**Appendix 1 Review of** **Zoledronate Safety in Prostate Cancer, Study
039**

**Study \# CGP 42446-03-039**: "A randomized, double-blind,
placebo-controlled, multicenter, comparative, safety and efficacy study
of intravenous zoledronate (4 and 8 mg) in prostate cancer patients with
metastatic bone lesions receiving antineoplastic therapy."

This is a multicenter (136 sites), international study from June 22,
1998, until January 26, 2001. The study duration was 96 weeks, of which
Phase 1, the 60-week Safety and Efficacy portion, is the subject of this
review. Phase 2 was a 36-week Extension phase.

The study population consists of men with rising serum prostate specific
antigen (PSA) while on hormonal therapy for prostate cancer metastatic
to bone. No prior chemotherapy was allowed, although patients could
receive antineoplastic therapy concomitant with the study, which could
be hormonal or chemotherapy. Three sequentially rising PSA's were
required, within 8 weeks of visit 1, and patients had to demonstrate
castrate levels of testosterone. The creatinine was to be
[\<]{.underline} 3. Corrected serum calcium was required to be in the
range of 8.0-11.6 mg/dL. Patients were stratified according to the
presence or absence of metastatic disease at time of initial diagnosis.

Patients were randomized to receive zoledronate 4 mg or 8 mg or placebo
by intravenous (i.v.) infusion q 3 weeks for 24 months. Initially
zoledronate or placebo was given as a 5 minute i.v. infusion in 50 ml
every 3 weeks. After Amendment 3, on June 24, 1999, the infusion time
and volume were increased to 15 minutes and 100 ml, respectively. This
was instituted in response to SAEs of renal failure in 3 patients
receiving 8 mg dosing of zoledronate. By recommendation of the Data
Safety Monitoring Board (DSMB) and the Renal Advisory Board (RAB),
Amendment 4 was instituted on June 7, 2000. This required that all
patients who received zoledronate would receive only 4 mg. Serum
creatinine would be measured before each dose, and zoledronate held for
worsening of creatinine, until the level was within 10% of the baseline
creatinine. (Prior to the amendment, chemistries were required only at 3
weeks, 3months and then at 6 week intervals.)

The primary efficacy analysis was at the end of the study (month 15).
The main efficacy endpoint was the "proportion of patients having at
least one skeletal related event (SRE), which were defined as
"pathologic bone fractures, spinal cord compression, surgery to bone,
radiation therapy to bone and change in antineoplastic therapy to treat
bone pain." Hypercalcemia (HCM) was not included as an SRE.

# Applicant assessment and analysis of safety

Adverse events, serious adverse events, laboratory studies and survival
data were the main safety variables. Baseline and end of study physical
examination, EKG, and laboratory evaluations were done, including
hematology, blood chemistry, urine. Interim physical examination, vital
signs, assessment for adverse events and laboratory studies were
repeated every 3 weeks, except urine studies were approximately every 3
months. Serum creatinine was measured prior to each dose of study drug
per amendment 4 (June 7, 2000). The time to discontinuation of study
drug and duration of survival were assessed.

"For laboratory and adverse event analysis, data were cut at the end of
the study drug period," either the end of phase 1 or the last date of
study medication plus 28 days. For time to death and renal deterioration
analysis, all available data was included, up to the date of data base
lock For other safety parameters, the last visit date was used.

Renal toxicity was assessed by the number of patients experiencing "a
renal adverse event using selected terms and the number of patients who
met the predefined criteria of renal function deterioration."
Kaplan-Meier curves were used to define the time course of renal
function deterioration.

# Study population

There were 643 patients randomized to the following groups:

Zometa 4 mg \# 214

Zometa 8/4 mg \# 222

Placebo \# 208

"The safety evaluable population included all patients who were
randomized and received study drug." The number of patients in each arm
is shown in applicant's table 7-2. Three of the randomized patients did
not receive study drug and were not included in the safety analysis. One
patient was randomized to the 4 mg group and 2 patients were randomized
to the 8/4 mg group. One patient was randomized to the 8/4 mg group but
actually received 4 mg for all treatments. This patient (USA/1891/11002)
was included in the 8/4 mg group for efficacy, but was included in the 4
mg dose for safety analysis.

