to perform a
pooled analysis of important adverse events of all monotherapy clinical
trials in the database of leflunomide using a survival analysis. The
database included the three pivotal studies that appear in the approved
label as well as other studies done before and after marketing approval.

This analysis was intended to expand the database from the original NDA
and add the dimension of exposure time to the analysis. The crude rates
that currently appear in the label may be less informative than a
kaplan-meier analysis that controls for exposure and has the ability to
reflect changes in hazard rate over time. This pooled analysis also
addresses potential safety concerns raised in the citizens petition
including:

1.  Hepatotoxicity

2.  Hypertension

3.  Serious skin reactions such as Stevens-Johnson Syndrome

4.  Malignancy, particularly lymphoma

5.  GI adverse events including diarrhea and nausea

6.  Weight loss

Listing of studies included in the pooled analysis of controlled
clinical trials

# List of therapeutic phase II/IV trials with leflunomide in RA patients included in pooled analysis (monotherapy only) {#list-of-therapeutic-phase-iiiv-trials-with-leflunomide-in-ra-patients-included-in-pooled-analysis-monotherapy-only .H1}

+----------------+---------------------------+------------+------------+
| HMR internal\  | Study title               | Number of  | Dates      |
| study number   |                           | subjects   |            |
+----------------+---------------------------+------------+------------+
| HWA            | Efficacy and safety of    | 23 LEF     | Oct 89 -   |
| 48             | leflunomide in the        | subjects   | Aug 91     |
| 6/6/USA/201/RA | treatment of patients     |            |            |
|                | with severe rheumatoid    |            |            |
|                | arthritis                 |            |            |
+----------------+---------------------------+------------+------------+
| HWA            | Pilot study on the        | 23 LEF     | Jan 90 -   |
| 48             | efficacy and safety of    | subjects   | Jun 90     |
| 6/6/YU/201/RA, | 5,10 and 25 mg            |            |            |
| HWA            | leflunomide in the        |            |            |
| 4              | treatment of patients     |            |            |
| 86/6/YU/202/RA | with severe rheumatoid    |            |            |
|                | arthritis - including an  |            |            |
|                | analysis of the           |            |            |
|                | pharmacokinetics of       |            |            |
|                | leflunomide               |            |            |
+----------------+---------------------------+------------+------------+
| HWA            | Efficacy and safety of    | 300 LEF    | Dec 90 -   |
| 4              | leflunomide in the        | subjects   | Aug 92     |
| 86/6/YU/203/RA | treatment of patients     |            |            |
|                | with severe rheumatoid    | 102 PLA    |            |
|                | arthritis                 | subjects   |            |
+----------------+---------------------------+------------+------------+
| HWA            | Efficacy and safety of    | 54 LEF     | Oct 90 -   |
| 4              | leflunomide in the        | subjects   | Sept 91    |
| 86/6/YU/204/RA | treatment of patients     |            |            |
|                | with severe rheumatoid    |            |            |
|                | arthritis. Multiple dose  |            |            |
|                | pharmacokinetic study.    |            |            |
+----------------+---------------------------+------------+------------+
| HWA            | 18-month, open-label,     |            | May 91 -   |
| 4              | multiple-dose, safety and |            | Jan 94     |
| 86/6/YU/205/RA | efficacy extension study  |            |            |
|                | (to HWA 486/6/YU/203/RA   |            |            |
|                | and 204/RA) of            |            |            |
|                | leflunomide in patients   |            |            |
|                | with rheumatoid arthritis |            |            |
+----------------+---------------------------+------------+------------+
| HWA            | Safety and                | 49 LEF     | Mar 92 -   |
| 4              | pharmacokinetics of       | subjects   | Oct 92     |
| 86/6/YU/206/RA | leflunomide in the        | (weekly    |            |
|                | treatment of patients     | dosage)    |            |
|                | with severe rheumatoid    |            |            |
|                | arthritis                 |            |            |
+----------------+---------------------------+------------+------------+

+----------------+--------------------------+------------+------------+
| HWA            | 18-month, open-label,    |            | Aug 92 -   |
| 4              | multiple-dose, safety    |            | Aug 93     |
| 86/6/YU/207/RA | and efficacy extension   |            |            |
|                | (to HWA 486/6/YU/206/RA) |            |            |
|                | of leflunomide in        |            |            |
|                | patients with rheumatoid |            |            |
|                | arthritis                |            |            |
+----------------+--------------------------+------------+------------+
| HWA            | Comparative trial of the | 133 LEF    | Feb 94 -   |
| 4              | efficacy and safety of   | subjects   | May 95     |
| 86/6/MN/301/RA | leflunomide and          |            |            |
|                | sulfasalazine versus     | 133 SSZ    |            |
|                | placebo in patients with | subjects   |            |
|                | active rheumatoid        |            |            |
|                | arthritis                | 92 PLA     |            |
|                |                          | subjects   |            |
+----------------+--------------------------+------------+------------+
| HWA            | 24-week comparative      |            | Aug 94 -   |
| 4              | trial of the safety and  |            | Nov 96     |
| 86/6/MN/303/RA | efficacy of leflunomide  |            |            |
|                | versus sulfasalazine in  |            |            |
|                | patients with active     |            |            |
|                | rheumatoid arthritis -   |            |            |
|                | extension of Study HWA   |            |            |
|                | 486/6/MN/301/RA          |            |            |
+----------------+--------------------------+------------+------------+
| HWA            | Comparative extension    |            | Jan 95 -   |
| 4              | trial of the safety and  |            | Nov 98     |
| 86/6/MN/305/RA | efficacy of leflunomide  |            |            |
|                | versus sulfasalazine in  |            |            |
|                | patients with rheumatoid |            |            |
|                | arthritis - extension of |            |            |
|                | Study HWA                |            |            |
|                | 486/6/MN/303/RA          |            |            |
+----------------+--------------------------+------------+------------+
| HWA            | Comparative trial of the | 501 LEF    | Feb 94 -   |
| 4              | efficacy and safety of   | subjects   | Mar 97     |
| 86/6/MN/302/RA | leflunomide versus       |            |            |
|                | methotrexate in patients | 498 MTX    |            |
|                | with rheumatoid          | subjects   |            |
|                | arthritis                |            |            |
+----------------+--------------------------+------------+------------+
| HWA            | Comparative extension    |            | Feb 95 -   |
| 4              | trial of the efficacy    |            | Nov 98     |
| 86/6/MN/304/RA | and safety of            |            |            |
|                | leflunomide versus       |            |            |
|                | methotrexate in patients |            |            |
|                | with rheumatoid          |            |            |
|                | arthritis - extension of |            |            |
|                | Study HWA                |            |            |
|                | 486/6/MN/302/RA          |            |            |
+----------------+--------------------------+------------+------------+
| HWA            | A Phase III, double      | 190 LEF    | May 95 --  |
| 48             | blind, randomized,       | subjects   | Nov 98     |
| 6/F/USA/301/RA | placebo-controlled study |            |            |
|                | to compare the activity  | 190 MTX    |            |
|                | and safety of            | subjects   |            |
|                | leflunomide to           |            |            |
|                | methotrexate or placebo  | 128 PLA    |            |
|                | in subjects with active  | subjects   |            |
|                | rheumatoid arthritis     |            |            |
+----------------+--------------------------+------------+------------+
| HWA486/3006    | An explorative study     | 18 LEF     | Jan 98 --  |
|                | into the                 | subjects   | Sep 99     |
|                | immunohistochemical and  |            |            |
|                | magnetic resonance       | 21 MTX     |            |
|                | imaging (MRI) changes of | subjects   |            |
|                | the knee in patients     |            |            |
|                | with rheumatoid          |            |            |
|                | arthritis after          |            |            |
|                | treatment with           |            |            |
|                | leflunomide (HWA486) or  |            |            |
|                | methotrexate             |            |            |
+----------------+--------------------------+------------+------------+
| HWA486/3009    | Open-label trial on the  |            | May 98 --  |
|                | safety and efficacy of   |            | Feb 00     |
|                | leflunomide (extension   |            |            |
|                | of MN304 and MN305, and  |            |            |
|                | re-started leflunomide   |            |            |
|                | subjects from YU205)     |            |            |
+----------------+--------------------------+------------+------------+
| HWA486/3010    | Extension trial of the   |            |            |
|                | comparison of the        |            |            |
|                | activity and safety of   |            |            |
|                | leflunomide and          |            |            |
|                | methotrexate in subjects |            |            |
|                | with active rheumatoid   |            |            |
|                | arthritis -- extension   |            |            |
|                | to study                 |            |            |
|                | HWA486/USA/301/RA        |            |            |
+----------------+--------------------------+------------+------------+
| HWA486/3012    | Comparative trial of the | 402 LEF    | May 00 --  |
|                | efficacy and safety of   | subjects   | Feb 02     |
|                | leflunomide 10 mg versus |            |            |
|                | 20 mg daily doses in     |            |            |
|                | patients with active     |            |            |
|                | rheumatoid arthritis     |            |            |
+----------------+--------------------------+------------+------------+

The exposure over time for the expanded clinical trial database is
displayed in Table 1. Over 80% of the leflunomide subjects were
receiving [\>]{.underline} 20 mg/day, the maximum approved dose. The
exposures should be kept in mind given the rapid loss of exposure to
placebo and sulfasalazine within several months. The variance associated
with rates for rare events is high and statistical comparisons may be of
limited value. Qualitative comparisons of events however are relevant in
the absence of statistical power when considering potentially serious
adverse events. Exposure expressed as patient years was 2533, 1340, 188
and 201 for leflunomide, methotrexate, sulfasalazine and placebo
respectively.

Exposure in terms of survival analysis is shown in table 1.

####### Table 1

**Exposure to leflunomide and comparators during phase II, III and IV
monotherapy trials. (number of patients surviving in trial during
interval )**

+---------------+---------------+---------------+---------------+-----+
|               | #             | ###  **MTX**  | ###           |     |
|               | # Leflunomide |               | # **SSZ Pbo** |     |
+---------------+---------------+---------------+---------------+-----+
| # Enrolled    | 1693          | 709           | 133. 322      |     |
|               |               |               |               |     |
| 3months       | 1477          | 647           | ```{=html}    |     |
|               |               |               | <!-- -->      |     |
| 6 months      | 948           | 567           | ```           |     |
|               |               |               | 100. 281      |     |
| 12 months     | 790           | 476           |               |     |
|               |               |               | ```{=html}    |     |
| 18 months     | 654           | 403           | <!-- -->      |     |
|               |               |               | ```           |     |
| 24 months     | 513           | 354           | 75. 54        |     |
|               |               |               |               |     |
| 36 months     | 295           | 176           | ```{=html}    |     |
|               |               |               | <!-- -->      |     |
| 48 months     | 181           | 2             | ```           |     |
|               |               |               | 60. 38        |     |
|               |               |               |               |     |
|               |               |               | ```{=html}    |     |
|               |               |               | <!-- -->      |     |
|               |               |               | ```           |     |
|               |               |               | 55. 30        |     |
|               |               |               |               |     |
|               |               |               | ```{=html}    |     |
|               |               |               | <!-- -->      |     |
|               |               |               | ```           |     |
|               |               |               | 47. 23        |     |
|               |               |               |               |     |
|               |               |               | ```{=html}    |     |
|               |               |               | <!-- -->      |     |
|               |               |               | ```           |     |
|               |               |               | 26. 13        |     |
|               |               |               |               |     |
|               |               |               | ```{=html}    |     |
|               |               |               | <!-- -->      |     |
|               |               |               | ```           |     |
|               |               |               | 2.  0         |     |
+---------------+---------------+---------------+---------------+-----+

**Results:**

The adequacy of the extent of exposure in the assessment of toxicity is
related to the frequency of the event of interest. Thus for very rare
events, even an exposure of 1000 subjects is not adequate for robust
comparative analysis.

Given the limited exposure in the placebo and SSZ treated groups, this
reviewer does not consider the safety exposure beyond three months to be
meaningful for these groups. The exposure for methotrexate and
leflunomide is significant out to 24 months with over 500 leflunomide
treated subjects and over 350 methotrexate treated subjects "surviving"
at month 24.

Graphs and tables with statistical analyses are located in the
appendices. All statistical analyses are limited due to multiplicity of
comparisons made and the post-hoc nature of such analyses. Likewise
trends without nominal statistical significance cannot be ignored as the
sample size may be under powered to assess the events of interest. These
qualifications are true of any safety assessment of any drug.

## ii. Pooled analysis of nonhepatic events

## 

## Deaths

There was a numerical trend towards higher rate of deaths in the
methotrexate group compared to the leflunomide group as displayed in
appendix 1. The 95% confidence intervals displayed in appendix 1 do not
suggest that there is significant difference among the groups.

######## [Serious Adverse Events Analyses]{.underline}

The rate of SAEs overall was quite similar between methotrexate and
leflunomide. For the placebo-controlled period there was a statistically
significantly higher rate of SAEs in all three active groups compared to
placebo (See appendix 2)

######### [SAE: Infection]{.underline}

The rates for serious infections were very similar between methotrexate
and leflunomide. These rates were consistently higher than the placebo
group during the three months of placebo exposure. (see appendix 3)

## SAE: Anemia

Rates for anemia were highest in the SSZ treated group during the three
months of SSZ exposure. Methotrexate and leflunomide treated groups
experienced similar rates over the course of 2 years although during the
first three months the leflunomide treated group had a slightly higher
rate. (see appendix 4).

Data from studies at high dose leflunomide (50-200mg/day) revealed that
only 1/48 subjects treated with 2-10 times the approved dose developed
anemia requiring withdrawal from study.

## SAE: Cancer/Lymphoma

Rates for malignancy and specifically lymphoma were low as would be
expected in a database of this size and duration (for all but the most
oncogenic agents) in all groups and did not appear to differ among
groups. The exposure in terms of numbers and duration may not have
adequate power to address this issue robustly in a comparative manner
but the observed rates for leflunomide were numerically lower compared
to the methotrexate group. (see appendix 5).

## SAE: Skin related

###### The rates of serious skin related adverse events were low in all treatment groups. There was a trend toward a higher rate of skin related SAEs in the leflunomide treated group compared to the other three groups. (see appendix 6) 

The Aetna cohort study submitted by the sponsor (see appendix 26)
identified no cases of serious skin reactions in a database of over 4000
patients. There were 4 cases of serious skin events in 9842 the
methotrexate treated group in that cohort study. (The definition of
severe skin reactions included Stevens-Johnson Syndrome, Toxic Epidermal
Necrolysis as well as Scalded Skin Syndrome, Lyell's Syndrome Erythema
iris and Herpes iris).

**[Withdrawal analyses]{.underline}**

######### [Subjects withdrawn due to adverse events]{.underline}

There was a trend towards a higher rate of withdrawals due to adverse
events in the leflunomide group compared to the methotrexate and placebo
groups. The sulfasalazine group had the highest rate of withdrawals due
to adverse events. (See appendix 7)

## Withdrawal due to nausea

Withdrawal due to nausea was highest in the SSZ treated group followed
by the methotrexate group. (See appendix 8)

######### [Expanded analyses of reported adverse events of interest: hypertension, diarrhea and weight loss]{.underline}

## Hypertension

Hypertension reported as an adverse event was highest in the
sulfasalazine group during the three months of meaningful exposure.
Otherwise, leflunomide was associated with the highest rate of
hypertension (nominally statistically significantly higher than the
methotrexate group.) followed by placebo and methotrexate.

However, due to an imbalance in the baseline rates of hypertension in
the pivotal studies (as noted in the current label) withdrawals due to
hypertension and new onset hypertension may reflect better comparative
effects than simply reports of hypertension in the meta-analysis. The
rates of hypertension as an AE, new onset hypertension, withdrawal due
to hypertension and hypertension as an SAE are all included in
appendices 9,10, 11 and 12). There was no trend for higher rates for
these endpoints for leflunomide compared to the other agents suggesting
that the baseline imbalance in some of the clinical studies may account
for the pattern of hypertension seen in the simple AE reporting
statistic

*The Aetna Cohort study discussed in section "C" of this review likewise
did not suggest a higher rate of hypertension in association with
leflunomide compared to methotrexate.*

**[Diarrhea:]{.underline}**

Diarrhea was a common adverse event in all groups including placebo.
Over a two-year database cumulative rates may reflect more background
"noise" than true drug effect. Certainly not all these events were
attributable to drug effect. Interestingly the diarrheal events for all
treatment groups including placebo primarily occurred within the first
three-month period. The rates were the highest in the leflunomide group
however. There was a statistically significantly higher rate in the
leflunomide treated group compared to the methotrexate group.

Withdrawal due to diarrhea reflects the severity and therefore the
significance of diarrhea better than simply reports of diarrhea.
Interestingly, again, the leflunomide and placebo groups had similar
rates that were higher than the other groups. (see appendix 14)

The sponsor provided an analysis of diarrhea by dose. While there was
not a linear pattern over the doses studied (5, 10, 15, 20 and 25mg)
there was a dose response seen for the two doses with the most
interpretability based on the numbers exposed, 10 and 20 mg. The results
for these analyses are presented in appendix 15.

In summary, there is a dose response in the frequency of diarrhea seen
with leflunomide and a slightly higher rate of "diarrhea" as well as
"diarrhea requiring withdrawal from therapy" than with methotrexate.

Weight loss:

The current approved label lists weight loss as an adverse event in all
comparators and at similar rates. An article recently published by the
Arthritis Center at the Brigham and Women's Hospital in Boston (2)
identified weight loss of 19-53 pounds in 5 of 70 (7%) patients started
on leflunomide over a 14 month period in a 35 member rheumatology
practice. Evaluations to identify other causes of weight loss were
negative. None of these 5 patients reported diarrhea, The authors
hypothesized uncoupling of oxidative phosphorylation at the
mitochondrial level as the mechanism for weight loss due to increased
energy expenditure. This is based on the fact that dihydroorotate
dehydrogenase (the enzyme inhibited by leflunomide) is a flavin linked
enzyme that may nonspecifically inhibit mitochondrial electron transport
chain. Other pharmacological agents that are known to cause weight loss
have been thought to cause weight loss through this same mechanism.
Although this was an uncontrolled retrospective chart review, the
article is of concern. It is important to note however that 4/5 patients
continued on therapy despite the weight loss due to drug effectiveness.

In the published report on study MN301 (3), a 24 week study, the weight
change for the leflunomide, SSZ abd placebo treated groups was reported
to be --0.9kg, +0.7kg. and --0.4 kg respectively. During the study
period a weight loss of [\>]{.underline} 10% was reported in 6/133 in
the leflunomide treated group compared to 2/133 in the other active
comparator, SSZ.

It is important to note that confounding factors may well be present in
post hoc analyses of an event as potentially multifactorial as weight
loss. While weight loss is generally considered to be a sign of illness,
it may be a reflection of other factors such as steroid dose reduction
or increased activity, which may both be surrogates for a positive
response to therapy. Comparisons to active treatment arms however should
control for this variable.

Weight loss analysis in the pooled analysis of controlled clinical trial
database

[Weight loss: 10-20 pounds and \>20 pounds:]{.underline}

Weight loss of 10-20 pounds was surprisingly common in all groups
including placebo (15-30% across groups within the first three months).
Weight loss of greater than 20 pounds was between 2-4% across groups.
The rate in the leflunomide group trended higher than the other groups
and was nominally statistically significantly higher than the
methotrexate group for both categories of weight loss by 12 months into
exposure. (see appendices 17 and 18)

Data on dose response is difficult to interpret due to small exposures
in groups other than 10 and 20 mg. doses however it does appear that
there is a dose response for this event. (see appendix 19)

**Weight loss of at least 10% of baseline body weight**

An analysis of baseline demographics of patients enrolled in phase 2/3
studies reveals that 3.7%, 2.0%, 1.5%, and 1.5% of subjects were
described as obese in the leflunomide, methotrexate, SSZ and placebo
groups respectively. This difference may impact the rates of weight loss
as the weight loss reported in clinical trials does not differentiate
between intentional and unintentional weight loss.

During the period of adequate placebo control in phase three studies,
the % of subjects with weight loss of at least 10% was 9.1% (113/1243),
7.5% (53/709), 3.8% (5/133) and 5.9% (13/220) for the leflunomide,
methotrexate, SSZ and placebo treated groups.

A recent NDA efficacy supplement, 20905 supplement 8, included safety
data from a study of methotrexate versus methotrexate with add on
leflunomide in patients suboptimally responding to methotrexate. During
the first 6 months of therapy patients were randomized to either
methotrexate plus placebo versus methotrexate plus leflunomide. During a
second open phase period, the placebo arm was started on leflunomide.
The italicized quote that follows is taken from the medical officer's
review and identifies the same pattern of weight loss associated with
leflunomide in other studies.

*"NDA20-905/Suppl. 008 45*

*Weight loss*

*0-6 months*

*There was a mean decrease from baseline to month 6 in body weight of
0.08 kg in the*

*PLA+MTX treatment group compared with a decrease of 1.31 kg in the
LEF+MTX treatment group. The mean maximum weight loss relative to
baseline, for subjects with at least one weight loss relative to
baseline at any visit, was 1.7 kg in the PLA+MTX treatment group (range
0.1 to 9.1 kg) compared with 2.9 kg loss in the LEF+MTX treatment group
(range 0.0 to 13.7 kg). Four subjects (3.1%) in the LEF+MTX treatment
group experienced weight loss of greater than 10% of their baseline body
weight compared with 1 subject (0.8%) in the PLA+MTX treatment group.*

*6-12 months*

*In the LEF/LEF+MTX group, the mean decrease in weight from baseline to
month 12 was 1.98 kg, similar to the 1.31 kg decrease observed during
the first 6 months of treatment, suggesting no additional mean weight
loss occurring in the group during the second 6 months of treatment with
leflunomide. However of greater concern is that ten subjects (10.6%)
experienced a \>10% weight loss.*

*There was a mean decrease from baseline to Week 48 endpoint in body
weight of 1.28 kg in the PLA/LEF+MTX group, similar to the decrease seen
in the LEF+MTX group during the month 0-6 placebo controlled phase (1.31
kg) and a larger decrease than the 0.08 kg decrease that occurred in the
PLA+MTX group in the placebo-controlled phase. Six patients (6.3%)
experienced a \>10% weight loss.*

*Most of the cases of \>10% loss of body weight occurred in the open
label phase. Although some of the subjects had gastrointestinal
symptoms, diarrhea was not a prominent symptom among those who lost
weight. Most were on multiple concomitant medications and some had
infection adverse events, but there was no common identifiable
pattern."*

In summary, there is a consistent trend across multiple published
reports and analyses submitted to the Division suggesting that weight
loss is associated with leflunomide therapy. The cause of this
phenomenon is not known but possible causes include:

1.  Absorptive effects (possibly low level malabsorption based on immune
    effects on the intestinal immune system or effects on rapid turnover
    absorptive cells in the gut)

2.  Anorectic effect

3.  Effect on energy utilization on a cellular level

4.  Co-morbid events such as infection or drug interaction

5.  Surrogate for a clinically favorable response to therapy (lower
    steroid requirement or increased physical function)

6.  Other

Although clinically important weight loss was uncommon, such a
consistent pattern suggests a true phenomenon that may warrant notation
as such in the label.

Summary of safety data excluding hepatic effects

Compared to methotrexate, a current "gold standard" for the treatment of
RA, there was no evidence of higher death rates or serious adverse
events overall in this database of approximately 1700 patients on
leflunomide and 700 patients on methotrexate.

The pattern of withdrawals due to adverse events was nominally higher in
the leflunomide treated group. Specific events such as anemia,
malignancy and serious infections did not appear with more frequency in
the leflunomide group. Significant hypertension as reflected in new
onset hypertension, withdrawals due to hypertension and hypertension as
an SAE occurred with similar frequency between the two treatment groups.
Diarrhea and weight loss appear to occur more frequently with
leflunomide compared to methotrexate. This is reflected in the current
label. However the consistency of this finding across multiple studies
is of particular note.

######### iii. Hepatic Adverse Events

This category was broad and included all reports of hepatomegaly,
hepatitis (nonviral), hepatic coma, hepatorenal syndrome, liver event,
liver neoplasm, infarction, jaundice, AST elevation, ALT elevation, GGTP
elevation, alkaline phosphatase elevation. On review of cases the vast
majority were isolated spontaneously resolving AST or ALT elevations.
There were no cases of liver failure.

The data displayed in a graphic and tabular form in Appendix 20 indicate
that there was a nominally statistically significantly lower rate of
such events in the leflunomide group compared to the methotrexate group.
The minimal use of folate in some studies, notably MN301 impacts this
and subsequent analyses. These analyses are not fully indicative of
methotrexate use in the presence of folate. The similarity of event
rates between leflunomide and SSZ however is a reliable reflection of
hepatic event rates to be anticipated with these two products over the
first three months of exposure.

Although minor elevations of ALT were frequently transient in the
original NDA 20905 database as reflected in the current product label,
rates of AST/ALT above 3 ULN, 5 ULN, 10 ULN or cases of hepatocellular
injury associate with jaundice are of greater clinical relevance.
Appendices 21, 22and 23 reflect an analyses of these endpoints These
analyses indicates a nominally statistically significantly lower rate of
these biochemically defined hepatic events associated with leflunomide
compared to methotrexate.

**Discussion of medically significant hepatocellular injury.**

Elevations in serum hepatocellular enzyme levels reflect at a minimum,
increased permeability across hepatocellular membranes (or to the extent
other organs also contain these enzymes, membranes for these cell
associated enzymes; notably cardiac, red blood cell and skeletal muscle
and renal for AST and myocardial for ALT). Small elevations are
frequently not associated with clinically relevant outcomes and may
continue without clinical sequelae or reverse without intervention or
discontinuation. Clearly there are levels of AST and ALT elevation that
reflect permeability changes that are related to underlying
hepatocellular injury of significance. Various authors define such
elevations at 3 ULN-8 ULN

The presence of jaundice in the face of "hepatocellular injury " caused
by drug toxicity is widely accepted as a prognostic sign associated with
major hepatocellular injury and is associated with an approximate 10%
mortality. (4) Hepatocellular injury is a defined entity and does not
include minor transaminase elevations. According to the textbook
"Hepatotoxicity" by Hyman Zimmerman):

### "Hepatocellular injury resembles viral hepatitis in clinical as well as biochemical 

> features and often referred to as drug induced or toxic hepatitis."
>
> Jaundice associated hepatocellular injury is likewise a specific
> entity.
>
> " Necrosis- whether zonal, nonzonal or massive- is accompanied by high
> serum
>
> levels (8-200-fold elevated) of AST and ALT and usually slightly
> elevated ALP
>
> concentration. This biochemical pattern which mimics that of viral
> hepatitis is
>
> referred to as the *hepatocellular* or *hepatitis* type of drug
> induced jaundice" (5)

Thus, limited elevations of ALT in the range of 2-3 ULN are not of
similar meaning to the entity, hepatocellular injury or necrosis as
discussed above.