Applicant Table 7-2

  ----------------- ----------------- ------------------- -----------------
  **Table 7-2.**    **Number (%) of                       
                    patients in                           
                    analysis                              
                    populations by                        
                    treatment group**                     

                    **Zol 4 mg**      **Zol 8/4 mg**      **Placebo**

  **Populations**                                         

  Randomized        214 ( 100)        221 ( 100)          208 ( 100)

  ITT population    214 ( 100)        221 ( 100)          208 ( 100)

  Safety evaluable  214               218                 208
  population                                              

  Source: Post-text                                       
  table 7.1-1.                                            
  ----------------- ----------------- ------------------- -----------------

***Reviewer's Note**: From data provided by the applicant, for patients
assigned to the 8/4 mg group, 247 of 2400 administrations of*
*zoledronate were actually 4 mg rather than 8 mg, or approximately 10%.*

The following is an abbreviated, composite version of the applicant's
table 7-3, "Demographic summary by treatment group" and table 7-5,
"Baseline disease specific variable by treatment":

Reviewer table 1

**Zol 4 mg Zol 8/4 mg Placebo**

Age (years)

N 214 218 208 Mean ± SD 71.8±7.91 71.2±8.04 72.2±7.89 Median 72.0 72.0
73.0 Min-max 45-90 43-90 37-90

Age

≤ 60 19 ( 8.9) 19 ( 8.7) 15 ( 7.2) \>60 195 ( 91.1) 199 ( 91.3) 193 (
92.8)

Serum creatinine

Normal (\< 1.4 mg/dL) 173 ( 80.8%) 168 ( 77.1%) 170 (81.7%) Abnormal (≥
1.4 mg/dL) 41 ( 19.2) 47 ( 21.6) 33 (15.9) Missing 0 ( 0.0) 3 ( 1.4) 5 (
2.4)

Patient factors which might increase susceptibility to renal toxicity of
zoledronate are baseline renal function, age (which may relate to renal
function reserve), and exposure to other nephrotoxic therapy. The above
tables suggest similar age and baseline serum creatinine for the
treatment groups. The applicant states that concomitant medication was
similar for all treatment groups, and this seem to be the case
(Post-text tables 8.2-1,2,3,4), with patients experiencing little
exposure to potentially nephrotoxic drugs.

**Overall Exposure**

The applicant's table 8-1 demonstrates the overall exposure to study
drug by treatment group for the safety evaluable patients.

Applicant table 8-1

For patients who did not present with metastatic disease at diagnosis,
![](media/image1.png){width="5.998611111111111in"
height="3.422222222222222in"}the exposure (in months) to study drug is
similar, particularly for the 4 mg and placebo treatment groups. For
patients who presented at diagnosis with metastatic disease, the
duration of exposure was greater for zoledronate 4 mg than for placebo
or zoledronate 8/4 mg groups. The mean and median exposure was greater
for the 4 mg group when the exposure for both strata was totaled.

For patients who did not present with metastatic disease at diagnosis,
the exposure (in months) to study drug is similar, particularly for the
4 mg and placebo treatment groups. For patients who presented at
diagnosis with metastatic disease, the duration of exposure was greater
for zoledronate 4 mg than for placebo or zoledronate 8/4 mg groups. The
mean and median duration exposure was greater for the 4 mg group when
the exposure for both strata was totaled.

The following table, applicant table 8-2, demonstrates exposure to the
study drug by treatment group, separating pre and post 15-minute
infusion amendment patients. Data includes core (Phase 1) and extension
(Phase 2) treatment periods. "The distribution of duration from
randomization was similar before and after the amendment."

Applicant table 8-2

![](media/image2.png){width="5.995138888888889in"
height="5.3180555555555555in"}

# Overall incidence and severity of adverse events

Clincal study reports used the IMN dictionary to code adverse events but
the data for Study 039 is presented using the MedDRA dictionary. Adverse
events were mapped from IMN preferred terms to the corresponding MedDRA
terms, prior to pooling of data for analysis.

Almost all patients in each study group experienced at least one adverse
event. The applicant's Table 10-2 lists the frequency of AEs with an
incidence of at least 15% in each treatment group. Bone pain, nausea,
constipation, and fatigue were noted most often. Fatigue, anemia,
myalgia, pyrexia, and lower limb edema were more frequent in patients
receiving zoledronate versus placebo, but there was no apparent
correlation with dose. Nausea, anorexia and vomiting were more common in
the zoledronate 8/4 mg group. Bone pain was less in the 4 mg group.
Dizziness was higher in the 4 mg group (17.8%) compared with the 8/4 mg
group (10.1%) and placebo (11.5%). The significance of these differences
is uncertain, and there may be no direct relationship with treatment.

Applicant table 10-2

![](media/image3.png){width="5.802083333333333in"
height="4.395833333333333in"}.

Adverse events were thought to be study drug-related in 41.6%, 50.5% and
21.6% (Post-text table 10.1-5).

The incidence of grade 4 events was similar, 27.1%, 32.1%, and 25.0% for
the 4 mg, 8/4 mg and placebo groups, respectively (Post-text table
10.1-4, volume 109). Reviewer Table 2. Selected (more frequent) grade 4
adverse events by body system and treatment group:

+--------------+-------------+-------------+-------------+------------+
| Body system  | Preferred   | Zoledr 4 mg | Zoledr 8/4  | Placebo N  |
|              | term        |             | mg N (%)    | (%)        |
|              |             | N (%)       |             |            |
+--------------+-------------+-------------+-------------+------------+
| Any          | Total       | 58 (27.1)   | 70 (32.1)   | 52 (25.0)  |
+--------------+-------------+-------------+-------------+------------+
| Blood and    | Total       | 8 (3.7)     | 9 (4.1)     | 5 (2.4)    |
| lymph        |             |             |             |            |
+--------------+-------------+-------------+-------------+------------+
|              | Anemia      | 6 (2.8)     | 6(2.8)      | 2 (1.0)    |
+--------------+-------------+-------------+-------------+------------+
| Cardiac      | Total       | 10 (4.7)    | 10 (4.6)    | 8 (3.8)    |
+--------------+-------------+-------------+-------------+------------+
| GI           | Total       | 8 (3.7)     | 3 (1.4)     | 6 (2.9)    |
+--------------+-------------+-------------+-------------+------------+
| Metab and    | Total       | 7 (3.3)     | 13 (6.0)    | 7 (3.4)    |
| Nutrit       |             |             |             |            |
+--------------+-------------+-------------+-------------+------------+
|              | Dehydration | 4 (1.9)     | 2 (0.9)     | 2 (1.0)    |
+--------------+-------------+-------------+-------------+------------+
| Mus          | Bone pain   | 3 (1.4)     | 4 (1.8)     | 5 (2.4)    |
| culoskeletal |             |             |             |            |
+--------------+-------------+-------------+-------------+------------+
| Neoplasms    | Aggravated  | 10 (4.7)    | 14 (6.4)    | 6 (2.9)    |
|              | mal         |             |             |            |
+--------------+-------------+-------------+-------------+------------+
| Nervous      | Total       | 6 (2.8)     | 7 (3.2)     | 7 (3.4)    |
| system       |             |             |             |            |
+--------------+-------------+-------------+-------------+------------+
| Renal,       | Total       | 7 (3.3)     | 15 (6.9)    | 7 (3.4)    |
| urinary      |             |             |             |            |
+--------------+-------------+-------------+-------------+------------+
|              | RF Acute    | 6 (2.8)     | 6 (2.8)     | 1 (0.5)    |
+--------------+-------------+-------------+-------------+------------+

There is no clear signal suggesting a relation of grade 4 events to
treatment arm, except for renal adverse events.