Rates of bilirubin elevation over 2 ULN and AST or ALT over 5 ULN are
reflected in Appendix 24. The rates are zero for methotrexate and the
cumulative rate is 0.4% for leflunomide. As causality is a critical
issue, especially for rare events that are highly morbid, this issue was
analyzed further. The sponsor was asked to produce a line listing of all
subjects in the clinical studies database used for the meta-analysis of
studies that experienced an elevation of 1.5 ULN bilirubin. This might
allow detection of rare cases of clinically serious hepatitis that
cannot be identified through statistical analyses of attributed cases of
elevated transaminases. As many episodes of hepatic events may be
attributable to "background" unrelated causes, reliance on comparisons
of unevaluated hepatic events between groups may be misleading. A
careful analysis of the data resulted in identification of 6 cases with
any ALT elevations in addition to bilirubin elevations.

Case review of elevated bilirubin and transaminase levels

To ensure that cases of borderline jaundice associated with
hepatocellular injury were not missed, case report forms were requested
for all bilirubin elevations over 1.5 ULN. The 6 cases with any
elevation of ALT and bilirubin over 1.5 ULN are reviewed below. All
cases were subjects on leflunomide. There were no cases identified in
the methotrexate treated group. The issue of causality assessment is
further discussed in a later section of this review.

[Study 3012: Pt. ID 52-5213:]{.underline}

Concomitant drugs included sulfasalazine, hydroxychloroquine,
levothyroxine and celecoxib. The highest ALT was 1.5 ULN. Therefore this
was not a case of hepatocellular injury due to therapy.

#### MN 302: PT ID 89:1023

Pancreatic malignancy confirmed. This was not a case of hepatocellular
injury due to therapy

#### YU204: Pt ID 007

ALT 2000 range with bilirubin 80 (ULN=21)

Hepatitis B

Unlikely case of hepatocellular injury due to therapy

#### MN 302: Pt ID 65-1011

Max ALT 8 ULN, bili 2 ULN.

Within 3 weeks of discontinuation of drug ( t ½ of leflunomide 2 weeks):
ALT \<2ULN and bili 1.3ULN

Cytomegalovirus IgM positive

Concomitant medication: Medrol, ibuprofen, thyroxin, Librax,

History of elevated Alkaline phosphatase 2 years prior to study entry

Follow-up nine months after discontinuation of therapy, ALT fluctuating
in range of 2ULN with alk phos 2-8ULN despite normal bilirubin hepatic
ultrasound normal.

Unlikely case of serious hepatocellular injury due to therapy due to
concomitant CMV, history of elevated LFTs, near total resolution of
elevated LFTs before clearance of drug and persistent fluctuating LFTs
off therapy.

[MN301: Pt ID: 35-1004]{.underline}

Bilirubin 41(17= ULN), ALT 28 (22=ULN)

(At entry LDH and GGT were elevated less than 1.5ULN)

Concomitant medications: aluminum hydroxide, amitryptiline, amlodipine,
atenolol, codeine, furosemide, indomethacin, isosorbide dinitrate,
paracetamol, perindopril erbumine, prednisone, and propoxyophene.

Concomitant medical conditions: partial gastrectomy, total abdominal
hysterectomy

This is a case of cholestasis unassociated with hepatocellular injury.

##### MN 302: Pt ID 43-1011

Bili 73 (ULN=21) ALT 210 (ULN=34) AST 89 (ULN=34) Alkaline phosphatase
700 (ULN115)

Narrative description of the case reported
***[simultaneously]{.underline}*** started drugs allopurinol,
dihydrocodeine, furosemide, glibenclamid, hydrochlorothiazide,
indomethacin, nifedipine, quinalpril, spironolactone. Concomitant
medical illnesses included diabetes mellitus, hypertension, heart
failure, bronchitis, and hyperuricemia. The clinical presentation was
pruritis and abdominal pain.

This reviewer considers it highly unlikely that all 10 concomitant drugs
were started simultaneously. There may be a translation or semantic
confusion. Nevertheless they were in apparent use during the leflunomide
exposure. All drugs were discontinued along with leflunomide at the time
of the hepatic adverse event except glibenamid, hydrochlorothiazide and
quinapril.

Contemporaneous with the elevation in LFTs, the patient's diabetes and
associated hyperlipidemia deteriorated ( glucose 10.2 {wnl: 3.9-6.7},
triglyceride 7.7 {wnl: 0.5-2.4} and cholesterol 9.6 {wnl:4.0-7.8}.
Elevated LFTs resolved within a month of discontinuation of leflunomide.

This is a possible case of leflunomide associated cholestatic hepatitis
however:

a.  the cholestatic pattern is not suggestive of hepatocellular injury

b.  multiple other medications confound causality assessment

c.  concomitant medical conditions confound causality assessment.

Case review of all patients reported to have a "serious adverse event-
hepatitis or jaundice".

In addition to an analysis of case reports of patients with a lab
elevation threshold of ALT over 3 ULN or bilirubin over 1.5 ULN, the
sponsor was asked to provide information on hospitalizations for serious
hepatic events or jaundice. This review identified one patient with
clinical hepatitis manifested by headache, lethargy, headache, nausea,
vomiting, pruritis and weight loss after 2 months on leflunomide. Labs
were normal on 12/27/95 at visit four for study MN 301. Based on
telephone call with study nurse on 1/11/96 drug was stopped on that day.
At presentation to the emergency room on 1/14/96 labs revealed ALT of
1870, AP of 277 and total bilirubin of 28 (ULN: 21). Follow-up labs on
1/18//96 revealed ALT of 2710 and bilirubin of 24. On 1/25/96 labs were
improving with an ALT of 972 and bilirubin of 14. Ultrasound did not
identify an anatomic cause of hepatic enzyme elevation or illness and
viral and autoimmune studies did not suggest acute viral or autoimmune
hepatitis. Report form noted diclofenac exposure "??/??/1994 to
Unknown". No information on formal mental status or prothrombin time was
reported.

This report does represent a case of hepatocellular necrosis.

###### **In summary, detailed examination of a pooled analysis of leflunomide monotherapy in approximately 1600 subjects on leflunomide and 700 subjects on methotrexate suggests that leflunomide produces hepatocellular enzyme elevations and hepatic adverse events to a similar extent to methotrexate (combined folate and nonfolate groups). There was one confounded case of cholestatic hepatitis and one case of hepatocellular necrosis.**

######### b: Hepatotoxicity in phase IV studies of combination therapy

The meta-analysis discussed above excluded studies of combination
therapy. Combination therapy is used widely in clinical practice. The
currently approved label includes cautionary wording about combination
therapy with potentially hepatotoxic drugs and a small co-therapy study
of pharmacokinetics performed before approval is described in the
product label that references the potential for toxicity with
co-therapy.

(*quote from label)*

*[Hepatotoxic Drugs]{.underline}*

*Increased side effects may occur when leflunomide is given
concomitantly with hepatotoxic substances. This is also to be considered
when leflunomide treatment is followed by such drugs without a drug
elimination procedure. In a small (n=30) combination study of ARAVA with
methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of
30 patients. All elevations resolved, 2 with continuation of both drugs
and 3 after discontinuation of leflunomide. A \>3-fold increase was seen
in another 5 patients. All of these also resolved, 2 with continuation
of both drugs and 3 after discontinuation of leflunomide. Three patients
met \"ACR criteria\" for liver biopsy (1: Roegnik Grade I, 2: Roegnik
Grade IIIa). No pharmacokinetic interaction was identified (see
[CLINICAL PHARMACOLOGY](#K05)*

*(End of label quote)*

As part of the current review of hepatotoxicity, safety data from phase
IV studies of co-therapy were reviewed.

i\. ***Study 4001 An evaluation of leflunomide versus placebo for the
treatment of active Rheumatoid Arthritis receiving a stable doses of
Methotrexate***

This study enrolled approximately 260 patients with suboptimal responses
to at least 6 months of methotrexate (6). Approximately 130 subjects
were randomized onto continued methotrexate monotherapy and 130 were
randomized to have leflunomide added to their methotrexate therapy.
After six months, those randomized to methotrexate and placebo that were
still in the study were placed on open label leflunomide plus
methotrexate for a second six month study period. The data below related
to this study is excerpted from the medical officers review of this
study dated October 2002. As the table below indicates there were very
few withdrawals due to liver function test abnormalities although adding
leflunomide to background methotrexate did result in treatment emergent
LFT elevations, just as leflunomide monotherapy does.

Tables from MO review October 2002 NDA 20905 supplement 8

![](media/image1.png){width="7.052777777777778in" height="4.2875in"}

![](media/image2.png){width="4.0in" height="0.35138888888888886in"}

![](media/image3.png){width="5.911111111111111in"
height="3.348611111111111in"}

(Note ULN bilirubin in this study was 20.1)

Thus there were no cases of true hepatocellular injury associated with
jaundice in this small database.

Further analysis of the ALT elevations on combination therapy from the
analysis of this study are reproduced below from the medical officers
review.

*"A total of **41 subjects (31.5%) had abnormal ALT elevations**,
defined as **\>1.2 x ULN**, during the placebo-controlled phase **in the
LEF+MTX group** compared with **9 subjects (6.8%) in thePLA+MTX group.**
ALT elevations of **between 1.2 x ULN and 2.0 x ULN** occurred in
**21.5%** of the subjects in the **LEF+MTX group** compared with **4.5%
in the PLA+MTX** group. ALT elevations of **between 2 x ULN and 3 x
ULN** occurred in **6.2% of the LEF+MTX** subjects compared with **1.5%
in the PLA+MTX** group. ALT elevations of **greater than 3 x ULN**
occurred in **3.8% of LEF+MTX** group compared with **0.8% of the
PLA+MTX** group. There were **no ALT elevations 8 x ULN**.*

*Elevations in liver enzymes occurred throughout the 6-month study
period, although the*

*elevations were somewhat more common in the first 3 months of
treatment."*

*"The **highest** LFT **elevation** in month 0-6 in the **LEF+MTX**
treatment group occurred in subject at the month 5 visit. The ALT value
was 216 U/L or 4.8 x ULN and the AST value was 116 U/L or 2.8 x ULN. The
elevations were confirmed on retest (ALT 6.3 x ULN and AST 5.0 ULN) and
study drug was discontinued. ALT levels reversed to 2 x ULN in one month
after the Month 5 visit and normalized to 0.5 x ULN in 10 weeks after
the Month 5 visit. AST normalized to 1.1 x ULN in one Month after the
Month 5 visit.*

*The combination of **LEF+MTX** treatment was associated with an
increased incidence of*

*elevated liver enzymes when compared with patients tolerating
methotrexate alone (**PLA+MTX)** in this controlled study."*

In this database, the rate of ALT\>3ULN was 3.8% over 6 months for
patients who had been on methotrexate for at least 6 months and naïve to
leflunomide. This rate is similar to the rate seen in monotherapy
studies of leflunomide, suggesting no synergy between the drugs in terms
of simple transaminasemia. There were no cases of serious hepatocellular
toxicity as defined by ALT \>8 ULN or jaundice. Marginal elevations of
1.2-2 ULN occurred more frequently in the leflunomide exposed patients
compared to those not exposed (21.5% versus 4.5%). This is actually
quite similar to the rates in the original monotherapy studies (US 301,
MN301 and MN302) referenced in the current approved label. In those
studies the rate of ALT elevation of 1.2-2.0 ULN was 17-19% in
leflunomide treated patients ( page 61 of medical officers review NDA
20,905 dated 1998) .

Although there did not appear to be a signal for synergistic
hepatotoxicity in this study, the size was too small to exclude an event
as rare as serious liver injury and would therefore be too small to
identify an increased risk when adding methotrexate to leflunomide.
Furthermore the doses in the study were variable and there were less
than 100 subjects exposed for over 6 months to both leflunomide 20 mg
and methotrexate [\>]{.underline} 20 mg/wk. Also of concern is that the
hepatic events in this study were identified early and drug stopped
appropriately per protocol. The pattern of toxicity outside the setting
of clinical trial may be less benign. Also of particular note is that
potential subjects who might be particularly inclined to experience
synergistic toxicity may have been "depleted" or excluded from this
study. Patients with signs of liver injury on methotrexate would be
withdrawn from methotrexate therapy previously and therefore not
available for enrollment in this study. Therefore definite conclusions
cannot be drawn from the lack of serious hepatotoxicity in combination
therapy from this study regarding rare severe liver toxicity.

In summary, hepatic events occurred in this trial in a similar pattern
to monotherapy studies. Limitations discussed above are of note.

ii\. Study 4002: Evaluation of the (leflunomide/sulfasalazine)
combination versus sulfasalazine alone in

patients with active Rheumatoid Arthritis non responders to leflunomide

Study 4002 was a larger study than 4001 with an enrollment of 968
patients into the first open label 24 week period of leflunomide therapy
alone. Patients who responded well were maintained on this therapy for
an additional 24 weeks and patients who were not responsive had SSZ
added. Since there was no control group in the first phase of study,
comparative information is not available. A review of the final study
report revealed that 4.5% (44 subjects) of subjects enrolled had at
least 1 measurement of ALT \> 3ULN. This is very similar to the rate of
such ALT elevations in the original studies submitted to support
approval and that appear in the approved label. 34/44 improved or
resolved with continued therapy, and 4/44 remained at the same level
with continued therapy. Thus 6/968 or less than 1% of subjects exposed
to leflunomide 20 mg/day for 6 months experienced transaminase elevation
that resulted in withdrawal from therapy.

There were no cases of jaundice associated with ALT elevation in this
study

**In summary, LFT abnormalities on leflunomide therapy in study 4002
were consistent with the previous monotherapy studies. No cases of
hepatocellular injury associated with jaundice were identified.**

######### 

######### 

######### c. Overall Conclusions from pooled analysis of randomized controlled clinical trials 

1.  **Multiple studies from the original NDA and subsequent phase four
    studies that included approximately 2800 subjects on leflunomide
    reproducibly demonstrated rates of ALT\>3 ULN elevations in the
    range of 1. 5-5% (placebo group rate 2.5% in study US301 and 1.1 in
    study MN 01) . The vast majority of such events resolve with
    continued therapy or discontinuation.**

2.  **There was one highly confounded case in the clinical trial
    database of a primarily cholestatic rather than hepatocellular
    jaundice pattern of hepatitis that was possibly related to
    leflunomide.**

3.  **Minimal (\< 2 ULN) self limited elevations of ALT are common with
    leflunomide use.**

4.  **Analyses of hepatic events as defined clinically or biochemically
    trended higher in the methotrexate versus leflunomide treated
    cohorts.**

5.  **Weight loss was a consistent finding in this updated database.**

6.  **This database may not reflect experience in less controlled
    settings and cannot exclude rare events that occur with an incidence
    of less than 1 in 1000.**

**D. Post marketing cohort studies**

i.  **Aetna Cohort study:**

In a submission dated April 4, 2002 the sponsor submitted a post
marketing cohort study dated March 7, 2002. This study analyzed a
database of over 40,000 RA patients within an Aetna/US Healthcare
database of over 10 million covered lives. The details of study design
can be found in appendix 27.

The results including demographic data and results for various endpoints
are presented below. Of note, "other DMARD" included gold,
penicillamine, sulfasalazine, etanercept, infliximab, corticosteroids,
chlorambucil, cyclophosphamide, hydroxychloroquine, cyclosporine and
minocycline. The categories of primary concern are methotrexate and
leflunomide and the combination of the two.

##  CODES FOR THE HEPATIC EVENTS

  -------------------------------------------------------- --------------
  **Diagnosis**                                            **ICD-9CM**

  Acute or Subacute Liver Necrosis\*                       570

  Hepatitis, Noninfectious toxic\*                         573.3

  Jaundice                                                 782.4

  Cirrhosis of liver, no alcohol                           571.5

  Biliary cirrhosis                                        571.6

  Other specified liver disorder                           573.8

  Unspecified liver disorder                               573.9

  Hepatic coma                                             572.2

  **\*** cases of particular interest                      
  -------------------------------------------------------- --------------

##  DEMOGRAPHIC CHARACTERISTICS OF THE PATIENTS

  ------------------------- -------------------- -------------------- --------------------
  **[Age                    **[Male              **[Female            **[Total
  group]{.smallcaps}**      (%)]{.smallcaps}**   (%)]{.smallcaps}**   (%)]{.smallcaps}**

  **[18-30]{.smallcaps}**   408                  1554                 1962 (4.83)

  **[31-50]{.smallcaps}**   3341                 9951                 13 292 (32.74)

  **[51-64]{.smallcaps}**   3499                 9485                 12 984 (31.99)

  **[65+]{.smallcaps}**     3598                 8758                 12 356 (30.44)

  **[Total]{.smallcaps}**   10 846 (26.72)       29 748 (73.28)       40 594
  ------------------------- -------------------- -------------------- --------------------

## DESCRIPTIVE STATISTICS OF PERSON-TIME EXPOSURES ACROSS selected COHORTS

+---------------------------+--------------+--------------+-----------+
| **[DRUG(S)]{.smallcaps}** | **[PE        | **[MEAN      | **        |
|                           | RSON-YEAR]{. | EXPOSURE]{.  | [PATIENTS |
|                           | smallcaps}** | smallcaps}** | ON        |
|                           |              |              | THER      |
|                           | **           | **[TIME      | APY]{.sma |
|                           | [EXPOSURE]{. | (days)]{.    | llcaps}** |
|                           | smallcaps}** | smallcaps}** |           |
+---------------------------+--------------+--------------+-----------+
| leflunomide               | 2166 (2.54%) | 176.52       | 4478      |
+---------------------------+--------------+--------------+-----------+
| DMARD                     | 15 717       | 240.44       | 23 860    |
|                           | (18.43%)     |              |           |
+---------------------------+--------------+--------------+-----------+
| MTX                       | 4808 (5.64%) | 178.31       | 9842      |
+---------------------------+--------------+--------------+-----------+
| Monotherapy subtotal      | **33 613     |              |           |
|                           | (39.45%)**   |              |           |
+---------------------------+--------------+--------------+-----------+

+---------------------------+--------------+--------------+-----------+
| **[DRUG(S)]{.smallcaps}** | **[PE        | **[MEAN      | **        |
|                           | RSON-YEAR]{. | EXPOSURE]{.  | [PATIENTS |
|                           | smallcaps}** | smallcaps}** | ON        |
|                           |              |              | THER      |
|                           | **           | **[TIME      | APY]{.sma |
|                           | [EXPOSURE]{. | (days)]{.    | llcaps}** |
|                           | smallcaps}** | smallcaps}** |           |
+---------------------------+--------------+--------------+-----------+
| leflunomide + DMARD       | 2719 (3.19%) | 314.02       | 3161      |
+---------------------------+--------------+--------------+-----------+
| leflunomide + NSAID       | 1024 (1.20%) | 263.52       | 1418      |
+---------------------------+--------------+--------------+-----------+
| leflunomide + MTX         | 693 (0.81%)  | 213.19       | 1186      |
+---------------------------+--------------+--------------+-----------+
| leflunomide + Cox-2       | 988 (1.16%)  | 272.89       | 1321      |
+---------------------------+--------------+--------------+-----------+
| DMARD + NSAID             | 10 330       | 343.82       | 10 966    |
|                           | (12.12%)     |              |           |
+---------------------------+--------------+--------------+-----------+
| DMARD + Cox-2             | 4849 (5.69%) | 299.33       | 5913      |
+---------------------------+--------------+--------------+-----------+
| DMARD + MTX               | 8621         | 403.34       | 7802      |
|                           | (10.11%)     |              |           |
+---------------------------+--------------+--------------+-----------+
| MTX + Cox-2               | 1772 (2.08%) | 256.57       | 2521      |
+---------------------------+--------------+--------------+-----------+
| NSAID + MTX               | 4020 (4.72%) | 318.84       | 4602      |
+---------------------------+--------------+--------------+-----------+
| **Two-drug combination    | **35 360     |              |           |
| subtotal**                | (41.50%)**   |              |           |
+---------------------------+--------------+--------------+-----------+
| **TOTAL**                 | **85 210**   |              |           |
+---------------------------+--------------+--------------+-----------+
| **Any leflunomide**       | **13 200     |              |           |
|                           | (15.49%)**   |              |           |
+---------------------------+--------------+--------------+-----------+

The mean exposure was approximately one year. If as is generally the
case, drug related toxicity occurs within the first 6-12 months of
exposure, a study that looks only at individuals that have been on
therapy for at least 6-12 months will miss all cases of drug induced
hepatotoxicity and therefore be less informative. Depletion of
susceptibles is a potential confounder in this type of study. To enter
the study cohort, a subject had to be on therapy. Methotrexate has long
been a standard of therapy and was available for use on rheumatoid
arthritis well before the creation of this cohort in 1998. Leflunomide
however was approved in 1998 and it may well be that the leflunomide
cohort in this study overall was "newer" to therapy than the
methotrexate treated group. This phenomenon would bias the study results
in favor of a drug with a greater pre-cohort exposure to drug,
methotrexate. The sponsor was unable to provide any details on the
extent of therapy prior to enrollment in this cohort study.

## INCIDENCE RATES (PER 100 P-Y) OF SEVERE HEPATIC EVENTS (HEPATIC FAILURE, HEPATIC NECROSIS, BILLIARY CIRRHOSIS, AND HEPATITIS) 

+------------------+--------------+-------------+--------------------+
| **Monotherapy**  | *            | **[Adjusted | **[95% confidence  |
|                  | *[Unadjusted | Rate]{.s    | inter              |
| #######          | Rate]{.      | mallcaps}** | val]{.smallcaps}** |
| [(number of even | smallcaps}** |             |                    |
| ts)]{.smallcaps} |              |             | **[(adjust         |
|                  |              |             | ed)]{.smallcaps}** |
+------------------+--------------+-------------+--------------------+
| leflunomide (6)  | [0.28]       | 0.17        | 0.05, 0.56         |
|                  | {.smallcaps} |             |                    |
+------------------+--------------+-------------+--------------------+
| DMARD (76)       | [0.48]       | 0.25        | 0.15, 0.40         |
|                  | {.smallcaps} |             |                    |
+------------------+--------------+-------------+--------------------+
| MTX (17)         | 0.35         | 0.26        | 0.12, 0.53         |
+------------------+--------------+-------------+--------------------+
| **Two-drug       | Unadjusted   | **[Adjusted | **[95% confidence  |
| therapy**        | Rate         | Rate]{.s    | inter              |
|                  |              | mallcaps}** | val]{.smallcaps}** |
| **[(number of    |              |             |                    |
| events           |              |             | **[(adjust         |
| )]{.smallcaps}** |              |             | ed)]{.smallcaps}** |
+------------------+--------------+-------------+--------------------+
| leflunomide +    | 0.30         | 0.27        | 0.08, 0.93         |
| cox-2 (3)        |              |             |                    |
+------------------+--------------+-------------+--------------------+
| leflunomide +    | 0.18         | 0.07        | 0.01, 0.29         |
| DMARD (5)        |              |             |                    |
+------------------+--------------+-------------+--------------------+
| leflunomide +    | 0.43         | 0.30        | 0.07, 1.32         |
| MTX (3)          |              |             |                    |
+------------------+--------------+-------------+--------------------+
| leflunomide +    | 0.10         | 0.09        | 0.01, 0.65         |
| NSAID (1)        |              |             |                    |
+------------------+--------------+-------------+--------------------+
| DMARD + cox-2    | 0.14         | 0.03        | 0.01, 0.14         |
| (7)              |              |             |                    |
+------------------+--------------+-------------+--------------------+
| DMARD + NSAID    | 0.14         | 0.05        | 0.02, 0.13         |
| (14)             |              |             |                    |
+------------------+--------------+-------------+--------------------+
| MTX + cox-2 (3)  | 0.17         | 0.17        | 0.05, 0.60         |
+------------------+--------------+-------------+--------------------+
| MTX + DMARD (11) | 0.13         | 0.08        | 0.03, 0.20         |
+------------------+--------------+-------------+--------------------+
| MTX + NSAID (13) | 0.32         | 0.23        | 0.10, 0.54         |
+------------------+--------------+-------------+--------------------+

As anticipated there were few events in this category of severe hepatic
events (6 and 17 in the leflunomide and methotrexate groups
respectively). The adjusted and unadjusted rates for leflunomide was
numerically lower than the methotrexate group. The small number of
events in the group on combination therapy is of note.

Analysis of specific codes of hepatic events may help better
characterize hepatocellular injury. Acute and subacute necrosis and
jaundice are most relevant as discussed earlier in this review. This
type of study is based on reporting from claims forms, which may not
accurately reflect causality. Thus, "jaundice" maybe due to biliary
obstruction or sepsis and not drug induced hepatocellular necrosis or
cholestasis. Nonetheless, the absence of any events of jaundice and only
one event reported for acute and subacute necrosis in the leflunomide
treated cohort is of note. The absence of any events of jaundice in this
cohort suggests that no cases of hepatocellular injury associated with
jaundice occurred The absence of any of these events in the co-therapy
cohort receiving methotrexate and leflunomide is of note, however this
is based on a relatively small number of subjects.