# Renal adverse events 

A Renal Advisory Board (RAB) was established in November of 1999 to
monitor the renal safety of zoledronate, because of concerns about renal
dysfunction associated with treatment. Amendment 3 had been instituted
June 24, 1999, in response to SAEs of renal failure in 3 patients
receiving 8 mg zoledronate. This changed administration volume from 50
ml to 100 ml and administration time from 5 minutes to 15 minutes. The
pre-amendment data (applicant's table 10-4), suggests a possible
dose-related renal toxicity for overall events, "renal failure acute," "
renal impairment NOS," and "blood creatinine increased." Also of
interest is the marked increase in "urinary retention" in the
zoledronate 8/4 group, which could have exaggerated the apparent
renal-toxic effect of study drug. One would anticipate that urinary
retention is disease-, rather than drug-related.

Reviewer table 3.

Selected renal AEs by preferred term and treatment group for pre
15-minute infusion amendment patients

  ----------------------- ------------------ --------------- -------------
                          Zoledr 4 mg        Zoledr 8/4 mg   Placebo

                          N (%)              N (%)           N (%)

  Total \# patients       117                125             124

  Total \# with renal AE  36 (30.8)          54 (43.2)       33 (26.6)

  RF, Acute               6 (5.1)            9 (7.2)         4 (3.2)

  Renal impair, NOS       6 (5.1)            8 (6.4)         3 (2.4)

  Urinary retention       5 (4.3)            18 (14.4)       11 (8.9)

  Blood creatinine        4 (3.4)            6 (4.8)         0
  increas                                                    
  ----------------------- ------------------ --------------- -------------

The following table demonstrates renal AEs following amendment 3. The
incidence of "Acute renal failure" is still higher for the zoledronate
patients compared with placebo. However, "renal failure NOS" and
"increased creatinine" are no longer reported in the 4 mg group. "Renal
impairment NOS" is highest in the 4 mg group, with the 8/4 mg and
placebo groups being similar.

Applicant table 10-5

![](media/image4.png){width="5.998611111111111in"
height="5.610416666666667in"}

***Reviewer comment:** Amendment 3 may have resulted in some slight
improvement in the renal toxicity profile, but the important analysis of
safety is for patients who were randomized following amendment 3 and
amendment 4 (see below). Also note that the number of patients with
urinary retention is less disproportionately distributed to the 8/4 mg
group compared with the pre-third amendment patients.*

The following table (applicant table 10-7) summarizes events which the
applicant suggests are associated with bisphosphonates as a class.
Electrolyte abnormalities are increased in zoledronate patients compared
with placebo, possibly in a dose-dependant way.

Applicant table 10-7

![](media/image5.png){width="6.0in" height="2.7291666666666665in"}
Deaths and other serious and other significant adverse events:

In Section 3.5.3.2 of the protocol, the applicant defines a serious
adverse event (SAE) as an event which:

1.  Is fatal or life threatening.

2.  Requires or prolongs hospitalization

3.  Is significantly or persistently disabling or incapacitating

4.  Constitutes a congenital anomaly or a birth defect

5.  Encompasses any other clinically significant event

Item 5 is not clearly explained. "Clinically significant AEs" are
defined as events which were not SAEs, but "resulted in withdrawal of
study drug or were considered to be clinically important and required
concomitant therapy."

Applicant table 10-8 lists "patients who died, had other serious or
clinically significant AEs or discontinued therapy because of them."

Applicant table 10-8

![](media/image6.png){width="5.666666666666667in"
height="2.8541666666666665in"}

SAEs occurred in fewer of the zoledronate 4mg patients (49.5%), compared
with 8/4 (58.7%) or placebo groups (56.3%). However, deaths were
greatest in the zoledronate 8/4 mg group, followed by placebo.
Similarly, discontinuation due to SAEs was greatest in the 8/4 mg group.

SAEs

Applicant's Table 10-9 shows the body systems most often involved in
SAEs, with greater than 10% incidence in any treatment group.

Applicant table 10-9

![](media/image7.png){width="5.998611111111111in"
height="4.506944444444445in"}

The incidence of SAEs for zoledronate 4 mg seems favorable when compared
to placebo, except for the category of "metabolism and nutrition". In
contrast, the incidence of SAEs was higher for zoledronate 8/4 compared
with both the 4 mg and placebo groups, for "blood and lymphatic" and
"renal and urinary". "Anemia NOS" occurred in 5.1% of the zoledronate 4
mg group, 8.3% of the 8/4 mg group, and 3.8% of placebo patients. It
should be noted that skeletal related events (SRE) were not included as
SAEs.

Applicant's post-text table 10.2-1 (volume 109) summarizes SAEs,
regardless of cause, by body system, preferred term and treatment group.
Reviewer's Table 4 is abstracted from this table, and shows SAEs
occurring in at least 5% of patients in any treatment group. These
events include anemia, nausea, vomiting, weakness, dehydration, bone
pain, malignant neoplasm aggravated, acute renal failure, and urinary
retention.

Reviewer Table 4

SAE's occurring in at least 5% of patients in any treatment group

  ------------------------ --------------- ----------------- -------------
  Preferred term           Zoled 4 mg N    Zoled 8/4 mg N    Placebo N (%)
                           (%)             (%)               

  Anemia NOS               11 (5.1)        18 (8.3)          8 (3.8)

  Nausea                   13 (6.1)        13 (6.0)          7 (3.4)

  Vomiting NOS             12 (5.6)        11 (5.0)          7 (3.4)

  Weakness                 14 (6.5)        7 (3.2)           7 (3.4)

  Dehydration              16 (7.5)        9 (4.1)           7 (3.4)

  Bone pain                11 (5.1)        21 (9.6)          25(12.0)

  Malignant neopl.         13 (6.1)        20 (9.2)          13 (6.3)
  aggravated                                                 

  Acute renal failure      10 (4.7)        12 (5.5)          3 (1.4)

  Urinary retention        3 (1.4)         14 (6.4)          9 (4.3)
  ------------------------ --------------- ----------------- -------------

*Reviewer comment: The incidence of anemia in the* *zoledronate 8/4
population seems significant compared with the placebo population,
although unexplained. The distribution of bone pain for the 3 treatment
groups does [not]{.underline} suggest a dose-dependant benefit of the
study drug for this parameter. Acute renal failure is comparably
increased in both* *zoledronate groups compared with placebo.*

Deaths

One hundred fourteen patients died during the study or within 28 days of
the last dose of study drug. The incidence of deaths was similar for
placebo (16.8%) and zoledronate 4 mg (14.5%), but there was a higher per
cent deaths in the zoledronate 8/4 mg group (22%). The most frequent
cause of death was "aggravated malignant neoplasm."

Post-text table 10.2-3 lists the cause of death in the 97 patients who
died before completing the study, who discontinued because of death. Of
these patients, there were

10 (4.7%) in the 4 mg group, 16 (7.3%) in the 8/4 mg group and 11 (5.3%)
in the placebo group. Of the 4 patients (1.8%) who died during the study
due to urinary or renal disorders, all were in the zoledronate 8/4 mg
group, with 2 deaths due to acute renal failure, 1 death due to "renal
failure NOS" and 1 death due to hematuria.

When deaths were analyzed by stratum (patients without or with
metastases), those with metastases at diagnosis had a shorter time to
death if they were in the zoledronate 8/4 mg group compared with
zoledronate 4 mg. In patients with no metastases at diagnosis, the time
to death was similar in the 3 treatment groups. This data appears in
post-text table 10.2-7. For the overall group, the median survival in
days was 464 for placebo, 546 for the 4 mg group, and 407 for the 8/4 mg
group.

Treatment discontinuations

Applicant table 10-11 lists the number of patients discontinued for
adverse events by body system.

Applicant table 10-11

![](media/image8.png){width="4.885416666666667in"
height="4.572916666666667in"}The discontinuations for "General
disorders" were predominantly for nonspecific symptoms such as weakness
and fatigue and seem unlikely to be study-drug related. The
discontinuations for "Renal and urinary disorders" are of concern.
Reviewer's Table 5 (from post-text table 10.2-4) shows selected renal
AEs associated with discontinuation.

Reviewer table 5.

Number (%) of patients discontinued for (selected) renal AEs by
preferred terms and treatment group.