## INCIDENCE RATES (PER 10 000 P-Y) OF INDIVIDUAL LIVER EVENTS: MONOTHERAPY RATES (95% CI IN PARENTHESIS) 

  ------------------------- ---------------------- ---------------------- ----------------------
  **[event]{.smallcaps}**   **[lef                 **[dmard               **[mtx
                            \[n\]]{.smallcaps}**   \[n\]]{.smallcaps}**   \[n\]]{.smallcaps}**

  [Acute & subacute         4.62 (0.82, 26.17)     2.55 (0.99, 6.55)      2.08 (0.37, 11.79)
  Necrosis]{.smallcaps}     \[1\]                  \[4\]                  \[1\]

  [Biliary                  0 (0, 17.75)           5.73 (3.01, 10.89)     0 (0, 7.99)
  cirrhosis]{.smallcaps}                           \[9\]                  

  [hepatic                  0 (0, 17.75)           2.55 (0.99, 6.55)      0 (0, 7.99)
  coma]{.smallcaps}                                \[4\]                  

  [noninfectious            23.10 (9.87, 54.09)    37.56 (29.12, 48.45)   33.30 (20.50, 54.10)
  hepatitis]{.smallcaps}    \[5\]                  \[59\]                 \[16\]

  [Cirrhosis]{.smallcaps}   0 (0, 17.75)           13.37 (8.75, 20.44)    4.16 (1.14, 15.18)
                                                   \[21\]                 \[2\]

  [Unsp chronic             0 (0, 17.75)           1.27 (0.35, 4.64)      0 (0, 7.99)
  liver^1^]{.smallcaps}                            \[2\]                  

  [Other unsp liver         9.24 (2.53, 33.70)     13.37 (8.75, 20.44)    12.49 (5.72, 27.25)
  dis^2^]{.smallcaps}       \[2\]                  \[21\]                 \[6\]

  [Unsp liver               9.24 (2.53, 33.70)     15.28 (10.27, 22.74)   33.30 (20.50, 54.10)
  dis^3^]{.smallcaps}       \[2\]                  \[24\]                 \[16\]

  [Jaundice]{.smallcaps}    0 (0, 17.75)           3.82 (1.75, 8.33)      8.32 (3.24, 21.41)
                                                   \[6\]                  \[4\]

  [Enzymes]{.smallcaps}     23.10 (9.87, 54.09)    21.65 (15.49, 30.25)   6.24 (2.12, 18.36)
                            \[5\]                  \[34\]                 \[3\]

  **[Total]{.smallcaps}**   **69.3 (42.0, 114.4)** **117.15 (101.4,       **99.90 (75.4,
                                                   135.3)\***             132.4)\*\***
  ------------------------- ---------------------- ---------------------- ----------------------

^1^ includes hepatic sclerosis, postnecrotic liver scarring, liver
stasis

^2^ includes hepatoptosis, hemorrhage, lesion, obstruction, induration,
prolapse, nutmeg, acute hypertrophic, pleurohepatitis, nontraumatic
rupture

C.  includes distention of gaseous liver, torpid liver, palpable liver

D.  p-value = 0.031 (lef v DMARD)

## TABLE 12.11 INCIDENCE RATES (PER 10 000 P-Y) OF INDIVIDUAL LIVER EVENTS FROM THE COHORT STUDY: TWO-DRUG THERAPY RATES (95% CI INPARENTHESES) 

## 

  ------------------------- ---------------------- ---------------------- ----------------------
                            **[lef + mtx           **[lef + dmard         **[mtx + dmard
                            \[n\]]{.smallcaps}**   \[n\]]{.smallcaps}**   \[n\]]{.smallcaps}**

  [Acute & subacute         0 (0, 55.48)           0 (0, 14.13)           0 (0, 3.72)
  Necrosis]{.smallcaps}                                                   

  [Biliary                  0 (0, 55.48)           0 (0, 14.13)           0.97 (0.17, 5.49)
  cirrhosis]{.smallcaps}                                                  \[1\]

  [hepatic                  0 (0, 55.48)           3.68 (0.65, 20.84)     0 (0, 3.72)
  coma]{.smallcaps}                                \[1\]                  

  [noninfectious            43.33 (14.74,          14.72 (5.72, 37.85)    9.69 (5.26, 17.83)
  hepatitis]{.smallcaps}    127.42)\* \[3\]        \[4\]                  \[10\]

  [Cirrhosis]{.smallcaps}   0 (0, 55.48)           0 (0, 14.13)           2.91 (0.99, 8.55)
                                                                          \[3\]

  [Unsp chronic             0 (0, 55.48)           0 (0, 14.13)           0.97 (0.17, 5.49)
  liver^1^]{.smallcaps}                                                   \[1\]

  [Other unsp liver         0 (0, 55.48)           3.68 (0.65, 20.84)     3.87 (1.51, 9.96)
  dis^2^]{.smallcaps}                              \[1\]                  \[4\]

  [Unsp liver               0 (0, 55.48)           11.04 (3.75, 32.46)    11.62 (6.65, 20.32)
  dis^3^]{.smallcaps}                              \[3\]                  \[12\]

  [Jaundice]{.smallcaps}    0 (0, 55.48)           3.68 (0.65, 20.84)     0.97 (0.17, 5.49)
                                                   \[1\]                  \[1\]

  [Enzymes]{.smallcaps}     14.44 (81.83)\*\*      7.36 (2.02, 26.83)     9.69 (5.26,17.83)
                            \[1\]                  \[2\]                  \[10\]

  **[Total]{.smallcaps}**   **57.78 (22.47,        **44.16 (25.26,        **40.69 (30.10,
                            148.53)**              77.19)**               54.99)**
  ------------------------- ---------------------- ---------------------- ----------------------

^1^ includes hepatic sclerosis, postnecrotic liver scarring, liver
stasis

^2^ includes hepatoptosis, hemorrhage, lesion, obstruction, induration,
prolapse, nutmeg, acute hypertrophic, pleurohepatitis, nontraumatic
rupture

E.  includes distention of gaseous liver, torpid liver, palpable liver

F.  rate based on three cases

\*\* rate based on one case

In summary:

1.  This study of over 4000 patients on leflunomide and almost 10,000
    patients on methotrexate did not identify a signal for higher rates
    of hepatotoxicity in association with leflunomide compared to
    methotrexate.

2.  This study suggests that the rate of *serious* acute hepatotoxicity
    is low with both products. No events of hepatocellular necrosis
    associated with jaundice were identified. This finding is consistent
    with the expanded clinical trial database.

3.  It is of note that these results are from a less well controlled
    setting than the clinical trial data and hence add information from
    patients with a broader range of co-morbidities and potential risk
    for drug induced hepatotoxicity than the artificial setting of
    clinical trials. The limitations in ascertainment and causality
    assessment of such studies are noted.

4.  The absence of any cases of acute or subacute necrosis or jaundice
    associated with coadministration of leflunomide and methotrexate in
    study this study or in study 4001 is of note. A synergistic
    hepatotoxic effect has not been identified. However the exposure to
    20 mg for a full 6 months in study 4001 and the exposure in this
    study is limited.

**ii. Protocare and Pharmetrics bi-cohort study:**

In order to assess a large database that may shed light on rare hepatic
events as well as overall comparative safety, the sponsor has submitted
preliminary results of a health claims database performed by Samy Suissa
PhD. of the McGill University Health Centre. The final report is
pending. The completed study report is appended (appendix 32). The
Protocare database includes longitudinal health benefit claims from
Medicaid, Medicare, private health maintenance organizations (HMO) and
preferred provider organizations (PPO). The Pharmetrics database
consists of claims data from 40 different managed care organizations.
(see appendix 28)

**Study design:**

Subjects with a diagnosis of rheumatoid arthritis who filled a
prescription for a DMARD between September 1, 1998 and December 31, 2001
were included. Cohort members were followed from entry to the occurrence
of serious events as defined in the study report. A nested case control
(10-100 controls/case) was used. Logistic regression was used to
estimate the rate ratio (RR) for the various endpoints of interest
adjusted for age gender, non-DMARD use and comorbidity. Methotrexate was
the reference drug set at a RR of 1.0 for all analyses.

***Reviewers comment***

*A potential source of bias in an uncontrolled nonrandomized study
includes channeling bias into the various therapies. Methotrexate has a
well-established efficacy and safety profile and has been a gold
standard for many years prior to the initiation of this study.
Leflunomide on the other hand was approved the same year as this cohort
was defined. This may result in two forms of bias which may inflate the
adverse event rate of leflunomide vis a vis methotrexate. Firstly,
patients channeled into leflunomide therapy may be sicker and previously
unresponsive or intolerant to prior therapy especially methotrexate.
Also, patients on methotrexate from 1998-2001 are very likely to have
been on methotrexate for a period of time and those that remained on
therapy during this study period would be "depleted" of patients "at
risk" for methotrexate toxicities. Thus the rate of events in the
methotrexate group will be an underestimate of what would happen in
methotrexate naïve patients. Furthermore, all patients on leflunomide
for the first year of this study must have been relatively naïve to
leflunomide since the drug was approved in 1998 and thus the rates of
events relative to methotrexate may be inflated. One can not rule out
potential sources of bias that would minimize the relative risk of
leflunomide such as channeling sicker or fragile patients away from a
new therapy with a less well defined safety and efficacy profile as was
the case with leflunomide compared to methotrexate. This reviewer's best
judgement is that this study is more likely overall to be subject to
bias that would inflate the rate of leflunomide toxicity relative to
methotrexate. This position however cannot be verified.*

*Additional concern regarding this type of study is that causality
assessment and ascertainment of events is not well controlled, as no
clinical information is available. The quality and consistency of coding
is not verifiable.*

*Given the importance of obtaining information regarding rare but life
threatening drug toxicity, such databases must be accessed and utilized.
Randomized and controlled long-term data cannot be collected practically
or ethically on the large populations needed for such analyses.*

**Results:**

The cohort of subjects with RA receiving a DMARD included 33,009 and
8876 in the Pharmetrics and Protocare databases respectively. 2300
subjects were on leflunomide and 15000 on methotrexate.1700 patients on
biologic DMARDs were included. Mean exposure during the study was 436
days. DMARDs included leflunomide, methotrexate, gold, anti-malarials,
minocycline, chelating agents, sulfasalazine cytotoxic rugs and anti-TNF
biologics. Only

Two event definitions were used. The first and primary analysis included
only events that resulted in hospitalization. This defined the events as
serious. A second analysis included all events with the relevant ICD-9CM
codes. The complete results are appended (appendix 28). A summary of the
results follows. (Rates are adjusted. Crude RR are presented in appendix
28.)

**Rate ratios are based on a reference of methotrexate set as 1.0**

1.  Hospitalization rates for hepatic events (coded as acute or subacute
    liver necrosis, cirrhosis of the liver without mention of alcohol,
    noninfectious toxic hepatitis and hepatic coma) in patients on
    leflunomide therapy at entry into the trial was 0.0 (0 cases)
    compared to the reference rate of 0.9 (7 cases). Interestingly,
    "other DMARDs" had a RR of 2.3 compared to methotrexate. The
    analysis of all similarly coded events (with and without
    hospitalization) revealed a RR of 1.0 for leflunomide and 1.1 for
    other DMARDs.

2.  The RR for hospitalization for hematologic events was 0.8 for
    leflunomide compared to methotrexate. The adjusted rate for all
    hematologic events for leflunomide monotherapy for was 1.0.

3.  The RR for hospitalization for septicemia and opportunistic
    infections was 0.9 for leflunomide compared to methotrexate.
    Biologic DMARDs had a RR of 2.0

4.  Severe skin reactions occurred only in the "other" DMARD group. The
    RR for the expanded all skin events analysis revealed a RR of 1.8
    for leflunomide therapy ( 95%CI 0.4-7.3)

5.  The analysis for lymphoma revealed only 4 cases in the entire DMARD
    database. None of the cases has current or prior year exposure to
    methotrexate or leflunomide. No statistical analysis was possible on
    such a small database of events.

6.  The RR for a composite of hospitalizations for any severe adverse
    event was 1.0 for leflunomide monotherapy. The rate for biologic
    DMARDs was 1.8

The RR for all nonbiologic DMARDs was surprisingly similar. This
reviewer would expect that the commonly thought of immune modulators,
leflunomide and methotrexate would have higher rates of serious
infection, septicemia and opportunistic infections compared to other
DMARD drugs based both on immune mechanisms as well as channeling bias
of sicker patients into these treatments. Given the concerns over
hepatotoxicity rates would have expected above the other DMARDs. This
however was not the case.

The only events for which the 95% confidence interval did not include
one were:

1.  hospitalizations for hepatic events for which biologic DMARDs had a
    higher rate than methotrexate

2.  hospitalizations for any serious event for which biologic DMARDs had
    a higher rate than methotrexate

3.  hospitalizations for any opportunistic infection and septicemia
    event for which biologic DMARDs had a higher rate than methotrexate

4.  hospitalizations for hepatic events for which biologic DMARDs had a
    higher rate than methotrexate

5.  Any adverse event (hospitalized or not hospitalized) for which
    biologic DMARDs and leflunomide as part of multiple therapies had a
    higher rate than methotrexate

6.  Any hepatic events for which biologic DMARDs had a higher rate than
    methotrexate

7.  Any hematologic event for which biologic DMARDs had a higher rate
    than methotrexate

*Patient co-morbidity as well as concomitant therapy is a critically
important part of any statistical adjustment for these analyses. It is
not clear whether the statistical adjustments for co-therapies truly
normalized this potential effect.*

*As this was not a controlled experience, comparisons between therapies
are limited by channeling bias. It is possible that subjects on biologic
DMARDs had more co-morbidities at baseline that could not be adequately
adjusted in the logistic regression.*

**In summary, this cohort study did not suggest higher rate for
leflunomide for serious events as defined by hospitalization, serious
and non-serious hepatic events, hematologic events or infections
compared to methotrexate. Non- serious skin adverse events did trend
higher in the leflunomide treated cohort. Overall biologic DMARDs tended
to have higher rate ratios than leflunomide and methotrexate for all
study endpoints. The potential for channeling bias for these agents
cannot be dismissed. The limited data collected in such studies is not
comparable to clinical studies that access actual case reports. Thus
serious rare events may be missed. To the limits of such studies to
study safety, this study does not suggest that leflunomide is less safe
than methotrexate.**

**iii. American College of Rheumatology abstract 2002: Abstract 968:
American College of Rheumatology: Frederick Wolfe MD. Low rates of
serious Liver Toxicity to Leflunomide (LEF) and Methotrexate (MTX)**

A recent analysis of a longitudinal patient reporting surveillance
program maintained by the National Data Bank for Rheumatic Diseases was
presented in abstract form at the 2002 American College of Rheumatology
meetings (abstract 968)

In this presentation (which is in manuscript form) 4298 users of
leflunomide and 7687 users of methotrexate participated in a
questionnaire form of follow-up. Hospitalizations for liver associated
adverse events occurred at a rate of 0.2 per 100 pt.year in the
leflunomide group and 0.27 per 100-pt. year in the methotrexate group.
Statistical analysis of so few events is of limited value although 95%
confidence intervals were reported to overlap. The list of ICD-9 hepatic
codes included over two dozen codes, most of which do not pertain to
potential drug induced liver disease. Therefore many of the events
included in this statistical analysis can only obscure the ability to
assess drug-related injury. This analysis is therefore of limited
relevance.

However, a more detailed look at the data may provide valuable safety
information. One patient in each group was hospitalized for 'acute
necrosis of the liver". Two patients (both on methotrexate) were
hospitalized for "abnormal serum enzyme level. In patients not
participating in the questionnaire program, death certificate
information included cirrhosis and liver failure in one patient that had
been on both methotrexate previously and then leflunomide for two years.

In summary, this study identified one patient with apparent
leflunomide-induced hepatotoxicity requiring hospitalization and one
such patient on methotrexate. As discussed earlier in this review under
"Liver specific events", adverse events coded as "liver related" is very
broad and even more likely to be confounded by the patient reporting
methodology used in this study compared to a clinical trial database.
Patient reporting may not be as accurate as clinical trials or medically
coded databases. Thus without medical records to assess causality, it is
possible that both, either or neither of the reported hospitalizations
were truly due to drug induced hepatotoxicity.

**Summary of Hepatotoxicity in clinical trials and cohort studies**:

**Clinical trials database as well as the Aetna/ United Health Care,
Protocare/Pharmetrics cohort studies submitted by the sponsor suggest no
excess of "liver injury" (using various definitions) in association with
leflunomide compared to methotrexate. However, cohort studies are
limited in sensitivity and specificity for specific events (such drug
induced hepatocellular necrosis associated with jaundice) due to the
limitations of ICD-9 coding as well as channeling bias and cannot
accurately ascertain causality. Thus for small numerator events
especially, cohort studies are significantly limited. The one case of
clinical hepatitis with biochemical evidence of hepatocellular necrosis
in the controlled clinical trial database of 2700 subjects on
leflunomide is of concern.**

**However, this reviewer cannot conclude that overall acute liver injury
is more common in association with leflunomide compared to methotrexate.
The inconsistent minor trends in the various databases suggest that the
true comparative rates between these two agents may be quite similar.**

**C. Post-marketing reports of acute liver failure (ALF)**

Post marketing reports of hepatic events that were reported from the
time of approval until August 25, 2002 have been identified by the
Office of Drug Safety (ODS) . Review date 11/7/02.

This section of the review will:

1.  Discuss definitions of acute liver failure

2.  Discuss causality assessment

3.  Review consultation by ODS

4.  Independently assess the cases identified by ODS

5.  Review 2 hepatology consultant opinions on these postmarketing
    reports

ODS has identified 16 cases of acute liver failure and 38 cases of
serious liver injury.

These cases form the database of analysis of post-marketing serious and
lifethreatening hepatic injury. While the ODS review does reference
international reports of ALF and consultants have also reviewed these
cases, the primary discussion of risk analysis by ODS addresses US
cases.

Definitions are critical to the assessment of liver disease in general
and causality in particular. ODS reviewers Renan Bonnel and David Graham
have adopted a methodology of assessing risk by identifying
post-marketing case reports, generating reporting rates, hazard and
usage (persistence of use) rates, as well as adjustments for
underreporting". A cumulative rate of risk is then calculated based on
the extrapolation from the above rates. While there are multiple
assumptions that require further assessment and validation in this
emerging area of risk quantitation, this section of the review will deal
primarily with the case identification/definition of ALF. Validation of
the methodology used by Bonnel and Graham has not been presented.
Clearly, the extrapolation from individual cases to population risk
quantitation involves amplification by multiple orders of magnitude.
This, if there is error in the index case assessment, the error will be
amplified. Therefore, case analysis is critical at this juncture. A
further critique of the methodologies used in the ODS review is beyond
the scope of this review

## i. Definitions

Acute liver failure (ALF):

The ODS review uses the following referenced definition of ALF:

*"**Acute liver failure (ALF), fatal or non-fatal***

*Interval from the development of liver-related signs or symptoms or
jaundice to any of the*

*following within a period of 3 months or less: hepatic encephalopathy;
placement on a liver*

*transplant list; or liver transplantation; or death in the setting of
acute liver injury. In some reports,*

*specific information on timing was not provided and classification was
based on the case report*

*narrative suggesting a rapid time course."*

This definition is mainstream and well referenced. A critical component
of this definition however is the setting of acute liver injury.
Progression of underlying liver disease to end stage and liver failure
is not ALF. If it were then every death from chronic liver failure would
be ALF, clearly not the clinical meaning of acute liver failure. The ODS
dataset included such cases (including a patient with longstanding end
stage liver disease manifested by documented portal hypertension for
years).

The following quote from a seminal article on ALF identifies the
clinical syndrome, setting and timing of ALF. Importantly, it defines
this term only in the context of ***[previously well
people]{.underline}***. This is an important point when evaluating
reports of acute liver failure.

" Few conditions in medicine are more dramatic or more devastating than
acute liver failure. Severe liver-cell dysfunction strikes [previously
well people suddenly]{.underline}, and many of them die. Acute liver
failure embraces a number of conditions whose common thread is severe
injury of hepatocytes or massive necrosis. ....

> *Altered mental status (hepatic encephalopathy) and coagulopathy in
> the setting of an acute hepatic disease define acute liver failure.
> The term "fulminant hepatic failure" is generally applied to patients
> in whom hepatic encephalopathy develops within 8 weeks of the onset of
> illness, whereas subfulminant hepatic failure" is used to describe a
> minority of patients in whom hepatic encephalopathy develops after a
> longer illness, up to 26 weeks in duration (also called late onset
> hepatic failure). Acute hepatic failure is used as the most suitable
> umbrella term since it encompasses all these clinical presentations."
> (7)*

A very controversial aspect of case definition was included in the ODS
analysis.

"*This category will also include reports with a diagnosis of liver
failure without supporting clinical*

*or laboratory data*." (ODS review dated 11/7/02: page 5)

A decision was made by the ODS reviewer to expand the case definition to
undocumented reports. No rationale or justification was given for this
expansion of the definition. It is reasonable when attempting to
identify potential signals in a post marketing database, to seriously
consider such cases and aggressively pursue the individual cases through
contact with the case reporter and to look more scrupulously at the
entire post marketing database. However, in the current context of
quantitation of *[absolute risk]{.underline}* such inclusion criteria
are problematic. To include reports that have no documentation and are
reported by individuals who will not provide such information opens the
entire process to corruption as well as seriously flawed analyses. Such
cases were included in the ODS calculations of absolute risk.

######### ii. Causality

Causality is difficult to assess in the analysis of post-marketing
adverse events in general. Quality and reliability of reports is
uncontrolled. Concomitant medications and medical conditions as well as
background rates in the population at large cannot be ignored. If one
were to assume that all events (regardless of other potential or likely
causes of an adverse event) that occur on a particular therapy are
causally related to the therapy, then every therapy would carry the risk
profile of the universe of concomitant therapies. Without a valid
assessment of causality, quantitation of risk cannot be valid. The
challenge to those charged with assessing causality is to establish a
standardized, consistent and validated way to assess attributability.
The ODS review fails to do this despite the case definition referenced
in the review as quoted below.

"Probable/likely:

*Hepatic event, including lab test abnormality, occurring in a plausible
time relationship to drug*

*administration;*

*The event is unlikely attributed to concurrent disease or other drugs;
and*

*Positive dechallenge and rechallenge is not required.*

***Possible:***

*Hepatic event, including lab test abnormality, occurring in a plausible
time relationship to drug;*

*There are other factors present that could plausibly have contributed
to liver injury, but were not*

*the most likely explanation for the adverse event, and*

*Dechallenge or rechallenge information is not required.*

***Unlikely:***

*Hepatic event, including lab test abnormality are not temporally
related to drug.*

*or*

*Other medications or underlying disease provide more likely explanation
for the adverse events."*

###### This definition is derived from the WHO definition and is valid but incomplete. In the current context this is a critical and fundamental area that has not been articulated or dealt with by the ODS review. It does not address how to define or quantitate "concurrent disease or other drugs" in the context of causality. Others have attempted to address this issue. In a recent editorial by William Lee the difficulty in assessing causality is bluntly stated.

*"Unfortunately, causality assessment is not an exact science. It
involves marshalling bits of evidence much like a legal case, after the
fact, and trying to convict a drug of a crime, that is causing
hepatitis. As with hardened criminal, the fact that a drug is capable of
causing an adverse reaction doses not mean that it did....*

*A systematic approach to identifying and to assessing drug
hepatotoxicity should improve current haphazard methods. Developing a
case identification system which is validated and which uses commonly
available clinical information should be helpful. In addition, making
causality assessment more uniform should exonerate some drugs from
suspicion while implicating others. CAMs stand a good chance of
hastening the withdrawal of toxic agents and improving the process of
post-marketing surveillance." (8)*

Standardization of causality assessment is gaining acceptance through
consensus and validation.

A series of consensus meetings under the auspices of the Roussel Uclaf
Group since 1985 have proposed the RUCAM (Roussel Uclaf Causality
Assessment method) (9).

More recently another instrument to assess causality, the Clinical
Diagnostic Scale has been proposed.(10) The categories within the RUCAM
instrument include:

-   time to onset

```{=html}
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```
-   course of the reaction

-   risk factors

-   concomitant drugs

-   non-drug related causes

-   previous information on the drug

-   confirmation

While this list of categories suggest a simple process, clinical
judgement, as suggested in the quote from William Lee, is needed to
assess essentially all of these categories. In the context of
post-marketing reports of acute liver failure in patients on new drug
therapies, there is by definition little "previous information"
available. The most difficult issues to assess in the context of
post-marketing reports is screening for other causes of hepatic disease.
According to Danan and Benichou (11) the non-drug related causes to be
applied in the RUCAM include the following six categories:

1.  IgM to Hepatitis A

2.  IgM to Hepatitis B

3.  Non-A, non-B hepatitis: Hepatitis C antibody with circumstantial
    evidence or recent exposure

4.  Alcohol induced injury is suggested when the ratio of ASL/ALT \> 2

5.  Ultrasound of the liver to rule out biliary tract causes

6.  An episode of recent hypotension

The following explanatory notes follow this list in the article by Danan
and Benichou.

*"However, it is recognized that the role of HAV virus is unlikely in
elderly patients, that ultrasonography of the liver is a mandatory
diagnostic procedure in patients with cholestatic or mixed liver injury
and that acute recent hypotension should mainly be investigated in
specific circumstances such as arrhythmias, congestive heart failure and
coronary insufficiency. The search for the second group of causes is
optional, depending on clinical and/or biological context: natural
history of the underlying disease and recent infection with
Cytomegalovirus, Epstein-Barr virus or Herpes virus."*

Thus, the presence of a clearly identifiable cause of liver failure must
be taken into account and is the strongest mitigating factor against
considering a case of ALF or serious hepatic injury.

The ODS review failed to meaningfully address causality. Eight of
sixteen cases of ALF in the ODS review were concomitantly using drugs
with known association with acute liver failure documented in the
approved labels. Three other patients were taking methotrexate
concomitantly. Causality assessment in such cases requires expertise and
judgement. One cannot assume that all other concomitant therapies with
known hepatoxic potential are innocent bystander drugs and leflunomide
is the hepatoxin. This methodology would result in a chaotic and
inaccurate quantitation of risk for *[all drugs]{.underline}*
co-administered with other drugs with known risk. Patterns of toxicity,
timing of therapy and known risk level of co-therapies must be weighed.

Thus, the majority of cases of ALF had identifiable causes of drug
induced hepatotoxicity.

An additional three cases did not comment on whether concomitant
medications were used.

A separate form of confounding that is equally important is
co-morbidity. The same caveats discussed for co-therapy with drugs above
are relevant for morbidity as well. Articles and texts on drug induced
ALF uniformly exclude cases where clinical conditions such as sepsis,
multisystem organ failure, viral hepatitis and ischemic or congestive
hepatopathy are possible. The ODS review included case reports that
presented with cardiac arrest followed by multisystem organ failure and
post mortem liver histology absent hepatic injury beyond "fatty liver"
as well as cases with documented hypotension and cardiac failure. Thus,
the reports used to extrapolate reporting rates of liver failure as well
as time related hazard rates, cumulative risk rates and numbers needed
to harm statistics in the ODS review were seriously flawed.

The epidemiologic assessment of "persistency" on leflunomide that was
used in the risk analysis in the ODS review was based on two databases
with a total patient base of 3557 patients (Medicaid and United Health
Care coverage plans). The median duration in therapy in these two
databases was surprisingly similar at 4-5 months with only 19% still on
therapy at 1 year. However, two other databases recently presented at
the American College of Rheumatology 2002 reviewed this same issue of
"persistence on therapy and came to different conclusions. One study
(Abstract 1438: Leflunomide use in the first 33 months after FDA
approval: Experience in a National Cohort of 3325 patients) showed a
median duration on therapy of 17.6 months. This study was based on a
national VA pharmacy database. In the second abstract, 1441 (Leflunomide
in clinical practice: Two-year population-based data with clinical
validation), the median duration on therapy was approximately 12 months.
This was a smaller study of a 159 patients in a prescription registry in
Manitoba Canada.

The flaws in the ODS review impact both the number of cases to be used
in a quantitative assessment as well as the validity of performing
analyses of time dependent risk hazard and cumulative toxicity.

**Summary**

**In summary, for signal generation and preliminary analysis of drug
toxicity liberal case definitions may be valuable to avoid missing
possible signals of hepatotoxicity. However before deriving cumulative
risk, causality assessment must be rigorous, standardized and exclude
highly confounded cases. If any given drug bears the toxicity burden for
all morbidity in any treated patient essentially any drug (that is used
in patients with underlying significant illness and or concomitant
therapy) may be inappropriately assessed as inadequately safe for use.**

**Discussion of ODS methodology**

An analysis similar to the current cumulative risk analysis in the ODS
was performed in 1999 on the drug troglitizone.
(<http://www.fda.gov/ohrms/dockets/ac/99/backgrd/3499b1a.PDF>).

This reviewer undertook an analysis of the cases that comprised that
database of ALF in relation to troglitizone to assess the application of
the ODS methodologies to the leflunomide database. There is a striking
difference in the case descriptions in the troglitizone database versus
the current database. The majority of the ALF cases on troglitizone were
not on relevant hepatotoxic agents and did not have underlying liver
disease or co-morbid conditions that are strongly associated with liver
failure. Case after case in the troglitizone database presented with
clear and a strikingly consistent pattern of evidence of fulminant
hepatic failure *both clinically and biochemically*. As will be
discussed later in this review, it is evident in the appended Medwatch
forms themselves, the vast majority of cases of ALF included in the ODS
analysis of leflunomide were not typical of ALF nor formed a consistent
clinical pattern. The overall impression of this database is in fact
that of a collection of dissimilar clinical vignettes not suggestive of
a common etiology. In summary, the methodologies used in the analysis of
troglitizone hepatotoxicity cases is not directly applicable to the post
marketing database of leflunomide associated hepatotoxicity. This
conclusion is based on the heterogeneity of cases and flawed causality
assessments.

Of note the methodology used in the current ODS review has not been
applied to other therapies and toxicities including other
*[new]{.underline}* therapies for rheumatoid arthritis. The methodology
described in the ODS review is elegant, and may be of value when a true
database of adequate number of events from which one may extrapolate is
available. As will be discussed in greater detail later in this review,
the current database of US cases identifies no more than two or three
cases of likely or probable ALF due to leflunomide. These cases surely
reflect a larger experience in the total population of leflunomide users
and are not insignificant. However, analyses proposed by the ODS review
and the conclusions regarding absolute risk of ALF cannot be based on
such few cases

Conceptually, the techniques proposed in the ODS review for quantitation
of cumulative risk and risk benefit analysis are valuable tools. However
several issues must be addressed when creating a methodology for
quantitation of risk and benefit, particularly based on post marketing
uncontrolled data.

1\. The use of valid and reproducible methodology for case definition
and causality assessment

2.  Use of validated and accurate exposure data

3.  Use of validated "persistence on therapy" data

4.  The use of credible and meaningful analyses of benefit

5.  When considering comparative safety, credible comparative analyses
    of both *[overall]{.underline}* safety and benefit with other
    products for the same condition are vital

This reviewer applauds the goal of rigorous comparative assessment of
risk and benefit with the goal of informative labeling or if necessary
removal of a marketed drug. It is clear that methodologies to accomplish
this need to be developed and tested across historic examples for
validation. Such analyses will be complex and require adequately sized
databases. Metrics such as numbers needed to harm and quantitation of
risk: benefit as discussed in the ODS review will hopefully be important
to the emerging science of safety assessment and risk benefit analysis
in drug regulation.

#  **iv. Review of Post-marketing case reports of ALF**

The results of an independent review of the post marketing cases of ALF
has been conducted by this reviewer (a board certified
gastroenterologist with over 15 years of clinical experience in treating
patients with liver disease). In view of the complexity of causality
assessment and liver disease the division has also obtained consultation
with expert hepatologists to assist in the assessment of ALF and serious
liver injury in the leflunomide post marketing database.

**Division of Antiinflammatory, Analgesic and Ophthalmic Drug Product
Review**

# This review will use the same definition as that outlined by the ODS reviewer for causality assessment The texts of the Medwatch reports are found in appendix 27. Analysis of causality as probable, possible, unlikely or unassessable will be addressed. The analysis of each case will be organized based on indication, age, dose, concomitant therapy (with comment on potential hepatotoxicity of concomitant therapy), co-morbid conditions (with comment on potential for associated liver injury), presentation and finally clinical assessment of likelihood of causality.

**Case #1 (report 200110085US)**

ADULT ONSET STILLS

+-----------------------------------------------------------------------+
| 29y/o                                                                 |
+-----------------------------------------------------------------------+
| 20mg x 3 months                                                       |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  Atovaquone: unclear indication and **reported to be at three      |
|     times recommended dose for undetermined period of time: per       |
|     product label Atovaquone is associated with elevated LFTs in      |
|     clinical trials as well as hepatic effects in animal toxicology   |
|     studies**.                                                        |
|                                                                       |
| 2.  Methylprednisolone                                                |
|                                                                       |
| 3.  Azithromycin: ALT elevations of 5XULN are reported in 5% of       |
|     subjects receiving prophylaxis against disseminated MAC. Hepatic  |
|     necrosis, hepatic failure and death are reported                  |
|                                                                       |
| 4.  Oxycodone/acetaminophen (APAP): APAP may cause liver injury that  |
|     may be potentiated by alcohol use.                                |
|                                                                       |
| 5.  Infliximab:                                                       |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Possible alcohol abuse (acute or chronic hepatotoxicity possible) |
|                                                                       |
| 2.  "very difficult" adult onset Still's Disease                      |
|                                                                       |
| 3.  Herpetic peri-rectal disease (in view of severe immunosuppression |
|     systemic infection including herpetic hepatitis possible)         |
|                                                                       |
| 4.  Fungal UTI                                                        |
|                                                                       |
| 5.  Baseline liver status unknown                                     |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Liver failure within several weeks of "markedly elevated liver        |
| enzymes".                                                             |
|                                                                       |
| Reference to "DIC which clotted off supply to the liver"              |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Unlikely to be causally related to leflunomide given multiple other |
| causes with documented associations with liver failure including      |
| medications ( including overdose with potentially hepatotoxic drug),  |
| infection (herpetic hepatitis) and alcohol and unstated indication    |
| for use of Atovaquone.**                                              |
+-----------------------------------------------------------------------+

# 

Case #2 (report 200020914 US)

RA

+-----------------------------------------------------------------------+
| 51y/o                                                                 |
+-----------------------------------------------------------------------+
| 20mg x 4-5 months (after loading dose)                                |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  Celebrex                                                          |
|                                                                       |
| 2.  Prednisone                                                        |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1\. none                                                              |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Maculopapular rash, fever, chest pain, jaundice                       |
|                                                                       |
| AST/ALT \>1000 bili 13                                                |
|                                                                       |
| Liver biopsy: Centrilobular necrosis with portal inflammation c/w     |
| drug reaction                                                         |
|                                                                       |
| Death following post-operative complications associated with a        |
| perforated duodenal ulcer                                             |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **ALF probably due to leflunomide. No more likely etiology            |
| identified**                                                          |
+-----------------------------------------------------------------------+

Case #3 (report 2000111689 HMRI) **Patient report: No supporting
documentation Patient refused permission to contact physician**

**RA**

+-----------------------------------------------------------------------+
| 53 y/o                                                                |
+-----------------------------------------------------------------------+
| **100 mg for 87 days (medication error overdose)**                    |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  **Sulfasalazine: A labeled cause of "fatal liver damage"**        |
|                                                                       |
| 2.  **Misoprostol**                                                   |
|                                                                       |
| 3.  prednisone                                                        |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1\. none reported                                                     |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Patient informed of elevated liver function tests and instructed to   |
| continue leflunomide. One month later hospitalized with "complete     |
| liver failure". Liver biopsy 6 months later resolution of liver       |
| damage                                                                |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **ALF probably due to leflunomide overdose although sulfasalazine     |
| hepatotoxicity is also possible. Other causes cannot be ruled out due |
| to inadequate documentation**                                         |
+-----------------------------------------------------------------------+

Case #4 ( report 199920773HMRI)

RA

+-----------------------------------------------------------------------+
| 55 y/o                                                                |
+-----------------------------------------------------------------------+
| **Unknown dose: 2 months**                                            |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  **TMP-SMX: Warning in label regarding hepatic necrosis**          |
|                                                                       |
| 2.  **Allopurinol: Warning in label regarding irreversible            |
|     hepatotoxicity**                                                  |
|                                                                       |
| 3.  **Lisinopril: Warning in label regarding syndrome of cholestatic  |
|     jaundice followed by fulminant hepatocellular necrosis and        |
|     death**                                                           |
|                                                                       |
| 4.  Amitriptyline                                                     |
|                                                                       |
| 5.  Prednisone                                                        |
|                                                                       |
| 6.  **Verapamil: Warning in label regarding hepatocellular injury     |
|     with positive rechallenge**                                       |
|                                                                       |
| 7.  Heparin                                                           |
|                                                                       |
| 8.  Triamcionolone                                                    |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| **1 Alcohol abuse**                                                   |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Hospitalized with liver failure including coagulopathy, ascites,      |
| jaundice, encephalopathy. No data to characterize as acute versus     |
| chronic liver failure.                                                |
|                                                                       |
| No information on hepatic function prior to hospitalization           |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Inadequate information to define as ALF. Premorbid hepatic function |
| in an alcohol "abuser" not known.**                                   |
|                                                                       |
| **Liver failure possibly due to leflunomide however alcohol related   |
| liver failure is common and other drug related hepatotoxicity also    |
| possible.**                                                           |
+-----------------------------------------------------------------------+

Case #5 (report 199813621HMRI)

ARTHRITIS

+-----------------------------------------------------------------------+
| 55 y/o                                                                |
+-----------------------------------------------------------------------+
| **Loading dose followed by 20 mg for total of 5 days**                |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  hydroxychloroquine                                                |
|                                                                       |
| 2.  naproxen                                                          |
|                                                                       |
| 3.  propranolol                                                       |
|                                                                       |
| 4.  conjugated estrogens                                              |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| **1. Alcohol abuse**                                                  |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Presented with end stage liver disease: jaundice and AST/ALT 288/68.  |
| Most c/w alcohol related hepatitis superimposed on chronic liver      |
| disease rather than "acute drug induced hepatocellular injury".       |
| Alkaline phosphatase 766                                              |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Inadequate information to define as ALF.**                          |
|                                                                       |
| **Liver failure unlikely due to leflunomide. End stage liver disease  |
| secondary to alcohol related liver disease is more likely.**          |
+-----------------------------------------------------------------------+

Case #6 (report 200010080HMRI)

RA

+-----------------------------------------------------------------------+
| 61                                                                    |
+-----------------------------------------------------------------------+
| **20 mg unknown duration**                                            |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1\. **methotrexate: Warning in label regarding hepatoxicity:          |
| typically occult cirrhosis or minor acute elevated LFTs**             |
|                                                                       |
| 2.atenolol                                                            |
|                                                                       |
| 3.  trazolam                                                          |
|                                                                       |
| 4.  alprazolam                                                        |
|                                                                       |
| 5.  **Verapamil: Warning in label regarding hepatocellular injury     |
|     with positive rechallenge**                                       |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  **Anxiety**                                                       |
|                                                                       |
| 2.  **Benign prostatic hypertrophy**                                  |
|                                                                       |
| 3.  **Cataract**                                                      |
|                                                                       |
| 4.  **hypertension**                                                  |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Respiratory failure including lethargy and confusion requiring        |
| intubation. Vital signs on presentation not provided. Condition       |
| improved within 24 hours                                              |
|                                                                       |
| AST 4600 on admission falling to 74 five days later. Only bilirubin   |
| reported was 5 days after presentation was 1.2                        |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **This is not a case of ALF.**                                        |
|                                                                       |
| **Lethargy and confusion and respiratory failure with rapid           |
| resolution likely due to trazolam and alprazolam.**                   |
|                                                                       |
| **Elevated AST/ALT rapidly resolving prior to drug clearance suggest  |
| lack of leflunomide causality.**                                      |
|                                                                       |
| **Pattern and course of LFT elevation c/w acute congestion associated |
| with acute respiratory failure**                                      |
+-----------------------------------------------------------------------+

Case #7 (report 200123598US)

RA

+-----------------------------------------------------------------------+
| 66 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg for 4 months                                                    |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  **methotrexate: Warning in label regarding hepatoxicity:          |
|     typically occult cirrhosis or minor acute elevated LFTs**         |
|                                                                       |
| 2.  rofecoxib                                                         |
|                                                                       |
| 3.  prednisone                                                        |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
+-----------------------------------------------------------------------+
| **Presentation:**                                                     |
|                                                                       |
| **1. "viral illness" , "physician believed that events could be due   |
| to the patients consumption of oysters which possibly contained       |
| vibrio parahaemolyticus or salmonella"**                              |
|                                                                       |
| **Presentation with renal failure (creatinine 8.4), thrombocytopenia  |
| and gangrenous**                                                      |
|                                                                       |
| **Fingers and toes. During hospitalization "labs are improving.       |
| Creatinine 2.2"**                                                     |
|                                                                       |
| **"liver failure" noted no LFTs noted**                               |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **This is not a case of ALF.**                                        |
|                                                                       |
| **No documentation of hepatic injury.**                               |
|                                                                       |
| **If hepatic injury occurred likely due to underlying illness**       |
+-----------------------------------------------------------------------+

Case #8 (report 200022670 US)

RA

+-----------------------------------------------------------------------+
| 66 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg/day (no information on loading dose) for 3 weeks                |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  ibuprofen                                                         |
|                                                                       |
| 2.  prednisone                                                        |
|                                                                       |
| 3.  lansoprazole                                                      |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| None listed                                                           |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Patient presented in cardiac arrest following 1 week of a diarrheal   |
| illness and rectal bleeding. On presentation acute renal failure,     |
| metabolic acidosis and "liver enzymes in the thousands" were noted.   |
| Liver pathology at the time of autopsy revealed "only fatty liver".   |
+-----------------------------------------------------------------------+
| Causality:                                                            |
|                                                                       |
| **This is not a case of ALF or drug related hepatic injury**          |
|                                                                       |
| Diarrheal illness could have been related to leflunomide. Diarrheal   |
| illness could have been related to renal failure, metabolic acidosis  |
| and cardiac arrest.                                                   |
+-----------------------------------------------------------------------+

Case #9 (report 200210502)

RA

+-----------------------------------------------------------------------+
| 67 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg for 4 months (no comment on loading dose)                       |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  "She takes many concomitant medications"                          |
|                                                                       |
| 2.  Azathioprine and methotrexate in the past: Hepatotoxicity,        |
|     particularly cirrhosis is associated with chronic methotrexate    |
|     therapy. Hepatic injury is associated with azathioprine.          |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Portal hypertension based on endoscopically confirmed esophageal  |
|     varices, grade                                                    |
|                                                                       |
| three, 2 years prior to initiating leflunomide.                       |
|                                                                       |
| 2.  Sjogren's syndrome                                                |
|                                                                       |
| 3.  Hypertension                                                      |
|                                                                       |
| 4.  "steroid induced diabetes"                                        |
|                                                                       |
| 5.  Vertebrobasilar insufficiency                                     |
|                                                                       |
| 6.  gastritis                                                         |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| The patient presented with end stage liver disease with jaundice.     |
| AST/ALT 48/27.                                                        |
|                                                                       |
| Liver biopsy revealed fibrosis and marked canalicular cholestasis     |
| suggestive of a possible medication reaction.                         |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **This is a case of end stage liver disease with no evidence of acute |
| hepatocellular injury. Microscopic description of liver biopsy does   |
| not suggest mention acute hepatocellular injury.**                    |
|                                                                       |
| **This is not a case of ALF.**                                        |
+-----------------------------------------------------------------------+

Case #10 (report :3720213-1: direct)

RA

+-----------------------------------------------------------------------+
| 75 y/o                                                                |
+-----------------------------------------------------------------------+
| Dose and duration unknown                                             |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  prednisone                                                        |
|                                                                       |
| 2.  tramadol                                                          |
|                                                                       |
| 3.  amiodarone: **a known hepatoxin**                                 |
|                                                                       |
| 4.  dicloxacillin                                                     |
|                                                                       |
| 5.  oxycodone/APAP                                                    |
|                                                                       |
| 6.  alendronate                                                       |
|                                                                       |
| 7.  rofecoxib                                                         |
|                                                                       |
| 8.  neurontin                                                         |
|                                                                       |
| 9.  venaflaxine                                                       |
|                                                                       |
| 10. aspirin                                                           |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Hepatitis C                                                       |
|                                                                       |
| 2.  Hypertension                                                      |
|                                                                       |
| 3.  Osteoarthritis                                                    |
|                                                                       |
| 4.  CHF                                                               |
|                                                                       |
| 5.  Atrial fibrillation                                               |
|                                                                       |
| 6.  Interstitial lung disease                                         |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| "Patient admitted secondary \^LFTs, MS changes possibly secondary     |
| amiodarone & leflunomide. Meds discontinued on admit Pt less confused |
| & MS improved." (direct quote from medwatch report)                   |
|                                                                       |
| Telephone follow-up per ODS reviewer: Baseline LFTs 2 months before   |
| event WNL. 2 days after presentation AST/ALT: 1187/999 alk phos: 205  |
|                                                                       |
| Hepatology consult verbally: LFTs secondary ischemic hepatitis, drug  |
| induced.                                                              |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **This is a case of altered mental status in a patient on four drugs  |
| that can cause mental status changes. On withdrawal of polypharmacy,  |
| mental status improved suggesting centrally acting drugs caused       |
| mental status changes. In view of history of CHF and interstitial     |
| lung disease, hypoxemia may have been contributory.**                 |
|                                                                       |
| **No other information on functional impairment of liver to suggest   |
| hepatic encephalopathy as the cause of a rapidly resolving mental     |
| status change.**                                                      |
|                                                                       |
| **Acute hepatocellular injury: possible causes include:**             |
|                                                                       |
| 1.  **Vascular/hemodynamic: related to CHF/ right sided failure due   |
|     to cardiac and pulmonary disease and acute respiratory effects of |
|     mental status change.**                                           |
|                                                                       |
| 2.  **Drug induced hepatitis: amiodarone or leflunomide**             |
|                                                                       |
| **This is not a case of ALF.**                                        |
+-----------------------------------------------------------------------+

Case #11 (200121594)

RA

+-----------------------------------------------------------------------+
| 72 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg for 3 months (no information on loading dose)                   |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  **amiodarone: a known hepatoxin. Cases of fulminant hepatic       |
|     failure with death within days in label**                         |
|                                                                       |
| 2.  **propofenone: hepatocellular injury with fatal hepatitis in      |
|     label. Hepatitis with rechallenge in label**                      |
|                                                                       |
| 3.  coumadin                                                          |
|                                                                       |
| 4.  omeprazole                                                        |
|                                                                       |
| 5.  Premarin                                                          |
|                                                                       |
| 6.  hydroxychloroquine                                                |
|                                                                       |
| 7.  quinapril: Warning in label notes rare association between ACE    |
|     inhibitors and fulminant hepatic failure, starting with jaundice  |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Cutaneous lupus                                                   |
|                                                                       |
| 2.  Atrial fibrillation (AF)                                          |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Patient presented with AF and rapid ventricular response and was      |
| electrically cardioverted in addition to receiving a dose of          |
| amiodarone within 24 hours. LFTs (unknown if drawn before or after    |
| presentation) " later that morning" AST/ALT 1186/669. Over 48 hours   |
| death in association with AST/ALT: 4682/2202 (baseline AST/ALT 6      |
| weeks prior : "normal").                                              |
|                                                                       |
| No information on usual blood pressure range or blood pressure during |
| the course of illness prior to onset of liver failure. Such           |
| information is critical in assessment of an elderly patient           |
| hospitalized for arrhythmia.                                          |
|                                                                       |
| Creatinine on presentation (1.9) over twice previous known level      |
| (0.8) suggesting possible hemodynamic compromise developing prior to  |
| admission. BUN on admission 53.                                       |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| 1.  **Likely causes include hemodynamic compromise/ acute ischemia    |
|     associated with arrhythmia. Amiodarone known to cause             |
|     hepatotoxicity with identical pattern of fulminant hepatic        |
|     failure and death within days described in label. Acute fulminant |
|     hepatic failure causally associated with leflunomide is possible  |
|     but less likely in the setting of arrhythmia and possibly         |
|     hypoperfusion, acute renal insufficiency and possibly following   |
|     amiodarone use and electrocardioversion.**                        |
+-----------------------------------------------------------------------+

Case #12 (report 128229 direct report)

RA

+-----------------------------------------------------------------------+
| 76 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg for 1 year (no comment on loading dose)                         |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1.  Duragesic                                                         |
|                                                                       |
| 2.  oxycodone/APAP                                                    |
|                                                                       |
| 3.  APAP                                                              |
|                                                                       |
| 4.  Prednisone                                                        |
|                                                                       |
| 5.  Paroxetine: Label notes hepatic necrosis and jaundice noted in    |
|     association                                                       |
|                                                                       |
| 6.  Prinivil: Warning in label notes rare association between ACE     |
|     inhibitors and fulminant hepatic failure, starting with jaundice  |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  OA                                                                |
|                                                                       |
| 2.  HTN                                                               |
|                                                                       |
| 3.  COPD                                                              |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| Admitted with hypotension (80/50 in a patient with underlying         |
| hypertension) and confused. Stool Hemocult positive. AST/ALT          |
| \>4500/1019 and bilirubin 1.2 . Within one week AST/ALT: 62/78. Peak  |
| bilirubin was 2.4. Acute pancreatitis.                                |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Acute hepatic injury likely due to ischemia associated with         |
| hypotension.**                                                        |
|                                                                       |
| **Rapid resolution of ASL/ALT elevations without progressive jaundice |
| within a week during interval when systemic exposure to leflunomide   |
| continues**                                                           |
|                                                                       |
| **(based on long t ½) strongly suggests that this event is not        |
| related to leflunomide.**                                             |
|                                                                       |
| **Other potential drug causes noted but also unlikely.**              |
+-----------------------------------------------------------------------+

Case #13 (report 200010951HMRI)

RA

+-----------------------------------------------------------------------+
| Unknown age                                                           |
+-----------------------------------------------------------------------+
| 20 mg for 3 months following loading dose regimen                     |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| No comment in report                                                  |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Interstitial lung disease                                         |
+-----------------------------------------------------------------------+
| Presentation: report extremely limited.                               |
|                                                                       |
| Admitted with near syncope and shock. Died on the day of admission.   |
| Diagnoses included liver failure, pancreatitis and interstitial lung  |
| disease.                                                              |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Inadequate information, however, clinical course of pancreatitis    |
| causing hypotension and subsequent hepatic failure is possible.       |
| Hepatic failure as part of multisystem failure associated a terminal  |
| event is likely. A primary drug related ALF in this context is        |
| unlikely.**                                                           |
+-----------------------------------------------------------------------+

Case #14 (report 19992212130HMRI)

NO INDICATION NOTED

+-----------------------------------------------------------------------+
| Unknown age                                                           |
+-----------------------------------------------------------------------+
| Unknown dose and duration                                             |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| No comment in report                                                  |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| No comment in report                                                  |
+-----------------------------------------------------------------------+
| Presentation: report extremely limited.                               |
|                                                                       |
| " On an unspecified date, the patient experienced an elevated         |
| bilirubin, jaundice, alkaline phosphatase and vasculitis. Outcome     |
| unknown".                                                             |
|                                                                       |
| A physician reported a diagnosis of hepatic failure as an addendum    |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Inadequate information to consider diagnosis or causality**         |
+-----------------------------------------------------------------------+

Case #15 (report 200214805US)

OFF LABEL USE

+-----------------------------------------------------------------------+
| 55 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg for 3 months following loading dose protocol                    |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| 1\. Verapamil                                                         |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Scleroderma                                                       |
|                                                                       |
| 2.  Interstitial lung disease                                         |
|                                                                       |
| 3.  HTN                                                               |
|                                                                       |
| 4.  Alcohol abuse                                                     |
|                                                                       |
| NOT RA                                                                |
+-----------------------------------------------------------------------+
| Presentation: (baseline LFTs 2 months prior to event WNL)             |
|                                                                       |
| Dry cough 2/02                                                        |
|                                                                       |
| Productive cough and hemoptysis early 4/02                            |
|                                                                       |
| Admitted 4/27/02 with "possible pneumonia" on CXR AST/ALT: 200s :     |
| leflunomide discontinued                                              |
|                                                                       |
| Progressive pulmonary worsening and AST/ALT peaked at 6000 range      |
| within 4 days and bilirubin of 9. AST/ALT and pulmonary status        |
| improved over next week with AST/ALT falling to 700-800 range,        |
| bilirubin 6.7.                                                        |
|                                                                       |
| Discharged 5/8/02 on 60 mg prednisone for interstitial pneumonitis    |
| due to scleroderma. Prevacid and atenolol also prescribed on          |
| discharge                                                             |
|                                                                       |
| Readmitted 5/13/02 with bilirubin 26, "encephalopathic" and AST/ALT   |
| 400-500.                                                              |
|                                                                       |
| Echocardiogram revealed dilated cardiomyopathy with ejection fraction |
| of 10%                                                                |
|                                                                       |
| GI consultant:- "abnormal liver function tests were associated with   |
| hepatic congestion secondary to right sided heart failure, possibly   |
| alcoholic liver disease, and possibly drug induced liver disease".    |
| With management of cardiopulmonary condition three days later         |
| transferred out of intensive care unit with improved mental status    |
| and LFTs                                                              |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **ALF most likely associated with congestive hepatopathy.**           |
|                                                                       |
| **One year duration of therapy with leflunomide, course and pattern   |
| of transaminase elevation and improvement in transaminases before     |
| drug clearance are not consistent with drug induced hepatotoxicity.** |
+-----------------------------------------------------------------------+

Case #16 (reports 200215633 and HQ2644607 Jun2002)

RA

+-----------------------------------------------------------------------+
| 49 y/o                                                                |
+-----------------------------------------------------------------------+
| 20 mg for 6 weeks (following loading dose protocol)                   |
+-----------------------------------------------------------------------+
| Concomitant medications:                                              |
|                                                                       |
| Methotrexate                                                          |
|                                                                       |
| Prednisone                                                            |
|                                                                       |
| Infliximab                                                            |
|                                                                       |
| INH for TB prophylaxis                                                |
+-----------------------------------------------------------------------+
| Co-morbidities:                                                       |
|                                                                       |
| 1.  Positive PPD                                                      |
|                                                                       |
| 2.  HTN                                                               |
|                                                                       |
| 3.  Elevated LFTs                                                     |
|                                                                       |
| 4.  Anxiety                                                           |
+-----------------------------------------------------------------------+
| Presentation:                                                         |
|                                                                       |
| 5/22/02: patient presented with abdominal pain, nausea and vomiting,  |
| generalized aches, fever, chills cough, loss of appetite and dark     |
| colored urine. AST/ALT 1500-1800, Bilirubin 1.4. Hepatitis B surface  |
| antigen positive                                                      |
|                                                                       |
| LFTs over next week: AST/ALT 6000 range INR 4.3.                      |
|                                                                       |
| Liver transplant 6/1/02. Histology "submassive necrosis of the liver, |
| proliferation of bile ductules with small foci of hepatocytes with    |
| regenerative changes"                                                 |
|                                                                       |
| Chest x-ray revealed possible reactivation of TB                      |
+-----------------------------------------------------------------------+
| **Causality:**                                                        |
|                                                                       |
| **Complex potentially multifactorial hepatic injury with known        |
| hepatitis B as well as INH**                                          |
|                                                                       |
| **Possible but less likely leflunomide hepatotoxicity**               |
|                                                                       |
| **[Medical causes:]{.underline}**                                     |
|                                                                       |
| **Hepatitis B fulminant in association with polypharmecuetical        |
| immunosuppression**                                                   |
|                                                                       |
| **[Drug causes:]{.underline}**                                        |
|                                                                       |
| **INH**                                                               |
|                                                                       |
| **Leflunomide**                                                       |
|                                                                       |
| **In view of common causes of acute liver failure (Hepatitis B and    |
| INH), leflunomide is unlikely cause.**                                |
+-----------------------------------------------------------------------+

**In summary, in the US post marketing database there appear to be:**

1.  **Two cases of probable ALF associated with leflunomide (#2, 3): one
    of which was a therapeutic misadventure or accidental overdose**

2.  **Three cases of possible leflunomide associated ALF (#1, 11, and
    16,). In this context the term possible means that other causes were
    more compelling and these cases were significantly confounded with
    both co-morbities and known hepatotoxic medications that were more
    likely etiologic in all cases.**

3.  **Three cases were unlikely related (#12, 13 and 15). In this
    context there were compelling reasons why other causes of ALF were
    compelling and or the time course of illness was not suggestive.**

4.  **Five cases were not presentations of acute liver failure**