+----------------------+----------------+---------------+------------+
| Preferred term       | Zoledr 4mg,    | Zoledr 8/4mg, | Placebo    |
|                      | N=214          | N=218, N (%)  | N=208, N   |
|                      |                |               | (%)        |
|                      | N (%)          |               |            |
+----------------------+----------------+---------------+------------+
| *Total renal and     | 11 (5.1)       | 12 (5.5)      | 4 (1.9)    |
| urinary*             |                |               |            |
+----------------------+----------------+---------------+------------+
| Renal impairment NOS | 6 (2.8)        | 4 (1.8)       | 0          |
+----------------------+----------------+---------------+------------+
| Renal failure acute  | 3 (1.4)        | 5 (2.3)       | 1 (0.5)    |
+----------------------+----------------+---------------+------------+
| Oliguria             | 1 (0.5)        | 0             | 0          |
+----------------------+----------------+---------------+------------+
| Urinary retention    | 1 (0.5)        | 2 (0.9)       | 2 (1.0)    |
+----------------------+----------------+---------------+------------+

Laboratory parameters

The treatment groups were similar when hematology tests were analyzed by
number of patients reaching selected "notable" values of neutrophil
count \<0.5 x 10^9^, platelets \< 25 x 10^9^, and hemoglobin \< 6.5 g/dL
(applicant's table 10-13). However, applicant's table 10-14 demonstrates
that more patients in the zoledronate arms had a greater than 25%
decrease in hemoglobin, compared with placebo, possible in a
dose-dependant fashion.

Applicant table 10-12

![](media/image9.png){width="4.833333333333333in" height="1.21875in"}

The following table shows grade 3 or 4 hematologic toxicity for the
treatment groups.

Applicant table 10-15

![](media/image10.png){width="4.760416666666667in"
height="4.052083333333333in"}Grade 3 hemoglobin values were more than
twice as common in the zoledronate 8/4 mg group than either the 4 mg or
placebo groups. The significance of this is uncertain, but it could
relate to the higher incidence of renal dysfunction in the higher dose
zoledronate group.

When patients were analyzed for notable biochemistry values (other than
creatinine), there was almost twice the incidence in the zoledronate
groups of hypermagnesemia \> 3.0 (4 mg =6.4 %; 4/8 mg = 5.8%) compared
with placebo (3%). In the zoledronate groups, there was more
hypophosphatemia, and only a slight increase in hypokalemia and
hyponatremia compared with placebo. Applicant table 10-19 shows grade 3
or 4 chemistry abnormalities by treatment group, demonstrating excess
grade 3 hypermagnesemia, hypophosphatemia, and hypokalemia for the
zoledronate groups compared with placebo.

Applicant table 10-19

# ![](media/image11.png){width="4.791666666666667in" height="6.75in"}Serum creatinine and renal function deterioration

Baseline serum creatinine was considered normal if \<1.4 mg/dL and
abnormal if [\>]{.underline} 1.4 mg/dL. Renal function deterioration was
defined as any of the following:

-   Normal baseline with change from baseline [\>]{.underline} 0.5 mg/dL

-   Abnormal baseline with change from baseline [\>]{.underline} 1.0
    mg/dL

-   Post-baseline value [\>]{.underline} 2 time the baseline value.

Subsequent to amendment 3 (15 minute infusion), renal function
deterioration as defined in applicant table 10-16, was 17.4% for
zoledronate 4 mg, 25.3 % for zoledronate 25.3% and 11.5 % for placebo.

Applicant table 10-16

![](media/image12.png){width="5.995833333333334in"
height="3.904861111111111in"}

No patient experienced grade 4 creatinine elevation (\> 6xULN). Grade 3
(\>3xULN) creatinine values occurred in 5 zoledronate 4 mg patients and
in 2 of the 8/4 mg group following amendment 3, but none in the placebo
group. (Prior to amendment 3, 2 placebo patients had grade 3 elevation
of creatinine).

The incidence of renal function deterioration was increased in the
zoledronate treatment groups for patients with a baseline serum
creatinine of [\>]{.underline} 1.4, compared with those with a normal
baseline creatinine. The incidence of deterioration decreased after
amendment 3, but still was higher in the zoledronate groups. The
following table is abstracted from applicant table 10-21.