```{=html}
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```
a.  **#6: respiratory failure with lethargy and confusion on multiple
    CNS depressants with rapid resolution not clinically or
    pharmacokinetically consistent with drug induced ALF**

b.  **#7: no documentation of liver dysfunction in the face of
    documentation of multisystem injury**

c.  **#8: not a presentation of ALF. Status post cardiac arrest with
    only fatty liver at autopsy. "Enzyme" elevation a part of the
    terminal process**

d.  **#9: presentation of end stage liver disease with no acute
    hepatocellular injury in a patient with known chronic liver
    disease**

e.  **#10: Mental status changes in a patient on multiple medications
    that may cause mental status changes and underlying cardiopulmonary
    disease. Mental status improvement inconsistent clinically or
    pharmacokinetically with drug induced ALF. No evidence of liver
    failure**

```{=html}
<!-- -->
```
5.  **Three case had insufficient data to assess for the presence of
    ALF(#4, 5 and 14)**

The international cases including those from Australia were reviewed.
This reviewer considers four of these cases to be probable or possible
leflunomide related ALF or end stage liver disease:

manufacturer report numbers: 200114998FR, 200020014GDDC, 200114497DE,
and 200212447EU. One case (200114998FR) was published in France as a
case of Lyell's Syndrome associated with leflunomide and itraconozole.
They will no be discussed in detail here. The reader is referred to the
analyses by the external expert opinions by Dr. Lewis and Dr. Seef.

The expert opinions of Dr. Leonard Seef of the NIH and Dr. James Lewis
of Georgetown University are attached as appendices 28 and 29. These
analyses include the cases of serious hepatitis as well as ALF.

These consultants considered these cases to be highly confounded.
Excerpts are presented below.

Dr. Lewis;

Overall:

*" Nearly all of these cases were highly confounded with patients
receiving many other drugs including methotrexate and other agents that
in their own right are associated with hepatic injury..."*

*"I did not list any case as probably or definitely related from this
database given the quality of the information, as well as the fact that
I did not feel that any case was so unambiguous that no other
possibility existed except leflunomide as a cause of liver injury..."*

Acute liver failure or deaths in the US cases.

*There were 18 such cases that I reviewed. I considered five to be
possibly related, but all were confounded. One was a fatal case that I
consider to be unrelated to any hepatic injury (death was from a
perforated duodenal ulcer leading to septic shock from peritonitis). One
of these possibly related cases involved possible exacerbation of
underlying cirrhosis (which is a contraindication to the use of this
medication). The three other possibly related cases I felt were unlikely
to be related for various reasons including, one seemed much more likely
t be related to shock liver and one included exacerbation of underlying
hepatitis B infection.*

*Four of these cases were considered unlikely to be related. I felt that
there was a clear-cut evidence of shock liver (ischemic hepatitis) in
three of these cases. The fourth was highly confounded and I did not
feel that leflunomide by itself could be labeled as a causative. The
remaining nine cases contained inadequate information for me to assess
or draw many meaningful causality conclusions."*

The consultation on the serious liver injury cases in the US identified
only 7/38 that were **possibly** related and 21/38 were considered
inadequate to make any assessment.

Reports of ALF or serious liver injury from Australia were assessed
separately from the other international cases as they were referred to
the division from ODS separately. Only 1/18 cases referred were
considered to be possibly related.

Dr. Seef:

*" I will say that with the information provided, I am unable to
determine with absolute certainty that these reports contain any
instance of unequivocal hepatotoxicity. "*

Within the consultation Dr. Seef identifies 11/18 cases from the US
database of ALF cases that "might" be responsible for causing liver
damage. 23/38 cases of serious liver injury from the US database were
considered as possible. In the international database excluding
Australia 9/13 cases were considered possibly related and in the
Australian database "a diagnosis of possible leflunomide toxicity can be
eked out in about 6 cases " out of 18 referred by ODS.

**Summary:**

**While individual case analysis varies among the clinical assessments
of causality discussed in this review, there is consensus that few cases
of ALF in the US database are probably related to leflunomide toxicity
and a minority of the international reports of severe liver injury are
likely related to leflunomide. There is consensus among this reviewer,
the ODS reviewer and the external expert consultants that leflunomide is
associated with cases of ALF or life threatening hepatitis. The extent
of risk for ALF in the population of leflunomide users appears to be
overestimated in the ODS review, however risk communication and in
particular labeling should reflect this rare serious toxicity.**

**D. Overall conclusions:**

1.  **Hepatic events in the form of hepatocellular injury (ALT over 3X
    ULN) were infrequently seen in the original NDA database. A single
    case of serious hepatocellular necrosis and a case of cholestatic
    hepatitis associated with leflunomide occurred in the database of
    2700 patients treated with leflunomide in controlled clinical
    trials.**

2.  **The comparative overall safety of leflunomide verses methotrexate
    does not appear to differ substantially in controlled clinical
    trials.**

3.  **A meta-analysis of controlled clinical trials, as well as two
    post-marketing cohort studies comparing leflunomide to methotrexate
    does not identify a signal for significant differences in
    hepatocellular injury as defined by elevations in transaminases and
    is similar to the characterization as currently displayed in the
    product label.**

4.  **Rare cases of ALF and serious liver disease associated with
    leflunomide have been reported in the US and internationally and
    should be adequately described in the product label.**

######## 

######## 

######## References

1.  Weber JCP. Epidemiology of Adverse Reactions to Nonsteroidal
    Antiinflammatory Drugs. Advances in Inflammatory Research 1984; 6:
    1-7

2.  Coblyn JS et al. Leflunomide --associated weight loss in rheumatoid
    arthritis. Arthritis and Rheumatism 2001: 44:5; 1048-51)

3.  Smolen J et al. Efficacy and safety of leflunomide compared with
    placebo and sulfasalazine in active rheumatoid arthritis: a double
    blind, randomized, multicenter trial. Lancet, 1999; 353:259-66

4.  \"Drug-Induced Liver Disease,\" Editors: Neil Kaplowitz and Laurie
    DeLeve, October 2002 Marcel Dekker, New York. pages 747-750

5.  Hepatoxicity, the adverse effects of drugs and other chemicals on
    the liver. Second

Edition 1999, Hyman J. Zimmerman Lippincott, Williams and Wilkins (page
433)

6.  Kremer J et al. Concomitant leflunomide therapy in patients with
    active rheumatoid arthritis despite stable doses of methotrexate.
    Annals of Internal Medicine 2002: 137:9, 726-733

7.  Drug Induced Liver Disease Editor Farrell GC, Churchill Livingstone
    publishers 1994

8.  Lee WM. Acute Liver Failure, NEJM 1993329:25: 1862-1872

9.  Lee WM. Assessing causality in drug-induced liver disease.
    (Editorial) Journal of Hepatology 2000;33:1003-1005

10. Criteria of drug induced liver disease: Report of an international
    consensus meeting, Journal of Hepatology, 1990, 11:272-276

11. Aithal GP. Et al. Clinical Diagnostic Scale: a useful tool in the
    evaluation of suspected hepatotoxic drug reactions. Journal of
    Hepatology 2000, 33; 949-952

12. Danan G, Benichou C. Causality assessment of adverse reactions to
    drugs-I. A novel method based on the conclusions of international
    consensus meeting: application to drug induced liver disease. J Clin
    Epidemiol 46; 11 1993: 13223-1330

####### Appendix 1

![](media/image4.wmf){width="6.754166666666666in"
height="5.364583333333333in"}

Deaths

![](media/image5.wmf)

**Appendix 2**

**Serious Adverse Events**

![](media/image7.wmf){width="7.454861111111111in"
height="4.644444444444445in"}

########  Appendix 3

Serious Adverse Events: Infection

# Table 044 Serious adverse events - infections 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 97 4 58 6

with serious

adverse events -

infections

Kaplan - Meier cumulative rates \[1\]

\< 3 months 24 194 0.015 (0.009-0.021) 2 37 0.007 (0.000-0.016) 10 53
0.015 (0.006-0.024) 2 28 0.017 (0.000-0.041)

\< 6 months 39 709 0.027 (0.019-0.036) 3 263 0.013 (0.000-0.027) 14 129
0.021 (0.010-0.032) 3 53 0.028 (0.000-0.061)

\< 12 months 60 854 0.051 (0.038-0.064) 4 278 0.034 (0.000-0.079) 23 215
0.038 (0.023-0.054) 3 67 0.028 (0.000-0.061)

\< 18 months 70 972 0.065 (0.049-0.080) 4 286 0.034 (0.000-0.079) 33 282
0.061 (0.040-0.081) 4 72 0.045 (0.000-0.091)

\< 24 months 77 1112 0.076 (0.059-0.093) 4 292 0.034 (0.000-0.079) 44
322 0.089 (0.063-0.115) 5 80 0.064 (0.006-0.122)

\< 36 months 84 1315 0.093 (0.072-0.114) 4 302 0.034 (0.000-0.079) 54
484 0.125 (0.092-0.158) 6 99 0.091 (0.015-0.167)

\< 48 months 93 1409 0.128 (0.098-0.158) 4 315 - ( - - - ) 57 644 0.156
(0.109-0.203) 6 122 0.091 (0.015-0.167)

\< 60 months 96 1524 0.149 (0.111-0.187) - - - ( - - - ) 57 645 -
( - - - ) 6 124 - ( - - - )

all months 96 1584 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 6.1 2.6 5.9 7.0

\< 6 months 5.4 2.4 4.4 5.9

\< 12 months 5.2 2.7 3.9 3.4

\< 18 months 4.7 2.4 4.2 3.4

\< 24 months 4.3 2.2 4.5 3.5

\< 36 months 3.9 2.0 4.3 3.3

\< 48 months 3.9 1.9 4.3 3.0

\< 60 months 3.8 1.9 4.3 3.0

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with SAE, total
censored, cumulative probability of SAE, 95% CI

![](media/image8.wmf){width="7.7in" height="5.911111111111111in"}

######## Appendix 4

**Serious Adverse events: Anemia**

![](media/image9.wmf){width="7.502083333333333in"
height="5.809027777777778in"}

######## 

######## 

# Table 038 Serious adverse events - anemia 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Serious Adverse Event: Anemia

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 20 1 11 2

with serious

adverse events -

anemia

Kaplan - Meier cumulative rates \[1\]

\< 3 months 7 200 0.004 (0.001-0.008) 1 39 0.003 (0.000-0.010) 1 59
0.001 (0.000-0.004) 1 30 0.009 (0.000-0.026)

\< 6 months 14 727 0.010 (0.005-0.016) 1 265 0.003 (0.000-0.010) 2 137
0.003 (0.000-0.007) 2 53 0.020 (0.000-0.048)

\< 12 months 15 880 0.011 (0.006-0.017) 1 281 0.003 (0.000-0.010) 4 227
0.007 (0.000-0.014) 2 68 0.020 (0.000-0.048)

\< 18 months 16 1004 0.013 (0.006-0.019) 1 289 0.003 (0.000-0.010) 9 296
0.018 (0.006-0.030) 2 73 0.020 (0.000-0.048)

\< 24 months 17 1152 0.014 (0.007-0.022) 1 295 0.003 (0.000-0.010) 11
343 0.024 (0.010-0.038) 2 81 0.020 (0.000-0.048)

\< 36 months 18 1367 0.017 (0.008-0.025) 1 305 0.003 (0.000-0.010) 11
517 0.024 (0.010-0.038) 2 102 0.020 (0.000-0.048)

\< 48 months 19 1468 0.021 (0.009-0.032) 1 318 - ( - - - ) 11 690 0.024
(0.010-0.038) 2 126 0.020 (0.000-0.048)

\< 60 months 20 1595 0.028 (0.010-0.047) - - - ( - - - ) 11 692 -
( - - - ) 2 128 - ( - - - )

all months 20 1661 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 1.8 1.3 0.6 3.5

\< 6 months 1.9 0.8 0.6 3.9

\< 12 months 1.3 0.7 0.7 2.3

\< 18 months 1.1 0.6 1.1 1.7

\< 24 months 0.9 0.5 1.1 1.4

\< 36 months 0.8 0.5 0.9 1.1

\< 48 months 0.8 0.5 0.8 1.0

\< 60 months 0.8 0.5 0.8 1.0

**Appendix 5**

**Serious Adverse Events**

**Malignancy**

![](media/image10.wmf){width="7.597916666666666in"
height="5.889583333333333in"}

######## 

# Serious adverse events - malignancy 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 17 3 20 4

with serious

adverse events -

malignancy

Kaplan - Meier cumulative rates \[1\]

\< 3 months 2 203 0.001 (0.000-0.003) 0 39 0.000 (0.000-0.000) 2 58
0.003 (0.000-0.007) 0 30 0.000 (0.000-0.000)

\< 6 months 3 735 0.002 (0.000-0.004) 0 266 0.000 (0.000-0.000) 4 137
0.006 (0.000-0.012) 1 55 0.011 (0.000-0.034)

\< 12 months 7 888 0.007 (0.002-0.012) 1 282 0.022 (0.000-0.065) 7 226
0.012 (0.003-0.021) 2 70 0.026 (0.000-0.063)

\< 18 months 11 1010 0.012 (0.005-0.020) 2 290 0.053 (0.000-0.125) 9 297
0.017 (0.006-0.028) 2 75 0.026 (0.000-0.063)

\< 24 months 12 1158 0.014 (0.006-0.022) 2 295 0.053 (0.000-0.125) 14
343 0.030 (0.014-0.046) 3 82 0.046 (0.000-0.098)

\< 36 months 13 1370 0.016 (0.007-0.026) 3 303 0.105 (0.000-0.227) 18
515 0.045 (0.024-0.066) 4 100 0.072 (0.000-0.145)

\< 48 months 14 1471 0.020 (0.008-0.032) 3 316 - ( - - - ) 18 681 0.045
(0.024-0.066) 4 124 0.072 (0.000-0.145)

\< 60 months 16 1599 0.035 (0.011-0.059) - - - ( - - - ) 18 683 -
( - - - ) 4 126 - ( - - - )

all months 16 1664 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 0.5 0.0 1.2 0.0

\< 6 months 0.4 0.0 1.3 2.0

\< 12 months 0.6 0.7 1.2 2.3

\< 18 months 0.7 1.2 1.1 1.7

\< 24 months 0.7 1.1 1.4 2.1

\< 36 months 0.6 1.5 1.4 2.2

\< 48 months 0.6 1.4 1.3 2.0

\< 60 months 0.6 1.4 1.3 2.0

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with SAE, total
censored, cumulative probability of SAE, 95% CI

######## ![](media/image11.wmf){width="7.541666666666667in" height="5.846527777777778in"}

######## 

######## 

# Table 046 Serious adverse events - lymphoma 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 3 0 2 2

with serious

adverse events -

lymphoma

Kaplan - Meier cumulative rates \[1\]

\< 3 months 0 205 0.000 (0.000-0.000) 0 39 0.000 (0.000-0.000) 1 59
0.001 (0.000-0.004) 0 30 0.000 (0.000-0.000)

\< 6 months 0 737 0.000 (0.000-0.000) 0 266 0.000 (0.000-0.000) 2 136
0.003 (0.000-0.007) 0 55 0.000 (0.000-0.000)

\< 12 months 1 891 0.001 (0.000-0.003) 0 282 0.000 (0.000-0.000) 2 227
0.003 (0.000-0.007) 0 70 0.000 (0.000-0.000)

\< 18 months 2 1015 0.003 (0.000-0.006) 0 290 0.000 (0.000-0.000) 2 300
0.003 (0.000-0.007) 0 75 0.000 (0.000-0.000)

\< 24 months 2 1164 0.003 (0.000-0.006) 0 296 0.000 (0.000-0.000) 2 348
0.003 (0.000-0.007) 1 82 0.019 (0.000-0.057)

\< 36 months 3 1380 0.005 (0.000-0.011) 0 306 0.000 (0.000-0.000) 2 525
0.003 (0.000-0.007) 1 103 0.019 (0.000-0.057)

\< 48 months 3 1482 0.005 (0.000-0.011) 0 319 - ( - - - ) 2 699 0.003
(0.000-0.007) 2 126 0.087 (0.000-0.220)

\< 60 months 3 1612 0.005 (0.000-0.011) - - - ( - - - ) 2 701 - ( - - -
) 2 128 - ( - - - )

all months 3 1678 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 0.0 0.0 0.6 0.0

\< 6 months 0.0 0.0 0.6 0.0

\< 12 months 0.1 0.0 0.3 0.0

\< 18 months 0.1 0.0 0.3 0.0

\< 24 months 0.1 0.0 0.2 0.7

\< 36 months 0.1 0.0 0.2 0.5

\< 48 months 0.1 0.0 0.1 1.0

\< 60 months 0.1 0.0 0.1 1.0

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with SAE, total
censored, cumulative probability of SAE, 95% CI

######## 

######## Appendix 6 

######## Serious Adverse Events: Skin

![](media/image12.wmf){width="8.0in" height="6.186111111111111in"}

# Table 047 Serious adverse events - skin related events 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 27 1 7 1

with serious

adverse events -

skin-related

events

Kaplan - Meier cumulative rates \[1\]

\< 3 months 5 200 0.003 (0.000-0.006) 0 39 0.000 (0.000-0.000) 0 59
0.000 (0.000-0.000) 0 30 0.000 (0.000-0.000)

\< 6 months 10 728 0.007 (0.003-0.012) 0 266 0.000 (0.000-0.000) 1 137
0.002 (0.000-0.005) 0 54 0.000 (0.000-0.000)

\< 12 months 14 880 0.012 (0.005-0.018) 1 281 0.022 (0.000-0.065) 2 227
0.004 (0.000-0.009) 1 69 0.015 (0.000-0.043)

\< 18 months 17 1003 0.016 (0.008-0.024) 1 289 0.022 (0.000-0.065) 4 300
0.008 (0.000-0.016) 1 74 0.015 (0.000-0.043)

\< 24 months 20 1152 0.021 (0.011-0.031) 1 295 0.022 (0.000-0.065) 5 346
0.011 (0.001-0.020) 1 82 0.015 (0.000-0.043)

\< 36 months 23 1365 0.028 (0.016-0.041) 1 305 0.022 (0.000-0.065) 7 522
0.018 (0.004-0.032) 1 103 0.015 (0.000-0.043)

\< 48 months 24 1466 0.032 (0.017-0.047) 1 318 - ( - - - ) 7 694 0.018
(0.004-0.032) 1 127 0.015 (0.000-0.043)

\< 60 months 25 1591 0.040 (0.019-0.061) - - - ( - - - ) 7 696 - ( - - -
) 1 129 - ( - - - )

all months 27 1654 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 1.3 0.0 0.0 0.0

\< 6 months 1.4 0.0 0.3 0.0

\< 12 months 1.2 0.7 0.3 1.1

\< 18 months 1.1 0.6 0.5 0.8

\< 24 months 1.1 0.5 0.5 0.7

\< 36 months 1.0 0.5 0.5 0.5

\< 48 months 1.0 0.5 0.5 0.5

\< 60 months 1.0 0.5 0.5 0.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with SAE, total
censored, cumulative probability of SAE, 95% CI

######## Appendix 7

**Withdrawals due to Adverse Events**

![](media/image13.wmf){width="7.204861111111111in"
height="5.406944444444444in"}

# Table 025 Withdrawals due to an adverse event 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide placebo Methotrexate Sulfasalazine
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 351 26 141 34

withdrawn due to

adverse event

Kaplan - Meier cumulative rates \[1\]

\< 3 months 128 77 0.078 (0.065-0.091) 13 26 0.042 (0.020-0.065) 34 25
0.049 (0.033-0.065) 21 9 0.167 (0.102-0.233)

\< 6 months 211 526 0.139 (0.122-0.157) 23 243 0.098 (0.059-0.138) 69 69
0.103 (0.080-0.126) 24 31 0.195 (0.125-0.266)

\< 12 months 257 635 0.184 (0.163-0.204) 25 257 0.138 (0.072-0.203) 99
130 0.153 (0.125-0.181) 24 46 0.195 (0.125-0.266)

\< 18 months 274 742 0.202 (0.180-0.225) 25 265 0.138 (0.072-0.203) 118
184 0.189 (0.158-0.220) 27 48 0.236 (0.156-0.317)

\< 24 months 295 871 0.230 (0.206-0.255) 25 271 0.138 (0.072-0.203) 132
218 0.219 (0.185-0.252) 32 51 0.308 (0.213-0.402)

\< 36 months 319 1064 0.275 (0.246-0.303) 25 281 0.138 (0.072-0.203) 138
389 0.236 (0.201-0.272) 33 71 0.326 (0.228-0.425)

\< 48 months 330 1155 0.306 (0.273-0.339) 26 293 - ( - - - ) 138 563
0.236 (0.201-0.272) 33 95 0.326 (0.228-0.425)

\< 60 months 341 1274 0.362 (0.318-0.406) - - - ( - - - ) 138 565 -
( - - - ) 33 97 - ( - - - )

all months 347 1334 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 32.4 17.1 20.1 74.0

\< 6 months 29.0 18.2 21.6 46.9

\< 12 months 22.0 16.7 16.9 27.4

\< 18 months 17.9 14.9 14.8 23.0

\< 24 months 16.1 13.7 13.3 22.2

\< 36 months 14.4 12.3 10.7 18.0

\< 48 months 13.4 12.3 10.2 16.5

\< 60 months 13.1 12.2 10.1 16.2

**Appendix 9**

**Adverse event hypertension**

![](media/image14.wmf){width="7.7in" height="5.954861111111111in"}

# Table 061 Adverse events - hypertension 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 233 19 53 9

with adverse

events -

hypertension

Kaplan - Meier cumulative rates \[1\]

\< 3 months 72 189 0.046 (0.036-0.056) 10 37 0.034 (0.013-0.054) 11 58
0.016 (0.007-0.026) 7 28 0.060 (0.017-0.104)

\< 6 months 102 689 0.071 (0.057-0.084) 13 254 0.051 (0.023-0.080) 14
136 0.021 (0.010-0.032) 7 52 0.060 (0.017-0.104)

\< 12 months 141 821 0.116 (0.097-0.134) 13 269 0.051 (0.023-0.080) 24
221 0.041 (0.025-0.057) 7 67 0.060 (0.017-0.104)

\< 18 months 173 929 0.159 (0.136-0.182) 15 277 0.113 (0.026-0.199) 36
289 0.068 (0.046-0.090) 7 72 0.060 (0.017-0.104)

\< 24 months 190 1046 0.187 (0.162-0.213) 16 283 0.153 (0.040-0.266) 43
333 0.086 (0.061-0.112) 8 78 0.080 (0.023-0.137)

\< 36 months 206 1223 0.226 (0.195-0.256) 17 289 0.209 (0.059-0.360) 50
492 0.113 (0.082-0.144) 9 96 0.106 (0.031-0.181)

\< 48 months 212 1301 0.249 (0.214-0.284) 17 300 - ( - - - ) 50 648
0.113 (0.082-0.144) 9 119 0.106 (0.031-0.181)

\< 60 months 213 1402 0.257 (0.219-0.294) - - - ( - - - ) 50 650 -
( - - - ) 9 121 - ( - - - )

all months 217 1448 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 18.6 13.3 6.6 25.0

\< 6 months 14.4 10.5 4.5 14.0

\< 12 months 12.6 8.8 4.2 8.2

\< 18 months 12.0 9.1 4.6 6.2

\< 24 months 11.2 9.0 4.5 5.8

\< 36 months 10.1 8.6 4.1 5.1

\< 48 months 9.4 8.2 3.9 4.6

\< 60 months 8.9 8.0 3.8 4.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with AE, total
censored, cumulative probability of AE, 95% CI

**Appendix 10**

**New Onset Hypertension**

![](media/image15.wmf){width="7.4in" height="5.722916666666666in"}

# Table 064 New onset of hypertension 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 438 61 211 36

with new onset

of hypretension

Kaplan - Meier cumulative rates \[1\]

\< 3 months 241 172 0.151 (0.134-0.169) 48 33 0.159 (0.118-0.200) 90 54
0.133 (0.108-0.159) 23 22 0.193 (0.122-0.264)

\< 6 months 311 635 0.208 (0.188-0.229) 55 223 0.200 (0.151-0.249) 127
118 0.194 (0.164-0.224) 29 45 0.259 (0.177-0.342)

\< 12 months 376 750 0.284 (0.259-0.310) 57 234 0.245 (0.169-0.321) 165
184 0.266 (0.231-0.301) 33 54 0.317 (0.223-0.410)

\< 18 months 400 845 0.318 (0.290-0.346) 57 240 0.245 (0.169-0.321) 186
234 0.313 (0.275-0.351) 35 58 0.350 (0.250-0.450)

\< 24 months 414 950 0.343 (0.313-0.373) 60 244 0.358 (0.223-0.493) 199
269 0.347 (0.306-0.387) 36 62 0.369 (0.265-0.472)

\< 36 months 425 1080 0.372 (0.339-0.405) 61 250 0.412 (0.252-0.571) 210
386 0.387 (0.343-0.432) 36 75 0.369 (0.265-0.472)

\< 48 months 435 1130 0.413 (0.374-0.453) 61 258 - ( - - - ) 211 491
0.399 (0.350-0.447) 36 92 0.369 (0.265-0.472)

\< 60 months 437 1213 0.429 (0.385-0.473) - - - ( - - - ) 211 492 -
( - - - ) 36 94 - ( - - - )

all months 438 1243 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 66.6 68.5 57.5 86.0

\< 6 months 48.5 48.9 44.9 63.7

\< 12 months 38.9 43.5 33.5 45.7

\< 18 months 33.0 39.5 28.7 37.5

\< 24 months 29.5 38.7 25.5 32.3

\< 36 months 25.8 36.3 21.6 25.7

\< 48 months 24.2 35.1 20.7 23.6

\< 60 months 23.2 34.5 20.6 23.1

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with hypertension,
total censored, cumulative probability of event, 95% CI

**Appendix 11**

**Withdrawal due to hypertension**

![](media/image16.wmf){width="7.7in" height="5.957638888888889in"}

# Table 026 Withdrawals due to hypertension 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 13 3 2 1

withdrawn due to

hypertension

Kaplan - Meier cumulative rates \[1\]

\< 3 months 8 197 0.005 (0.002-0.009) 2 37 0.007 (0.000-0.016) 0 59
0.000 (0.000-0.000) 1 29 0.009 (0.000-0.026)

\< 6 months 10 727 0.007 (0.003-0.011) 3 263 0.013 (0.000-0.027) 0 138
0.000 (0.000-0.000) 1 54 0.009 (0.000-0.026)

\< 12 months 12 880 0.009 (0.004-0.014) 3 279 0.013 (0.000-0.027) 1 228
0.002 (0.000-0.006) 1 69 0.009 (0.000-0.026)

\< 18 months 13 1003 0.010 (0.004-0.016) 3 287 0.013 (0.000-0.027) 2 300
0.004 (0.000-0.010) 1 74 0.009 (0.000-0.026)

\< 24 months 13 1153 0.010 (0.004-0.016) 3 293 0.013 (0.000-0.027) 2 348
0.004 (0.000-0.010) 1 82 0.009 (0.000-0.026)

\< 36 months 13 1370 0.010 (0.004-0.016) 3 303 0.013 (0.000-0.027) 2 525
0.004 (0.000-0.010) 1 103 0.009 (0.000-0.026)

\< 48 months 13 1472 0.010 (0.004-0.016) 3 316 - ( - - - ) 2 699 0.004
(0.000-0.010) 1 127 0.009 (0.000-0.026)

\< 60 months 13 1602 0.010 (0.004-0.016) - - - ( - - - ) 2 701 - ( - - -
) 1 129 - ( - - - )

all months 13 1668 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 2.0 2.6 0.0 3.5

\< 6 months 1.4 2.4 0.0 2.0

\< 12 months 1.0 2.0 0.2 1.1

\< 18 months 0.9 1.8 0.3 0.9

\< 24 months 0.7 1.6 0.2 0.7

\< 36 months 0.6 1.5 0.2 0.5

\< 48 months 0.5 1.4 0.1 0.5

\< 60 months 0.5 1.4 0.1 0.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects withdrawn, total
censored, cumulative probability of withdrawal, 95% CI

**Appendix 12**

**Serious adverse event: Hypertension**

![](media/image17.wmf){width="7.6in" height="5.877083333333333in"}

# Table 035 Serious adverse events - hypertension 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 14 2 2 1

with serious

adverse events -

hypertension

Kaplan - Meier cumulative rates \[1\]

\< 3 months 2 203 0.001 (0.000-0.003) 1 38 0.003 (0.000-0.010) 0 59
0.000 (0.000-0.000) 1 29 0.009 (0.000-0.026)

\< 6 months 3 735 0.002 (0.000-0.004) 1 265 0.003 (0.000-0.010) 0 138
0.000 (0.000-0.000) 1 54 0.009 (0.000-0.026)

\< 12 months 6 890 0.006 (0.001-0.010) 1 281 0.003 (0.000-0.010) 1 228
0.002 (0.000-0.006) 1 69 0.009 (0.000-0.026)

\< 18 months 10 1011 0.011 (0.004-0.018) 1 289 0.003 (0.000-0.010) 2 300
0.004 (0.000-0.010) 1 74 0.009 (0.000-0.026)

\< 24 months 11 1158 0.013 (0.005-0.021) 1 295 0.003 (0.000-0.010) 2 348
0.004 (0.000-0.010) 1 82 0.009 (0.000-0.026)

\< 36 months 11 1373 0.013 (0.005-0.021) 2 304 0.057 (0.000-0.160) 2 525
0.004 (0.000-0.010) 1 103 0.009 (0.000-0.026)

\< 48 months 13 1475 0.021 (0.007-0.034) 2 317 - ( - - - ) 2 699 0.004
(0.000-0.010) 1 127 0.009 (0.000-0.026)

\< 60 months 13 1601 0.021 (0.007-0.034) - - - ( - - - ) 2 701 - ( - - -
) 1 129 - ( - - - )

all months 13 1667 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 0.5 1.3 0.0 3.5

\< 6 months 0.4 0.8 0.0 2.0

\< 12 months 0.5 0.7 0.2 1.1

\< 18 months 0.7 0.6 0.3 0.9

\< 24 months 0.6 0.5 0.2 0.7

\< 36 months 0.5 1.0 0.2 0.5

\< 48 months 0.5 1.0 0.1 0.5

\< 60 months 0.5 0.9 0.1 0.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**A**

**Appendix 13**

**Diarrhea as an adverse event**

![](media/image18.wmf){width="7.7in" height="5.957638888888889in"}

# Table 058 Adverse events - diarrhea 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 381 36 137 19

with adverse

events - diarrhea

Kaplan - Meier cumulative rates \[1\]

\< 3 months 224 161 0.140 (0.123-0.158) 27 34 0.089 (0.057-0.122) 71 48
0.105 (0.082-0.128) 10 27 0.086 (0.035-0.137)

\< 6 months 290 605 0.194 (0.173-0.214) 30 244 0.107 (0.070-0.145) 91
108 0.137 (0.111-0.163) 13 47 0.119 (0.058-0.180)

\< 12 months 322 726 0.229 (0.207-0.252) 33 258 0.178 (0.094-0.262) 108
184 0.168 (0.139-0.198) 16 61 0.161 (0.086-0.235)

\< 18 months 343 833 0.258 (0.233-0.283) 34 266 0.212 (0.108-0.316) 121
244 0.197 (0.165-0.229) 16 66 0.161 (0.086-0.235)

\< 24 months 352 959 0.273 (0.247-0.299) 35 270 0.258 (0.127-0.390) 128
281 0.214 (0.180-0.248) 18 71 0.198 (0.111-0.285)

\< 36 months 362 1129 0.299 (0.269-0.329) 36 275 0.323 (0.152-0.493) 135
428 0.239 (0.202-0.277) 19 87 0.222 (0.125-0.319)

\< 48 months 372 1186 0.344 (0.305-0.383) 36 283 - ( - - - ) 137 566 -
( - - - ) 19 110 0.222 (0.125-0.319)

\< 60 months 374 1263 0.361 (0.317-0.405) - - - ( - - - ) - - - ( - - -
) 19 111 - ( - - - )

all months 375 1300 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 62.2 37.5 44.6 37.2

\< 6 months 44.8 25.3 30.9 27.1

\< 12 months 31.9 23.9 20.4 19.7

\< 18 months 26.5 22.5 17.0 14.8

\< 24 months 23.2 21.7 14.7 13.7

\< 36 months 20.3 20.5 12.1 11.3

\< 48 months 19.1 19.8 11.7 10.4

\< 60 months 18.3 19.5 11.6 10.2

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with AE, total
censored, cumulative probability of AE, 95% CI

**Appendix 14**

**Withdrawal due to diarrhea**

![](media/image19.wmf){width="7.4in" height="5.722916666666666in"}

# Table 027 Withdrawals due to diarrhea 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 32 5 11 2

withdrawn due to

diarrhea

Kaplan - Meier cumulative rates \[1\]

\< 3 months 22 183 0.014 (0.008-0.020) 4 35 0.013 (0.000-0.026) 5 54
0.007 (0.001-0.014) 1 29 0.009 (0.000-0.026)

\< 6 months 30 707 0.020 (0.013-0.028) 5 261 0.019 (0.002-0.036) 8 130
0.012 (0.004-0.021) 2 53 0.020 (0.000-0.048)

\< 12 months 31 861 0.021 (0.014-0.029) 5 277 0.019 (0.002-0.036) 8 221
0.012 (0.004-0.021) 2 68 0.020 (0.000-0.048)

\< 18 months 31 985 0.021 (0.014-0.029) 5 285 0.019 (0.002-0.036) 9 293
0.015 (0.005-0.024) 2 73 0.020 (0.000-0.048)

\< 24 months 31 1135 0.021 (0.014-0.029) 5 291 0.019 (0.002-0.036) 11
339 0.020 (0.008-0.032) 2 81 0.020 (0.000-0.048)

\< 36 months 32 1351 0.024 (0.015-0.033) 5 301 0.019 (0.002-0.036) 11
516 0.020 (0.008-0.032) 2 102 0.020 (0.000-0.048)

\< 48 months 32 1453 0.024 (0.015-0.033) 5 314 - ( - - - ) 11 690 0.020
(0.008-0.032) 2 126 0.020 (0.000-0.048)

\< 60 months 32 1583 0.024 (0.015-0.033) - - - ( - - - ) 11 692 -
( - - - ) 2 128 - ( - - - )

all months 32 1649 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 5.6 5.3 3.0 3.5

\< 6 months 4.1 4.0 2.5 3.9

\< 12 months 2.7 3.3 1.4 2.3

\< 18 months 2.0 3.0 1.1 1.7

\< 24 months 1.7 2.7 1.1 1.4

\< 36 months 1.4 2.5 0.9 1.1

\< 48 months 1.3 2.4 0.8 1.0

\< 60 months 1.2 2.3 0.8 1.0

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects withdrawn, total
censored, cumulative probability of withdrawal, 95% CI

**Appendix 15**

**Withdrawal due to diarrhea by dose**

![](media/image20.wmf){width="7.5in" height="5.8in"}

**Appendix 16**

**Diarrhea as an adverse event based on leflunomide dose**

![](media/image21.wmf){width="7.54375in" height="5.834027777777778in"}

**Appendix 17**

**Weight loss 10-20 lb**

![](media/image22.wmf){width="7.5in" height="5.8in"}

# Table 056 Weight loss \>= 10 - 20 lb 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 397 34 162 19

with adverse

events with

weight loss of

\>=10 - 20 lb

Kaplan - Meier cumulative rates \[1\]

\< 3 months 76 189 0.048 (0.037-0.058) 12 37 0.040 (0.018-0.062) 50 57
0.074 (0.054-0.094) 6 28 0.052 (0.011-0.092)

\< 6 months 170 687 0.125 (0.107-0.142) 22 251 0.099 (0.058-0.141) 72
126 0.110 (0.086-0.135) 9 52 0.086 (0.031-0.140)

\< 12 months 261 809 0.229 (0.204-0.254) 31 264 0.310 (0.185-0.434) 110
197 0.182 (0.151-0.214) 13 66 0.145 (0.069-0.220)

\< 18 months 319 879 0.307 (0.277-0.336) 32 268 0.343 (0.209-0.477) 128
253 0.222 (0.188-0.257) 14 71 0.162 (0.081-0.244)

\< 24 months 339 976 0.339 (0.307-0.370) 32 272 0.343 (0.209-0.477) 142
290 0.258 (0.220-0.296) 15 77 0.182 (0.094-0.271)

\< 36 months 375 1117 0.419 (0.382-0.456) 33 278 0.402 (0.237-0.568) 157
416 0.312 (0.268-0.356) 18 92 0.263 (0.145-0.380)

\< 48 months 388 1174 0.466 (0.424-0.508) 33 285 - ( - - - ) 162 539
0.362 (0.303-0.421) 19 111 - ( - - - )

\< 60 months 392 1242 0.491 (0.445-0.538) - - - ( - - - ) 162 541 -
( - - - ) - - - ( - - - )

all months 397 1284 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 19.5 16.0 30.4 21.5

\< 6 months 24.2 17.9 23.9 18.1

\< 12 months 24.6 21.7 20.6 15.8

\< 18 months 24.0 20.8 18.0 13.0

\< 24 months 21.9 19.5 16.5 11.6

\< 36 months 20.6 18.5 14.5 11.1

\< 48 months 19.6 17.8 14.2 10.9

\< 60 months 19.0 17.4 14.1 10.7

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**Appendix 18**

**Weight loss over 20 lb**

![](media/image23.wmf){width="7.5in" height="5.8in"}

# Table 057 Weight loss \>= 20 lb 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 116 6 30 6

with adverse

events with

weight loss of

\>=20 lb

Kaplan - Meier cumulative rates \[1\]

\< 3 months 13 203 0.008 (0.004-0.013) 0 39 0.000 (0.000-0.000) 3 58
0.004 (0.000-0.009) 0 30 0.000 (0.000-0.000)

\< 6 months 31 725 0.023 (0.015-0.031) 1 265 0.006 (0.000-0.018) 6 136
0.009 (0.002-0.017) 1 55 0.011 (0.000-0.034)

\< 12 months 56 875 0.052 (0.038-0.065) 3 281 0.050 (0.000-0.111) 13 225
0.023 (0.010-0.035) 1 70 0.011 (0.000-0.034)

\< 18 months 72 985 0.074 (0.057-0.091) 4 289 0.081 (0.000-0.164) 18 296
0.034 (0.018-0.050) 2 75 0.029 (0.000-0.069)

\< 24 months 87 1122 0.099 (0.078-0.119) 5 294 0.120 (0.010-0.230) 20
343 0.039 (0.022-0.057) 3 83 0.049 (0.000-0.104)

\< 36 months 99 1314 0.127 (0.102-0.153) 6 304 0.179 (0.028-0.330) 29
507 0.073 (0.046-0.100) 6 101 0.130 (0.029-0.232)

\< 48 months 109 1396 0.166 (0.132-0.200) 6 313 - ( - - - ) 30 671 0.084
(0.050-0.118) 6 123 0.130 (0.029-0.232)

\< 60 months 113 1508 0.194 (0.151-0.236) - - - ( - - - ) 30 673 -
( - - - ) 6 124 - ( - - - )

all months 116 1565 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 3.3 0.0 1.8 0.0

\< 6 months 4.3 0.8 1.9 2.0

\< 12 months 4.9 2.0 2.2 1.1

\< 18 months 4.8 2.4 2.3 1.7

\< 24 months 4.9 2.8 2.1 2.1

\< 36 months 4.7 3.1 2.3 3.4

\< 48 months 4.6 3.0 2.3 3.1

\< 60 months 4.6 2.9 2.3 3.1

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with weight loss,
total censored, cumulative probability of SAE, 95% CI

**Appendix 19**

**Hepatic adverse events**

![](media/image24.wmf){width="6.902777777777778in"
height="5.631944444444445in"}

# Table 048 Adverse events - hepatic event / toxicity 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 138 8 140 9

with adverse

events - hepatic

event / toxicity

Kaplan - Meier cumulative rates \[1\]

\< 3 months 59 177 0.037 (0.028-0.046) 5 35 0.017 (0.002-0.031) 49 53
0.073 (0.053-0.092) 3 28 0.026 (0.000-0.055)

\< 6 months 82 683 0.056 (0.044-0.068) 7 261 0.029 (0.007-0.050) 85 115
0.131 (0.105-0.158) 5 51 0.049 (0.007-0.091)

\< 12 months 102 820 0.078 (0.063-0.093) 7 275 0.029 (0.007-0.050) 111
187 0.180 (0.149-0.211) 8 63 0.091 (0.029-0.153)

\< 18 months 111 936 0.090 (0.073-0.107) 7 283 0.029 (0.007-0.050) 124
247 0.209 (0.175-0.242) 8 68 0.091 (0.029-0.153)

\< 24 months 118 1080 0.102 (0.083-0.120) 7 289 0.029 (0.007-0.050) 133
283 0.231 (0.196-0.267) 8 75 0.091 (0.029-0.153)

\< 36 months 126 1278 0.121 (0.098-0.143) 7 298 0.029 (0.007-0.050) 136
416 0.242 (0.205-0.279) 8 95 0.091 (0.029-0.153)

\< 48 months 129 1369 0.132 (0.107-0.158) 7 311 - ( - - - ) 138 562
0.262 (0.217-0.307) 8 119 0.091 (0.029-0.153)

\< 60 months 131 1486 0.147 (0.115-0.179) - - - ( - - - ) 138 563 -
( - - - ) 8 121 - ( - - - )

all months 132 1543 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 15.1 6.6 29.8 10.6

\< 6 months 11.5 5.6 28.3 9.8

\< 12 months 8.9 4.7 20.7 9.2

\< 18 months 7.5 4.2 17.4 6.9

\< 24 months 6.7 3.9 15.3 5.6

\< 36 months 5.9 3.5 12.2 4.4

\< 48 months 5.4 3.3 11.7 4.0

\< 60 months 5.2 3.3 11.6 3.9

# Appendix 20

AST or ALT \>3ULN

![](media/image25.wmf){width="7.5in" height="5.803472222222222in"}

# Table 049 AST or ALT above 3xULN 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 81 4 121 5

with AST or ALT

above 3xULN

Kaplan - Meier cumulative rates \[1\]

\< 3 months 35 192 0.022 (0.015-0.029) 1 38 0.003 (0.000-0.010) 31 56
0.046 (0.030-0.062) 4 27 0.034 (0.001-0.067)

\< 6 months 43 710 0.029 (0.020-0.037) 2 265 0.009 (0.000-0.023) 70 120
0.110 (0.085-0.134) 5 51 0.045 (0.006-0.085)

\< 12 months 54 861 0.041 (0.030-0.052) 3 280 0.032 (0.000-0.077) 98 193
0.162 (0.132-0.192) 5 66 0.045 (0.006-0.085)

\< 18 months 61 977 0.051 (0.038-0.064) 4 288 0.062 (0.000-0.135) 109
258 0.186 (0.154-0.218) 5 71 0.045 (0.006-0.085)

\< 24 months 70 1117 0.066 (0.050-0.082) 4 294 0.062 (0.000-0.135) 114
292 0.199 (0.166-0.232) 5 79 0.045 (0.006-0.085)

\< 36 months 75 1326 0.078 (0.059-0.097) 4 302 0.062 (0.000-0.135) 121
431 0.224 (0.187-0.261) 5 99 0.045 (0.006-0.085)

\< 48 months 79 1417 0.093 (0.069-0.118) 4 315 - ( - - - ) 121 580 0.224
(0.187-0.261) 5 123 0.045 (0.006-0.085)

\< 60 months 80 1536 0.101 (0.073-0.129) - - - ( - - - ) 121 582 -
( - - - ) 5 125 - ( - - - )

all months 80 1600 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 8.9 1.3 18.6 14.2

\< 6 months 6.0 1.6 22.9 9.9

\< 12 months 4.7 2.0 18.0 5.8

\< 18 months 4.1 2.4 15.0 4.3

\< 24 months 3.9 2.2 12.9 3.5

\< 36 months 3.5 2.0 10.7 2.8

\< 48 months 3.3 1.9 10.1 2.5

\< 60 months 3.2 1.9 10.0 2.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with abnormal value,
total censored, cumulative probability of event, 95% CI

Appendix 21

ASTor ALT\> 5ULN

![](media/image26.wmf){width="7.5in" height="5.803472222222222in"}

# Table 050 AST or ALT above 5xULN 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 28 1 46 3

with AST or ALT

above 5xULN

Kaplan - Meier cumulative rates \[1\]

\< 3 months 12 198 0.008 (0.003-0.012) 1 38 0.003 (0.000-0.010) 13 58
0.019 (0.009-0.030) 3 27 0.026 (0.000-0.055)

\< 6 months 13 728 0.008 (0.004-0.013) 1 265 0.003 (0.000-0.010) 27 128
0.042 (0.027-0.058) 3 52 0.026 (0.000-0.055)

\< 12 months 15 881 0.011 (0.005-0.016) 1 281 0.003 (0.000-0.010) 35 214
0.057 (0.039-0.076) 3 67 0.026 (0.000-0.055)

\< 18 months 17 1004 0.013 (0.007-0.020) 1 289 0.003 (0.000-0.010) 42
284 0.073 (0.052-0.095) 3 72 0.026 (0.000-0.055)

\< 24 months 21 1151 0.020 (0.011-0.030) 1 295 0.003 (0.000-0.010) 44
327 0.078 (0.056-0.101) 3 80 0.026 (0.000-0.055)

\< 36 months 26 1366 0.032 (0.018-0.046) 1 305 0.003 (0.000-0.010) 45
490 0.082 (0.058-0.106) 3 101 0.026 (0.000-0.055)

\< 48 months 28 1464 0.040 (0.023-0.058) 1 318 - ( - - - ) 46 655 0.093
(0.061-0.124) 3 125 0.026 (0.000-0.055)

\< 60 months 28 1588 0.040 (0.023-0.058) - - - ( - - - ) 46 657 -
( - - - ) 3 127 - ( - - - )

all months 28 1653 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 3.0 1.3 7.7 10.6

\< 6 months 1.8 0.8 8.6 5.9

\< 12 months 1.3 0.7 6.1 3.4

\< 18 months 1.1 0.6 5.4 2.6

\< 24 months 1.2 0.5 4.6 2.1

\< 36 months 1.2 0.5 3.7 1.6

\< 48 months 1.1 0.5 3.5 1.5

\< 60 months 1.1 0.5 3.5 1.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with abnormal value,
total censored, cumulative probability of event, 95% CI

Appendix 22

AST or ALT \> 10 ULN

# Table 051 AST or ALT above 10xULN 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 7 0 6 1

with AST or ALT

above 10xULN

Kaplan - Meier cumulative rates \[1\]

\< 3 months 1 204 0.001 (0.000-0.002) 0 39 0.000 (0.000-0.000) 2 59
0.003 (0.000-0.007) 1 29 0.009 (0.000-0.026)

\< 6 months 1 736 0.001 (0.000-0.002) 0 266 0.000 (0.000-0.000) 5 137
0.008 (0.001-0.015) 1 54 0.009 (0.000-0.026)

\< 12 months 2 889 0.002 (0.000-0.004) 0 282 0.000 (0.000-0.000) 6 225
0.010 (0.002-0.018) 1 69 0.009 (0.000-0.026)

\< 18 months 4 1013 0.005 (0.000-0.009) 0 290 0.000 (0.000-0.000) 6 298
0.010 (0.002-0.018) 1 74 0.009 (0.000-0.026)

\< 24 months 5 1162 0.006 (0.001-0.012) 0 296 0.000 (0.000-0.000) 6 346
0.010 (0.002-0.018) 1 82 0.009 (0.000-0.026)

\< 36 months 7 1379 0.011 (0.002-0.020) 0 306 0.000 (0.000-0.000) 6 522
0.010 (0.002-0.018) 1 103 0.009 (0.000-0.026)

\< 48 months 7 1479 0.011 (0.002-0.020) 0 319 - ( - - - ) 6 695 0.010
(0.002-0.018) 1 127 0.009 (0.000-0.026)

\< 60 months 7 1608 0.011 (0.002-0.020) - - - ( - - - ) 6 697 - ( - - -
) 1 129 - ( - - - )

all months 7 1674 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 0.3 0.0 1.2 3.5

\< 6 months 0.1 0.0 1.6 2.0

\< 12 months 0.2 0.0 1.0 1.1

\< 18 months 0.3 0.0 0.8 0.9

\< 24 months 0.3 0.0 0.6 0.7

\< 36 months 0.3 0.0 0.5 0.5

\< 48 months 0.3 0.0 0.4 0.5

\< 60 months 0.3 0.0 0.4 0.5

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[1\]: Figures in the columns are - total subjects with abnormal value,
total censored, cumulative probability of event, 95% CI

![](media/image27.wmf){width="7.5in" height="5.8in"}

Appendix 23

AST or ALT \>3ULN plus bilirubin \>2ULN

![](media/image28.wmf){width="7.5in" height="5.803472222222222in"}

# Table 052 AST or ALT above 3xULN and bilirubin above 2xULN 

# 

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Kaplan - Meier cumulative rates with 95% confidence interval

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Leflunomide Placebo Methotrexate Sulfasalazine

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Total subjects 1693 322 709 133

treated

Total subjects 4 0 0 0

with AST or ALT

above 3xULN and

bilirubin above

2xULN

Kaplan - Meier cumulative rates \[1\]

\< 3 months 2 203 0.001 (0.000-0.003) 0 39 0.000 (0.000-0.000) 0 59
0.000 (0.000-0.000) 0 30 0.000 (0.000-0.000)

\< 6 months 2 735 0.001 (0.000-0.003) 0 266 0.000 (0.000-0.000) 0 138
0.000 (0.000-0.000) 0 55 0.000 (0.000-0.000)

\< 12 months 2 889 0.001 (0.000-0.003) 0 282 0.000 (0.000-0.000) 0 229
0.000 (0.000-0.000) 0 70 0.000 (0.000-0.000)

\< 18 months 3 1013 0.003 (0.000-0.006) 0 290 0.000 (0.000-0.000) 0 302
0.000 (0.000-0.000) 0 75 0.000 (0.000-0.000)

\< 24 months 4 1163 0.004 (0.000-0.009) 0 296 0.000 (0.000-0.000) 0 350
0.000 (0.000-0.000) 0 83 0.000 (0.000-0.000)

\< 36 months 4 1379 0.004 (0.000-0.009) 0 306 0.000 (0.000-0.000) 0 527
0.000 (0.000-0.000) 0 104 0.000 (0.000-0.000)

\< 48 months 4 1481 0.004 (0.000-0.009) 0 319 - ( - - - ) 0 701 0.000
(0.000-0.000) 0 128 0.000 (0.000-0.000)

\< 60 months 4 1611 0.004 (0.000-0.009) - - - ( - - - ) 0 703 - ( - - -
) 0 130 - ( - - - )

all months 4 1677 - ( - - - ) - - - ( - - - ) - - - ( - - - ) - - -
( - - - )

Cumulative rates per 100 patient years

\< 3 months 0.5 0.0 0.0 0.0

\< 6 months 0.3 0.0 0.0 0.0

\< 12 months 0.2 0.0 0.0 0.0

\< 18 months 0.2 0.0 0.0 0.0

\< 24 months 0.2 0.0 0.0 0.0

\< 36 months 0.2 0.0 0.0 0.0

\< 48 months 0.2 0.0 0.0 0.0

\< 60 months 0.2 0.0 0.0 0.0

> **Appendix 24**

**Post-Marketing cohort study of LEFLUNOMIDE and other DMARD**

**a comparative risk analysis**

# 1.Background

A post-marketing, retrospective cohort study comparing the rate of
adverse events (AEs) amongst leflunomide users to patients taking
Disease Modifying Anti-Rheumatic Drugs (DMARDs) (eg, gold salts,
azathioprine, hydroxychloroquine, D-penicillamine, and sulphasalazine),
and methotrexate was undertaken to address several issues. Leflunomide,
approved by the FDA in September 1998, was the first new DMARD
introduced in a decade, and is indicated for adults with active
rheumatoid arthritis (RA) to reduce signs and symptoms and to retard
structural damage as evidenced by X-ray erosions and joint space
narrowing. Spontaneous reports to drug regulators as well clinical cases
described in the literature warrant a formal investigation of these
potential signals. Specifically, this study focuses on the assessment of
serious hepatic, dermatologic, hematologic, infectious and other adverse
events.

# 2.Principal Aims

The principal aims of this cohort study were to:

-   determine the incidence rates of serious hepatic (e.g., liver
    necrosis, hepatitis, acute liver failure), dermatologic (e.g.,
    Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis), hematologic
    (e.g., agranulocytosis), hypertension, and other adverse events
    among leflunomide users and compare them to rates in users of other
    DMARDs, and methotrexate and

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-   evaluate the role of demographic and clinical variables associated
    with the drugs of interest.

# 3.Study Methods and Data Source

## 3.1 Study Design

The design is a dynamic retrospective cohort study. The advantage of
this design is its flexibility to identify a large number of patient
cohorts, defined by diagnosis and medication exposure, and follow them
through their course of therapy to estimate directly the strength of the
association between exposure and outcome (e.g., severe hepatic and other
events) over time. This approach, which reflects actual experience, also
allows for the identification of potential confounders, including
concomitant illnesses and therapies, that may influence the relationship
between the exposure and the outcome in a real-world setting without the
artificial influences of a clinical trial.

## 3.2 Data Source

The data source selected for this study is the Aetna-US Healthcare
claims database, a repository of health information on 10 million
covered lives, with linkage to medical, pharmacy, and laboratory data.
Aetna has a long history of clinical database research (1, 2) and an
established infrastructure for working with databases, as well as the
internal capability to abstract data from medical records. Insurance
claims databases are commonly used in pharmacoepidemiology research, as
they afford the investigator large numbers of subjects (often the
largest available) as well as data on medical services, pharmacy
services (including date of dispensing, drug name and dosage, and
duration of prescription), and enrollment time of members (which allows
calculation of person time at risk).

## Study period

Leflunomide was launched in September 1998 in the US. All leflunomide
users were identified in the dataset and similarly all comparator
subjects were identified during the same time frame. All leflunomide
users in the database through December 2000 were included.

## 3.4 definition of study cohorts

Several cohorts were defined for this study. As a reference cohort,
leflunomide monotherapy and leflunomide + methotrexate patients were
used, given that they are of most interest. Comparison cohorts include
methotrexate and DMARD monotherapy patients and leflunomide plus
methotrexate and leflunomide plus other DMARD patients. Comparisons were
limited to monotherapy and two-drug therapy cohorts. The design is
dynamic (or variable) meaning that persons may contribute exposure time
to any number of different cohorts. Time windows of exposure are defined
below.

## 3.5 definition of exposure period based on pharmacy files

Classification of each cohort member's person-time began with the first
prescription and proceeded through the end of the last prescription. To
take account of leflunomide's relatively long half-life (estimated to be
two weeks), the washout period was set at 60 days. Thus, the person-time
for a single prescription includes each day from the date of the first
prescription through either the last day for that prescription (plus 60
days) or the first day of the next prescription, whichever comes first.
Similarly for the other exposures of interest, the equivalent of five
half-lives were added to the end of the prescription period in order to
calculate person-time exposure (see Appendix C for the list of
half-lives).

In the case where a person has overlapping prescriptions for different
rheumatoid arthritis medications, his or her person-time was apportioned
to the appropriate combination exposure category for that period of
overlap time. This was easily accomplished with the Aetna database,
which records the following: days supply, units dispensed, strength, and
date of dispensing.

For any dispensing for which the days supplied are missing or zero, the
median days supplied for users of that medication was employed.

Person-time at risk was aggregated into the different time windows
according to leflunomide or other DMARD use and continued until the
earliest 1) confirmed event of interest; 2) end of washout for a given
medication, 3) date of last enrollment; 4) death; or 5) end of the study
period. Again, this is a dynamic cohort in which a subject may
contribute person-time to more than one cohort.

Exposure period at risk will end with the first of these events:

-   End of the study period

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-   Termination of enrollment in the health plan. Because small lapses
    in enrollment are not uncommon due to administrative procedures,
    gaps in enrollment of up to 31 days are permitted.

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-   Specific clinical outcomes of interest

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-   Death

The assumption is that the outcome of interest is acute, in that it has
a close temporal link to the exposure. To study this type of drug effect
it is necessary to track closely how drug use changes over time, because
the drug-induced risk begins when the drug is started. The half-life of
leflunomide is approximately two weeks and therefore the risk period for
leflunomide patients was defined as the time on leflunomide therapy plus
60 days (approximately 5 times the metabolic half-life) after the last
dose. Similarly, the methotrexate risk period was defined as the time on
methotrexate therapy plus 125 days. The half-lives of other DMARDs
varied from 0.1 to 27 days, and the exposure tails were calculated
accordingly.

In quantifying exposure to the study medications, attempts were made to
track changes that occur with time. Because it is never definitively
known how patients are taking their medication or when they actually
stop, only proxies for this exposure, as per instructions of
prescriptions filled, can be created.

## 3.6 Inclusion criteria into the cohort

-   Because several of the comparator medications have indications other
    than rheumatoid arthritis, inclusion in the study population for
    non-leflunomide patients was defined by a combination of diagnosis
    and treatment. Therefore, all leflunomide patients were included in
    the study (because the drug is indicated only for RA) while
    comparator drug users (ie, exposures to the other medications listed
    in Appendix A) required a rheumatoid arthritis diagnosis within 90
    days (before or after) the prescription date for the medication, to
    assure limiting the analyses to patients with rheumatoid arthritis.

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-   Sex and date of birth are known.

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-   Eighteen years of age or older on t~0~, the time of entry into the
    cohort.

## 3.7 Exclusion criteria

Amongst the non-leflunomide users, patients were excluded if they
experienced one of the hepatic events of interest (see Table 1) in the
90-day period prior to potential entry into the cohort. The standard
practice of excluding patients with the events of interest is critical
to the chosen design\--participants must be at risk of developing the
outcomes of interest. All leflunomide users were included in the study,
those with and without a history of hepatic disease (this issue is
addressed later in the report).

## 3.8 PRIMARY ENDPOINTS 

Any inpatient or outpatient encounter that reflects the key events of
interest will be considered a potential case. It is recognized that
these codes in and of themselves do not necessarily connote a
medication-induced event but they do allow the casting of a wider net
and do not exclude potential cases that may be of interest. ICD codes
for serious events are specified in the protocol (see Appendix B). As an
example, Table 1 lists several codes for hepatic events.

Other primary endpoints include hematologic (pancytopenia,
agranulocytosis, aplastic anemia); severe skin reactions
(Stevens-Johnson syndrome, toxic epidermal necrolysis); hypertension;
vasculitis and hemolytic anemia; pneumonitis; acute pancreatitis; GI
bleeding; upper respiratory tract infections and bronchitis; septic
arthritis; and pyelonephritis.

# 4. Analytic Plan

Simple descriptive characteristics of the cohort have been generated, in
addition to total subjects, person-time, mean length of exposure time,
and number of events. Incident rates have been calculated to compare
events between leflunomide monotherapy patients and a series of
comparator patients (eg, methotrexate monotherapy and various
combinations of drugs), along with 95% confidence intervals to
facilitate evaluation of product differences.

Adjustment for potential confounders was performed by putting age, sex,
and comorbidity into a Poisson regression model. The Poisson assumption
was chosen for the modeling strategy because it presumes that the number
of outcomes of interest are small compared to the total cohort size and
are statistically independent events. This assumption holds even if the
same individuals contribute person-time to more than one stratum.
Poisson regression theory presumes that the rarity of the outcome events
in any one time frame, whilst removing those individuals who experienced
those events from risk, nonetheless has little effect on the probability
of a specified number of events in the next time frame(3-6).

Adjustment for comorbidities utilized the scoring of the Charlson Index
(7). This is a weighted index used to classify comorbidities, taking
into account their number and severity.

# 5. CASE VALIDATION

An important element of this study is case validation. As originally
described in the study protocol, the validation process includes primary
data abstraction from the source medical records according to an
established procedure. The validation effort will be directed only to
severe hepatic events; the total number of AEs observed in the cohort is
16 000, which is beyond the scope of any validation endeavor. The final
sample of hepatic events to be validated were randomly selected from the
total of 651 such events, although all 12 of the liver necroses will be
examined.

Detailed data on the severe hepatic events were obtained. Approximately
61% of these events were noninfectious, toxic hepatitis; 4% were biliary
cirrhosis, 4% acute necrosis of the liver, 2% hepatic coma, and 28% were
'orphan events', ie, those AEs not associated with any drug exposure
because they did not occur within the defined exposure windows.

The formal protocol is as follows:

-   All patients in the RA cohort with a diagnosis code indicating a
    hepatic event of interest will be identified. A letter will be sent
    from the US Quality Assurance (USQA) department at Aetna to the site
    of care requesting copies of both the office/hospital notes at and
    around the time of the coded event of interest in addition to any of
    the following laboratory tests that may have been undertaken: liver
    biopsy, ultrasound, CT/MRI scan, serum chemistries including liver
    enzymes, bilirubin and hepatitis titres.

```{=html}
<!-- -->
```
-   The office or hospital will receive a financial incentive to
    respond.

```{=html}
<!-- -->
```
-   All responses will be de-identified by USQA.

```{=html}
<!-- -->
```
-   All responses will be collected centrally by USQA.

```{=html}
<!-- -->
```
-   A trained nurse-abstractor will review all returned material and
    complete as much as possible the attached form regarding the
    patient\'s pre- and post-diagnosis status as outlined in the
    abstract form in Appendix D (ref: P*h*RMA/FDA/AASLD Drug-Induced
    Hepatotoxicity White Paper: Postmarketing Considerations. November
    2000)

# 6. Results: the study cohort

The cohort chosen for this study, detailed below, totals 40 594 patients
with RA. These patients represent approximately 85 200 person-years
exposure to the drugs of interest, including 13 200 person-years
exposure to leflunomide. The demographics of the patients are presented
in Table 4. Examination of the different drug cohorts' contribution to
the total person-time, by age and sex, revealed no disparities between
or amongst cohorts (Figure 3). For example, males aged 18-30 contributed
approximately 1% of the person time, averaged across the five
monotherapy groups, females aged 18-30 contributed 2-4% of the person
time.

The female: male ratio is 2.7, confirming estimates from the literature.

The cohort itself is drawn from the larger Aetna-US Healthcare
population of 6 470 000 persons. Thus, the rate of RA in the Aetna
database is 40 594/6 470 000 or 0.63% which is, again, in accord with
estimates from the literature.

The cohorts that were developed for this study are presented in Table 5.
There were five potential sets of cohorts, depending on the number of
drug exposures (ie, monotherapy, two-, three, four-, and five-drug
therapy). However, the focus of the analysis is on the monotherapy and
two-drug therapy cohorts.

An assessment of the different cohorts' comorbidities was undertaken to
determine their comparability. Due to the time-on-drug dependent nature
of the cohorts, such a comorbidity analysis was limited to the
monotherapy groups.

The comorbidity analysis examined 72 different conditions prior to the
index date, ie, the date at which a person was included in the cohort
(Figure 1). There appeared to be a lower number of comorbidities at the
index date amongst the leflunomide (mean=1.62) and methotrexate
(mean=1.8) monotherapy compared to the DMARD group (mean=2.7). The
comorbidities are potential confounders and, as such, will be included
in the Poisson regression model. The cumulative person-year exposure,
mean exposure time, and the number of patients in the database on the
therapies of interest are displayed in Table 6.

The majority (81%) of RA patients are on either monotherapy or two-drug
therapy and that by far the single greatest exposure is to DMARD
monotherapy. DMARD + NSAID users and DMARD + methotrexate users are also
common (ie, account for \>10% of total person-year exposure). In terms
of mean exposure time, use of any DMARD was the longest (interestingly,
methotrexate and leflunomide exposure were almost identical) amongst the
monotherapy groups; DMARD + methotrexate had the longest average
exposure time amongst the two-drug therapies.

The primary aim of this study was to determine the rate of serious
outcomes associated with the use of certain drugs commonly used to treat
rheumatoid arthritis. Incidence rates were calculated using varying
'exposure tails' to avoid bias (8).

**Appendix 25**

**Consultation Dr. Leonard Seef**

r\~\',a **vnqr \~. . .**

**Public Health Service**

DEPARTMENT OF HEALTH & HUMAN SERVICES **National Institutes of Health**

> **National Institute of Diabetes and Digestive and Kidney Diseases
> Bethesda, Maryland 20892 December 12, 2002**
>
> Lawrence Goldkind, M.D.
>
> Deputy Director,
>
> Division of Analgesic and Anti‑Inflammatory
>
> Drug Products
>
> Food and Drug Administration
>
> 9201 Corporate Boulevard
>
> CPR2/N308
>
> HFD‑550
>
> Rockville, MD 20857
>
> Dear Dr. Goldkind,
>
> I am writing you in regard to the cases of presumed leflunomide
> (Arava) hepatotoxicity that you sent me for my opinion regarding their
> status. I received from you four different groupings: acute liver
> failure/death from the United States; serious liver injury from the
> United States; acute liver failure (International); and hepatotoxicity
> (Australia).
>
> As we discussed on the telephone, identification of hepatotoxicity
> ascribable to a single drug is often (usually) problematic and
> difficult to identify with certainty even in the best of
> circumstances, such as when an authoritative physician is personally
> involved in evaluating the situation. It is, of course, far more
> difficult when one has to rely on sparsely accumulated data gathered
> by persons not necessarily expert in the needed analysis and
> particularly when only minimal or even negligible data are provided.
>
> As you are well aware, in order to achieve some degree of certainty,
> it would be ideal to have, at a minimum, information on the following:
>
> 1\. A baseline panel of liver test results before initiating
> treatment;
>
> 2\. Regular (at least 1‑2 monthly) screening of liver chemistries
> after initiation of treatment over the course of at least one year;
>
> 3\. Preferably the use of only a single drug;
>
> 4\. Once liver test abnormalities or suggestive clinical symptoms
> develop, careful sequential screening of the liver chemistries are
> needed;
>
> 5\. Withdrawal of the drug, if possible, and follow‑up of the liver
> chemistries to determine the effect of drug withdrawal
>
> 6\. Complete evaluation of patient for other sources of liver
> dysfunction (viral serology; evaluation for autoimmune hepatitis, iron
> overload, obesity and diabetes; the use of over‑the‑counter drugs,
> herbal products or vitamin supplements; non‑hepatic causes such as
> congestive cardiac failure, etc)
>
> 7\. A liver biopsy or, if relevant, an autopsy.
>
> Clearly, even under ideal circumstances, relatively few of these items
> are satisfied. The greatest likelihood that these items will be made
> available is if the affected person is evaluated by a physician with
> knowledge and preferably expertise in this area (internist,
> gastroenterologist, hepatologist). More often than not, this is not
> the case, and time elapses before an appropriate

![](media/image29.png){width="0.8229166666666666in"
height="0.5597222222222222in"}

evaluation is **undertaken or a diagnosis is reached without full
consideration** of the possibilities.

This long preamble is made simply to underscore the difficulties
entailed in trying to squeeze an

\_2\_

accurate diagnosis from a series of reports that rarely contain the
complete information needed, that involve persons who are receiving
multiple other drugs, some known to have potential hepatotoxic effects,
and who often have diseases that themselves can lead to liver
dysfunction. Critical in the analysis, of course, is the fact of the
temporal relationship of the use of the drug to the beginning evidence
of liver dysfunction, plugging in all drugs administered. Complete
information will facilitate defining the \"incubation period\" to
development of hepatotoxicity and help define the mechanism responsible
for causing the injury.

As you know better than I do, the information found in the MedWatch
report often suffers from these omissions and lacks the needed
information so critical to reaching a comfortable and accurate
diagnosis. This is not meant as an excuse on my part, but simply
underscores the challenges posed in reaching even the lowest degree of
certainty.

All that having been said, I will present to you my views on what these
forms provide in determining whether, and with what frequency,
leflunomide causes liver damage as well as its severity. It is highly
probable that, even among a group of \"experts,\" there will be
differences of opinion. I will say that with the information provided, I
am unable to determine with absolute certainty that these reports
contain any instance of unequivocal hepatotoxicity. There are, however,
many instances of possible hepatotoxicity that can be attributable to
leflunomide.

> A. Acute liver failure/death, USA
>
> Among the 18 reports in this section, I assess that in 11 of them
> (1,2,4,5,6,10,12,13,
>
> 16,17,18), leflunomide might have been responsible for causing liver
> damage, but in some
>
> of them, there were other drugs taken that could also be incriminated.
> In a further 5
>
> instances (3,8,9,14,15), the information was insufficient to draw any
> conclusions, and in 2
>
> cases (5, 11), the diagnosis was uncertain.
>
> B. Serious liver injury, USA
>
> Among the 38 reports in this section, the diagnosis of leflunomide
> hepatoxicity seems
>
> possible in 23
> (1,6,7,9,11,13,15,18,19,20,21,22,24,25,26,27,28,29,30,33,34,36,38),
>
> although in some, the data are sparse while in many others, other
> drugs might be held
>
> responsible. An additional 12 (2,3,4,5,8,10,17, 23,31,32,35,37) have
> insufficient data
>
> with which to draw any conclusion, while among the remaining three,
> one (12) seems
>
> unlikely to be a consequence of leflunomide, another (14) is probably
> hepatitis C, and the
>
> third (16) has such sparse data that it is difficult to clearly
> implicate leflunomide

Among the above two groups, over two thirds are female and in four, no
gender is shown. The duration between drug institution and recognition
of potential hepatotoxicity is variable (ranging from weeks to over a
year), and the liver disease manifestation ranges from hepatocellular
injury, though a mixed pattern, to overtly cholestatic liver disease.

> C. Acute liver failure (International)
>
> Among the 13 cases in this section, leflunomide hepatoxicity is
> possible in 9
>
> (3,4,5,6,7,8,11,12,13), while the available data are insufficient to
> reach any conclusions in
>
> the remaining four (1,2,9,10). Again, when I indicate that
> hepatotoxicity is possible, I
>
> mean that it cannot be ruled out but in many instances is far from
> certain.
>
> D. Hepatotoxicity (Australia)
>
> This group has the least reported data. A diagnosis of possible
> leflunomide hepatoxicity
>
> can be eked out in about 6 cases but other drugs could also possibly
> be implicated. In most
>
> of the rest of the cases, the data are insufficient or entirely
> lacking with regard to reaching
>
> any diagnosis.
>
> In summary, there are clearly instances of definitive liver disease
> among many patients receiving

‑3‑

leflunomide, but in most instances, other drugs are also being taken;
principally methotrexate, prednisone, and celebrex. The question I would
have is whether there are a similar number of reports to MedWatch
regarding liver disease among recipients of anti‑rheumatic drugs of the
same class and in the same population who are not taking leflunomide. If
the numbers are far fewer, it would support the probability that
leflunomide itself, or perhaps in combination with the other drugs, is
responsible for the many instances of reported hepatotoxicity.

Finally, although I know that this is unlikely, it would be preferable
in reviewing these cases to have access to more complete data from the
actual sources in order to attempt to better define the temporal
association and the sequential laboratory values.

I hope that this is a useful exercise. Please let me know if you wish to
have the actual forms shipped back to you..

Sincerely ,

Leonard. B. Seeff, M.D. Senior Scientist for Hepatitis C Research
National Institutes of Diabetes and Digestive and Kidney Diseases
National Institutes of Health Bethesda, MD 20892 Tel. 301‑435‑3338 Fax.
303‑480‑7926 E‑mail. seeffl@extra.niddk.nih.gov

**Appendix 25**

**Consult: Dr. James Lewis**

> Georgetown Department of Medicine
>
> University Division of Gastroenterology
>
> Hospital November 21, 2002

Lawrence Goldkind, M.D.

Deputy Director

Division of Analgesic and Anti‑Inflammatory

Drug Products

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

> RE: Leflunomide Review

Dear Dr. Goldkind:

Thank you for requesting my review of the database on leflunomide
(Arava) hepatotoxicity. I have completed my review which encompasses the
materials that I received from your office including, by my count, 18
United States cases mentioning acute liver failure or death; 38 cases of
serious adverse events with respect to the liver from the United States;
13 cases of acute liver failure from international sources and 18 cases
of hepatotoxicity from Australia.

Following my assessment of all of these cases, my opinion is that the
overall quality of the case reports leaves much to be desired and for
many of these cases there was insufficient and often inadequate material
to assess causality. Nearly all of these cases were highly confounded
with patients receiving many other drugs including methotrexate and
other agents that in their own right are associated with hepatitic
injury. Moreover, the underlying diseases being treated (rheumatoid
arthritis, systemic lupus, etc.) are all associated with hepatitic
abnormalities in the absence of drug treatment.

I did not list any case as probably or definitely related from this
database given the quality of the information, as well as the fact that
I did not feel that any case was so unambiguous that no other
possibility existed except leflunomide as a cause of liver injury. Nor
did I classify any

> Stanley B. Benjamin, MD, FACP Firas H. Al‑Kawas, MD, FACP Richard G.
> Farmer, MD, MACP
>
> *Chief of Division* James H. Lewis, MD, FACP John E. Carroty MD
>
> Robynne Chutkan, MD Nadim G. Haddad, MD
>
> *MedStar Health*

3800 Reservoir Road, NW, Washington, DC 20007‑2197

*phone:* 202 687 8541 0 fox: 202 784 3957

![](media/image30.png){width="2.076388888888889in" height="0.80625in"}

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RE: Leflunomide Review

November 21, 2002

death as probably related to leflunomide. No chronic injury or cirrhosis
was felt to be related to leflunomide in any of these cases. In fact,
overall, there were so few cases where I felt comfortable in having the
minimum requisite information in order to carry out causality assessment
that no obvious or specific injury pattern could be discerned for the
cases that were deemed possibly related. All of these cases, considered
possibly related, were highly confounded and the designation of
\"possibly related\" does not exclude the fact that other causes
including drugs, might have been responsible for the injury.

As a result of my review of these cases, I do not feel that serious
hepatic injury has been demonstrated to the degree that would warrant a
change in the drug\'s current package labeling. I do not feel that there
is sufficient evidence to warrant any restrictions on the use of this
medication. I would certainly be happy to review any additional
information that you receive, but would hope that the quality of
spontaneous post‑marketing reports would be improved over the
information contained in the majority of these reports. For many of
these cases, only a review of the complete medical record might suffice
to truly determine causality of the liver injury reported; and that
assumes that all of the appropriate studies were done to exclude other
causes of hepatotoxicity. In my experience it is unusual that any of
these spontaneous reports contain sufficient information to make the
claim that all other causes have been reasonably ruled out.

I conducted my review of these cases much like I do any patient
information as I would in a clinical practice setting. While I am aware
of the regulatory definitions of probably related, possibly related,
unlikely to be related and unrelated, there is often insufficient
information provided for me to reach a definitive conclusion. As a
result, I employ my clinical experience and judgement garnered over the
past 24 years of reviewing such cases in order to make a clinical
assessment. For me, possibly related implies that sufficient information
is provided to exclude other reasonable causes, although it does not
mean that causality has been proven. Probably related is obviously a
stronger assessment that no other cause is likely to be responsible.
Unlikely to be related means that I found other explanations that were
more likely then leflunomide to have been responsible for the injury,
including whether or not the injury pattern fit the relatively wide
spectrum that is seen with other drug‑induced hepatotoxins. Unrelated
was assessed when there was a definitive reason for the injury that was
not due to the medication.

The minimal information that was required for any type of causality
assessment includes knowing the temporal relationship between the drug
and the event, determining the latency (the time during which the
patient was receiving the medication), being able to determine the
biochemical injury pattern, determining a response to discontinuation of
the medication (a positive dechallenge is defined as resolution of the
abnormalities after the offending agent is withdrawn), and being able to
determine that other common causes of hepatitic injury included viral
hepatitis, cholestatic syndrome, nonalcoholic steatohepatitis, as well
as other causes and factors were excluded. The literature is replete
with cases in which a drug has been alleged to cause injury, but the
relationship has been called into question when additional information
has

Page Three

RE: Leflunomide Review

November 21, 2002

been provided. I could only rely on the information available to me in
this data set. Having said that, I am always willing to expand the
spectrum of known hepatotoxins if the other factors seem to imply the
drug was responsible. On the other hand, saying that a drug is possibly
or probably related should be determined with great care so that other
causes of toxicity are not overlooked. In addition, stating that a drug
is possibly or probably the cause of toxicity implies that the drug will
not be used again in that patient, which in some cases deprives
individuals of useful medication for only circumstantial reasons.

My overall assessment of the four groups of cases is as follows:

1\. Acute liver failure or death in US cases.

There were 18 such cases that I reviewed. I considered five to be
possibly related, but all were confounded. One was a fatal case that I
consider to be unrelated to any hepatic injury (death was from a
perforated duodenal ulcer leading to septic shock from peritonitis). One
of these possibly related cases involved possible exacerbation of
underlying cirrhosis (which is a contraindication to the use of this
medication). The three other possibly related cases I felt were unlikely
to be related for various reasons including, one seemed much more likely
to be related to shock liver and one included exacerbation of underlying
a hepatitis B infection.

Four of these cases were considered unlikely to be related. I felt that
there was clear‑cut evidence of shock liver (ischemic hepatitis) in
three of these cases. The fourth was highly confounded and I did not
feel that leflunomide by itself could be labeled as causative. The
remaining nine cases contained inadequate information for me to assess
or draw any meaningful causality conclusions.

2\. Serious liver injury in US cases.

There were 38 of these reports that I reviewed. Seven were considered to
be possibly related, although two of these seven I felt were unlikely
though still possible. There were eight cases that explanations other
than leflunomide that I thought were more likely and therefore these
were listed as unlikely to be related to leflunomide. Two instances were
felt to be completely unrelated. There were 21 of the 38 cases that
contained insufficient or adequate information to make a proper
assessment. Even so, I felt that nine of these could be possibly
related, six were unlikely to be related, and another six simply had
inadequate information to assess.

Of the five cases that I considered possibly related with sufficient
information in this group, four of the five were receiving methotrexate
and several were also receiving other potential hepatotoxins including
sulindac. In one of the possibly related cases there was only minimal
evidence of hepatitic injury. Two of the five had a reasonable response
to withdrawing

Page Four

RE: Leflunomide Review

November 21, 2002

leflunomide constituting a positive dechallenge.

3\. Acute liver failure cases reported internationally.

There were 13 such cases and four were felt to be possibly related. Of
these four, one was unlikely as it involved shock and Lyell syndrome. Of
the other three possibly related cases, one had only minimal elevations
in liver enzymes, one occurred in the presence of the active hepatitis B
and the third involved a patient with underlying cirrhosis who had a
death that was not related.

There were three cases that I considered unlikely to be related and one
that was considered unrelated. There were five cases including one
undergoing a liver transplant that had insufficient information to fully
assess. The liver transplant case was listed as possibly related,
although the data were largely insufficient; three contained inadequate
information and the fifth case in this group was considered
insufficient, but unlikely to be related.

4\. Review of the hepatotoxicity from Australia.

There were 18 such reports, although 14 of these 18 contained
insufficient information. Of those, 11 had information that was
completely inadequate to assess and three others were felt to be
unlikely based on the limited information. There were three other cases
that I felt were also unlikely to be related, and only one case of the
18 did I list as possibly related, although this case included only an
incomplete dechallenge with very little follow‑up information provided.

I will provide a brief summary of each case of alleged acute liver
failure cases from the United States and my assessment. These cases
follow:

1\. Case Number 2001‑10085. This involved a 29‑year‑old female with
Still‑s disease who was treated for two to three months and developed an
AST of 1,574 and an ALT of 1,679 with a bilirubin of 31. She was taking
several medications including what was felt to be a toxic dose of
atovaquone, in addition to azithromycin, prednisone and OxyCodone. She
developed severe hypotension and was felt to possibly have herpetic
hepatitis. She required pressors to maintain her blood pressure and
these liver enzymes certainly could be explained by ischemic injury. The
issue of an overdose of atovaquone also entered into my assessment that
it was unlikely to be related to leflunomide. She died prior to
receiving a liver transplant.

2\. Case Number 2002‑20914. This involved a 51‑year‑old woman who took
leflunomide for four to five months for rheumatoid arthritis. Her ALT
and AST values rose to the 400‑600 range with an alkaline phosphatase
that was also elevated and a bilirubin of 17. She presented with rash,
fever, and pleuritic chest pain, along with jaundice and was diagnosed
with a left, lower lobe pneumonia. She was taking Celecoxib and
prednisone. A liver biopsy revealed inflammation and central lobular
necrosis consistent with a possible drug reaction. A bone

Page Five

RE: Leflunomide Review

November 21, 2002

marrow biopsy showed red cell aplasia. She developed a perforated
duodenal ulcer leading to peritonitis and septic shock with liver
enzymes that became markedly elevated. I listed this case as possibly
related, though highly confounded, but I did not feel that the death was
directly related to liver disease given the perforated ulcer.

3\. Case Number 2000‑11168. This involved a 53‑year‑old woman who took
leflunomide over the course of one month and then later on over a
three‑month period who was taking other medications including
Sulfasalazine, Cytotec, and prednisone. No liver enzymes were provided
and we are told that her liver failure resolved after a liver biopsy.
There was inadequate information to fully assess in this case.

4\. Case Number 1999‑20773. This involved a 55‑year‑old man who took
leflunomide for approximately two months with a history of ethanol use
who presents with ascites, jaundice and encephalopathy. Liver enzyme
values are not provided. He is on several other medications, including
allopurinol, a sulfamethoxazole trimethoprim, amitriptyline, lisinopril,
heparin, prednisone and verapamil. I felt that this case was a possible
exacerbation of underlying alcoholic cirrhosis, although it was
officially recorded as inadequate information.

5\. Case Number 1998‑13621. This involved a 55‑year‑old woman who, by my
reading, took leflunomide for approximately one week and presents with
deep jaundice, with a bilirubin of 22, an AST of 288 and an ALT of 63.
The alkaline phosphatase was markedly elevated at 766. There is a
history of ethanol use, along with several other medications including
Plaquenil, Naprosyn, Inderal, Synthroid, and Premarin. Although this was
a fatal case, there was inadequate information to assess. I listed it as
inadequate and unlikely in view of the information that I did have
because of the short latency period.

6\. Case Number 2000‑10080. This involved a 61‑year‑old man with
rheumatoid arthritis who received leflunomide for an unspecified amount
of time. He was on methotrexate and other medications, but had clear‑cut
evidence of significant hypotension and liver enzymes that were in
keeping with shock liver, with an AST of 4,600 and an LDH of 16,000 and
with a bilirubin that was essentially normal at 1.2. I listed this case
as unlikely to be related given the fact that this was probably shock
liver.

7\. Case Number 1999‑12102. This involved a 62‑year‑old man with
rheumatoid arthritis who took leflunomide for about a five‑month period
and had liver enzymes that were mildly elevated with an ALT of 84 and an
alkaline phosphatase of 131. He died following heart valve surgery, off
of leflunomide and probably developed a shock liver picture. I listed
this case as possibly related because of some improvement in his liver
enzymes on a lower dose of leflunomide, but overall felt it was unlikely
to be related.

8\. Case Number 2001‑23598. This involved a 66‑year‑old man with
rheumatoid arthritis who

Page Six

RE: Leflunomide Review

November 21, 2002

took leflunomide for about five months and presents with renal and
hepatic failure along with gangrenous digits. He was on methotrexate
among other medications and his treating physicians were concerned about
a vibrio infection. His outcome is not stated and this case was
insufficient to assess further.

9\. Case Number 2000‑22670. This involved a 66‑year‑old woman with
rheumatoid arthritis who presents with acute liver failure after
developing diarrhea and collapse with disseminated intravascular
coagulation and a Coombs positive anemia associated with respiratory
failure and a cardiopulmonary arrest. Her liver enzymes were in the
1,000\'s and this case was felt to be unlikely to be related to
leflunomide and much more likely to be related to shock liver secondary
to sepsis and other factors.

10\. Case Number 2002‑10502. This involved a 67‑year‑old woman with
rheumatoid arthritis who presents with jaundice two to three months
after starting leflunomide with a bilirubin of 9.5, but an AST of only
48 and an ALT of 27 with a mildly elevated alkaline phosphatase of 160.
She was taking piroxicam and had a history of taking methotrexate and
Imuran. She develops an acute pneumonic process and probably had
underlying cirrhosis, very possibly due to her diabetes leading to
non‑alcoholic steatohepatitis. I listed this case as possibly related as
an exacerbation of underlying cirrhosis, but more information would have
been nice to have.

11\. Case Number 143047. This involved a 25‑year‑old woman who was
taking leflunomide for an unspecified indication at an unspecified dose
and duration of therapy. We are only told that she had elevated‑liver
enzymes and mental status changes. She was, however, hepatitis C
positive and was receiving amiodarone among other drugs. I listed this
as inadequate to assess.

12\. Case Number 164596. This involved a 75‑year‑old woman with
rheumatoid arthritis and systemic lupus who undergoes cardioversion for
atrial fibrillation having been on leflunomide for about five months.
Although her liver enzymes are reported to have been normal previously,
in following the cardioversion the AST rises to 4,682 and the ALT to
2,202 and she has documented hypotension and a fatal outcome. I listed
this case as unlikely to be related since it appeared that she developed
shock liver following cardioversion.

13\. Case Number 128229. This involves a 76‑year‑old woman with
rheumatoid and osteoarthritis who develops acute liver failure after
about 12 months of leflunomide therapy, in addition to prednisone,
acetaminophen, and Percocet. She develops pneumonia and pancreatitis and
is known to have hypotension with an AST greater than 4,500 and an ALT
greater than 1,000. She was treated with an acetylcysteine. I rated this
case as insufficient information to fully assess, but I considered it
unlikely to be related to leflunomide and much more likely to be related
to either shock liver or possibly even acetaminophen injury.

14\. Case Number 2000‑10951. This involved a patient of unstated age
with rheumatoid arthritis

Page Seven

RE: Leflunomide Review

November 21, 2002

who develops a near‑syncopal episode three months after leflunomide is
started. Concomitant medications are not stated, but there is a history
of interstitial lung disease and hypotension is documented. This is a
fatal case, but I considered it insufficient information to assess. It
would be unlikely, if indeed, severe shock is demonstrated in the
medical record.

15\. Case Number 1999‑22130. This involves a patient of unstated age and
no stated indication of duration of therapy, where we are told that
there is an elevated bilirubin, alkaline phosphatase, and acute liver
failure in the setting of an underlying vasculitis. There was inadequate
information to assess in this case.

16\. Case Number 2002‑14805. This involves a 55‑year‑old man with
scleroderma who develops an AST and ALT in the 6,000 range, two to three
months after starting leflunomide. There is a history of alcohol use,
pulmonary fibrosis from his scleroderma, congestive failure and
cardiomyopathy with a markedly diminished ejection fraction of 10%. He
presented with a cough and hemoptysis when his liver enzymes were found
to be in the 200 range and leflunomide was discontinued. He was
described as improving off of leflunomide. I listed this case as
possibly related, although I felt it to be unlikely given the very high
nature of the transaminases later in the course of the hospitalization
which are more compatible with shock liver and/or severe hepatitic
congestion with shock.

17\. Case Number 169376. This involves a 55‑year‑old man with rheumatoid
arthritis and scleroderma taking leflunomide for approximately one year
with a history of alcohol use, who was admitted for pneumonia and sepsis
treated with antibiotics. There are no preadmission liver enzymes
available and we are told his ALT rises to 1,850 and his AST rises to
greater than 6,000. I listed this case as unlikely to be related and
more likely to be associated with shock liver given the height of the
AST and history of sepsis.

18\. Case Number 2002‑15633. This involved a 49‑year‑old man with
rheumatoid arthritis being treated with Infliximab, isoniazid,
prednisone and methotrexate which were discontinued after one month of
taking leflunomide. After approximately six weeks he is noted to have an
AST and ALT, both greater than 6,000. He is hepatitis B surface antigen
positive, although his viral load was undetectable. There was a concern
about reactivation of tuberculosis. A liver biopsy shows submassive
necrosis and ischemia changes of his gallbladder. He undergoes liver
transplant. While I listed this as possibly related, it was highly
confounded as the height of the liver enzymes are certainly out of the
range of idiosyncratic drug injury. The hepatitis B and his other
medications also make it extremely difficult to assess causality.

In conclusion, as I mentioned at the beginning of this report, the
quality of the spontaneous reports is often inadequate to fully assess
causality of leflunomide. Of the cases that I considered even possibly
related, all were confounded with other possible reasons in existence.
Therefore,

Page Eight

RE: Leflunomide Review

November 21, 2002

this database does not constitute sufficient concern about the
post‑marketing experience thus far on the basis of these reports.
Patients receiving leflunomide often have serious underlying disorders
related to their rheumatoid arthritis and other rheumatologic conditions
and are taking other potentially hepatotoxic medications. As a result, I
believe that the benefit/risk ratio of leflunomide is well maintained in
favor of the drug and I have no recommendations to revise or strengthen
the current package labeling. It already calls for baseline and monthly
liver enzyme monitoring with adequate information as to how to handle
elevations in ALT, if they occur, including a liver biopsy which should
be done. There are adequate stopping criteria. It is already listed that
the drug is not recommended for use in patients with preexisting
hepatitic disease since it has not been adequately studied in this
group. The use of cholestyramine, which was given in many of these cases
to help eliminate the drug, is also mentioned in the prescribing
information. There is still a question of whether there could be
additive hepatitic enzyme elevations in patients on methotrexate or
Sulfasalazine. In the clinical trials, elevations in the
aminotransferase values were seen in a frequency was often very similar
to the comparative drugs including methotrexate and Sulfasalazine. Most
of these enzyme elevations were less than twice ­normal and resolved
while treatment continued. Values later greater than three times normal
were infrequent, but did reverse when the dose was reduced or the drug
was discontinued. Recommendations that patients receive folic acid
supplements are based on an increased risk of liver enzyme elevations,
especially when receiving methotrexate.

It is clear that many of the individuals described in this data set were
either not following the prescribed liver enzyme monitoring schedule and
many had underlying liver disease. Nevertheless, I feel that the current
labeling is sufficient as written.

I will be happy to discuss my opinions and conclusions with you and
would be happy to review any additional information that becomes
available on•leflunomide potential hepatic injury.

> Sincerely
>
> James H. Lewis, M.D., F.A.C.P., F.A.C.G.
>
> Professor of Medicine
>
> Director of Hepatology

JHL:rmf

**Appendix 26:**

**Letter from Chairman of the Arthritis Advisory Committee**

> UNIVERSITY OF CALIFORNIA, SAN DIEGO UCSD
>
> \~tY pp
>
> y\~
>
> BERKELEY • DAVIS • IRVINE • LOS ANGELES • RIVERSIDE • SAN DIEGO • SAN
> FRANCISCO ?.ap SANTA BARBARA • SANTA CRUZ
>
> i
>
> r
>
> DIVISION OF RHEUMATOLOGY, ALLERGY AND IMMUNOLOGY GARY S. FIRESTEIN,
> M.D.
>
> SCHOOL OF MEDICINE *Professor of Medicine and Chief*
>
> 9500 Gilman Drive
>
> La Jolla, Ca 92093‑0656
>
> Tel: (858) 534‑2359
>
> Fax: (858)534‑2606
>
> June 10, 2002
>
> Food and Drug Administration
>
> Washington, D.C.
>
> To whom it may concern,
>
> A recent Citizen\'s Petition was submitted to the Department of Health
> and Human Services regarding the safety of leflunomide. The authors
> requested that this drug be withdrawn from the market due to its
> toxicity. In light of the importance of these issues and the need
> place the petition\'s comments into perspective, I would like to offer
> my unsolicited opinion on the matter. As the chairman of the FDA
> Arthritis Advisory Committee, a practicing physician/rheumatologist
> for over 20 years, a translational researcher on the pathogenesis of
> rheumatoid arthritis (RA), and the executive director of a clinical
> trial center (cit.ucsd.edu), I believe that I can provide some
> insights that will be useful to the FDA. I should note that the
> specific details of individual patient histories are not available to
> me, and that my conclusions are based on the information provided in
> the petition and my own familiarity with the field.
>
> The first issue that needs to be considered when evaluating the safety
> of any treatment for RA is that toxicity must be compared with the
> morbidity and mortality associated with active inflammatory synovitis.
> RA is not a benign condition, and many studies have demonstrated
> significantly higher mortality compared with controls (reviewed in Br
> J Rheumatol 1993;32 Suppl 1:28‑37). This is especially true for
> patients with significant limitations on their activities of daily
> living, evidence of active inflammatory disease (e.g., high CRP), or
> involvement of many joints. While the impact of treatment on mortality
> is not fully understood, recent information suggests that effective
> treatment can prolong life (Lancet 2002; 359:1173‑7). The mechanism of
> improved survival is not established, but is probably directly related
> to suppression of synovial and systemic inflammation. The impact of
> active RA on quality of life also needs to be considered when
> evaluating the risk/benefit ratio of a therapeutic agent. In other
> words, merely describing the potential toxicity of an agent in a
> vacuum is not only insufficient but can be misleading.
>
> ‑‑ Because of the serious long‑term consequences of active RA,
> rheumatologists have become increasing aggressive in its management.
> Immunosuppressive agents, cytokine antagonists, anti‑metabolites, and
> combination therapy have become mainstays. Instead of relying on the
> now outdated \"pyramid\" approach, treatment is initiated early and is
> accelerated rapidly in order to suppress inflammation (Am J Med.
> 2001;111:498‑500). Clinical trials using aggressive management, such
> as the **COBRA** trial and
>
> . . many others, have demonstrated improved outcomes compared with
> conservative approaches. In this context, the conservative and
> risk‑averse recommendations of the Citizen\'s Petition clearly fail to
> take into account two key elements of, modern management: 1) poorly
> controlled RA is a dangerous and morbid condition : and 2) aggressive
> treatment can alter the natural history of the disease.

address either the risk/benefit ratio or how the drug fits into the
constellation of agents available for use in RA. For instance, there are
a variety of assertions regarding the relative safety of methotrexate
compared with leflunomide. Perhaps most important is the putatively
lower rate of hepatotoxicity of the former. The comparative data are not
derived from controlled databases, but from voluntary physician
reporting. There is a well‑described bias introduced when comparing
toxicity of established agents to new agents that is clearly evident in
this analysis. There is also little information on the use of
concomitant drugs or the assiduousness of monitoring that could have
prevented serious adverse events. Therefore, it is impossible to draw a
conclusion regarding the relative rates of serious adverse events based
on this information. The comments related to the long half‑life of
leflunomide raise reasonable concerns; however, clinical practice has
supported the adequacy of cholestyramine in many cases where toxicity
has been observed. Based on the data provided by the petition, it would
be appropriate to recommend a study of the relative toxicities of
methotrexate and leflunomide in a more controlled setting. However,
withdrawing an effective agent like leflunomide based on this limited
information is both unjustified and counterproductive.

Perhaps the most important consideration in this discussion is how
leflunomide should be used compared with other anti‑rheumatic agents.
Even if one assumes that methotrexate is a safer agent, current clinical
practice guidelines indicate that leflunomide should be primarily
administered to patients that have an inadequate response to
methotrexate or have other contraindications. This makes comparisons of
the relative toxicities moot, since patients that receive leflunomide
would, by definition, have active disease and already received a
putatively safer agent. Since we already know that active RA is an
unacceptable alternative, then we are obliged to advance therapy using
agents that are either less effective, more toxic, or have other
undesirable attributes (e.g., expense or requirement for parenteral
administration).

The alternatives to leflunomide suggested in the petition under these
circumstances do not accurately represent state‑of‑the‑art clinical
practice. For instance, the use of \"Rest and nutrition\" as recommended
by the Merck Manual is part of the outdated pyramid approach that does
not recognize the long‑term consequences of active RA. Of the \"slow
acting\" agents recommended, two (gold and penicillamine) have not been
used by most rheumatologist for over a decade due lack of efficacy and
toxicity that far exceeds leflunomide. Hydroxychloroquine and especially
sulfasalazine are stated to be equivalent to methotrexate and
leflunomide. Sulfasalazine has been used extensively to treat patients
with RA, especially in Europe. However, clinical experience in the
United States does not support the assertion that it is as effective as
methotrexate or leflunomide. The reported equivalence with sulfasalazine
is likely due to inadequate dosing of comparators or type II errors due
to underpowered studies. Immunosuppressive agents, including
cyclosporine and azathioprine, have considerable toxicity and limited
efficacy. Reliance on a tertiary source like the Cochrane Library or the
Merck Manual as in the petition to determine the relative efficacy does
not necessarily provide the most up to date or useful information.

Overall, patients that have an inadequate response to methotrexate are
typically treated with a TNF inhibitor, leflunomide, or sulfasalazine
(either alone or, more commonly, in combination). The selection of a
particular agent depends on the patient\'s particular circumstances.
Moreover, the percentage that respond to each of these drugs is limited,
which means that several might be tried to determine the optimum
combination. For instance, only 15% of patients failing methotrexate
that receive the TNF inhibitors have an ACR70 response and only about
30% achieve an ACR50 response. The response rates for sulfasalazine are
likely lower. Therefore, most patients will require considerable
experimentation to find the best combination of drugs. Removing one of
these key agents from our armamentarium would be a major setback to
their management and is unjustified.

The final comments in the petition relate to the ineffectiveness of
changing labels or educating physicians. On the contrary, the
dissemination of information through the physician and patient

community is now rapid and has high penetration. For instance, new
guidelines to assess patients receiving TNF inhibitors for prior
tuberculosis exposure had a major impact on clinician practice. The
rapidity of processing new information is especially true for RA because
new anti‑rheumatic drugs are mainly prescribed by subspecialists. The
notion that rheumatologists do not modify their practice after
appropriate education is simply untrue and is likely based on outdated
information. The influence of patient advocacy also should not be
underestimated. In my own clinical practice, the majority of patients
receiving leflunomide specifically asked about the safety issue.

In conclusion, vigilance in post‑marketing safety is a major concern and
one must be ready to act if appropriate signals are observed. In the
case of leflunomide, one must be cognizant of the risks of uncontrolled
RA, the relative lack of efficacy for the alternatives to methotrexate,
and the contribution of inadequate monitoring or inappropriate
combination therapy to severe reactions. Leflunomide is an effective
agent in RA that decreases inflammation, improves quality of life, and
slows the progression of disease. The information provided by the
petition does raise questions that should be addressed with appropriate
studies, and the concomitant use with methotrexate should be carefully
addressed. However, withdrawing the agent is simply not justified with
the current information and would lead to increased morbidity (and
possibly mortality) in RA patients that do not respond to methotrexate.

Sincerely,

Gary S. Firestein, M.D.

Professor of **Medicine**

**UCSD** School of Medicine

Chairman

FDA Arthritis Advisory Committee

**Appendix 27**

![](media/image31.wmf){width="7.5in" height="8.121527777777779in"}

> *2. Possible (10):* Ten individuals have a history of alcohol abuse,
> underlying liver disease, and/or received methotrexate co‑therapy.
> These cases would meet criteria to be considered *\"Possibly\"*
> related to leflunomide.
>
> *3. Probable (5):* In five of the seventeen cases there were no
> apparent co‑morbidities or other drugs conventionally associated with
> severe hepatoxicity. However, it should be noted that four of these
> individuals were taking other medications, including celecoxib,
> hydroxychloroquine and amiodarone. In addition, one of these patients
> was administered leflunomide 100mg/ d for 87 days prior to the onset
> of liver failure. Using the Office of Drug Safety criteria, one cannot
> exclude a causal relationship to leflunomide, and, therefore, these
> cases would meet criteria as *\"Probably\"* related to leflunomide
> therapy.
>
> I have attached a table summarizing these cases and my assessment of
> drug related injury. I have also carefully reviewed the other US
> reported cases of serious liver injury and the Foreign reports of
> serious liver injury, acute liver failure or death. I have not
> provided specific assessments of drug‑related toxicity for these cases
> since there is generally less clinical detail provided, particularly
> with respect to co‑morbidities and other drug treatments. I can
> attempt to do so if you think it is important. In general, as in the
> seventeen cases described above, these clinical case histories are
> commonly complicated by polypharmacy and co‑morbidity. Therefore,
> given the presence of confounding variables, the lack of clinical
> detail, as well as the possibility that the reported events were due
> to chance alone, one cannot attribute the *\"Probable\"* cause of
> hepatic toxicity to leflunomide in the vast majority these reports.
>
> Finally, to place these reports in context, it should be noted that
> leflunomide can be highly effective in the treatment of difficult
> inflammatory arthritis and, for many individuals, is the mainstay of
> their DMARD therapy. As we know, it is difficult to properly assess
> the reported adverse events without information regarding the numbers
> of individuals treated with leflunomide worldwide, including an
> estimate of the number of patient/years of exposure. Such assessment
> must therefore be considered in the context of the overall
> risk‑benefit of leflunomide treatment, which based upon the clinical
> information published to date, does not appear to differ from other
> DMARD treatments.
>
> I appreciate the opportunity to review the case reports. Please let me
> know if you would like additional information or clarification.
>
> Sincerely,
>
> Steven B. Abramson, M.D.

cc: Dr. L.Simon

**Appendix 28**

**Submitted report**

**Bi-cohort study of the risks of leflunomide and other DMARDs in
rheumatoid arthritis**