Reviewer table 6

Patients who experienced renal function deterioration by baseline serum
creatinine (15-minute infusion)

+-----------------------+----------------+---------------+-------------+
|                       | Zoledr 4 mg N  | Zoledr 8/4 mg | Placebo     |
|                       | (%)            | N (%)         |             |
|                       |                |               | N (%)       |
+-----------------------+----------------+---------------+-------------+
| Patients with normal  | 82             | 68            | 68          |
| baseline creatinine   |                |               |             |
+-----------------------+----------------+---------------+-------------+
| \- - - with           | 10 (12.2)      | 14 (20.6)     | 7 (10.3)    |
| deterioration         |                |               |             |
+-----------------------+----------------+---------------+-------------+
| Patients with         | 10             | 19            | 20          |
| abnormal baseline     |                |               |             |
| creatinine            |                |               |             |
+-----------------------+----------------+---------------+-------------+
| \- - - with           | 4 (40.0)       | 4 (21.1)      | 2 (20.0)    |
| deterioration         |                |               |             |
+-----------------------+----------------+---------------+-------------+
| Total \# patients at  | 92             | 87            | 78          |
| baseline              |                |               |             |
+-----------------------+----------------+---------------+-------------+
| \- - - with           | 14 (15.2)      | 18 (20.7)     | 9 (11.5)    |
| deterioration         |                |               |             |
+-----------------------+----------------+---------------+-------------+

When time to renal function deterioration was analyzed by Cox regression
for patients treated post amendment 3, there were no statistically
significant differences in pairwise comparisons between any treatment
groups. The Kaplan-Meier curves of first renal function deterioration by
treatment group are similar for patients treated by 15-minute infusion
(Applicant's figure 10.2). The risk ratio between zoledronate 4 mg and
placebo was 1.066 for patients randomized after amendment 3. (The risk
ratio between zoledronate 8/4 mg and placebo was 1.764.) The differences
were not statistically significant.

Applicant figure 10.2

![](media/image13.png){width="5.996527777777778in"
height="5.427083333333333in"}

# Urinalysis

The percentage of patients with elevated urine protein ([\>]{.underline}
2+) post-baseline was greater in the zoledronate treatment groups than
in the placebo group (Post-text table 10.3-2).

# Vital signs 

More patients in the zoledronate groups had [\>]{.underline} 10% weight
decrease. In the 4mg group, the incidence was 30.5 %. 32.7 in the 8/4 mg
group, and 19.4% in the placebo group.

# ECGs 

For those patients who had follow-up ECGs, there were more abnormalities
compared with baseline in all study groups

# Special safety topics-PSA 

For patients who had serum PSA measured within 30 days of disease
progression, changes in PSA were similar for the zoledronate 4 mg and
placebo groups. The applicant suggests that zoledronate 4 mg has "no
effect on the secretion, clearance, or measurement of PSA". This seems a
reasonable interpretation of the data.

# Reviewer comment and conclusions 

# 

Increased risk of renal function deterioration is the only significant
safety issue for zoledronate in this and related clinical trials of
long-term treatment for patients with metastatic malignancy to bone.
This toxicity was dose and time-related.

Adverse events, seen with other bisphosphonates, and possibly class
effects of bisphosphonates, were reported more frequently with
zoledronate than placebo. These include fever, arthralgias/myalgias, and
electrolyte abnormalities, but do not present a safety issue.

Anemia was slightly more common in the zoledronate groups (approximately
27%) compared with placebo (17.8%). This is of uncertain, if any,
significance. In the zoledronate groups, there was an excess of
hypermagnesemia and hypophosphatemia compared with placebo.

Subsequent to the occurrence of acute renal failure in a total of 3
patients receiving zoledronate 8 mg in this and related trials for
disease metastatic to bone, a renal advisory board (RAB) of
nephrologists was convened and several amendments to the protocol were
made. The incidence of renal function deterioration was decreased by
prolonging the infusion time from 5 to 15 minutes (amendment 3).
Amendment 4 further improved the safety profile by eliminating the 8 mg
dose. The safety of the 4 mg dose was improved by requiring assessment
of serum creatinine before each dose. Zoledronate was held for renal
deterioration, as defined in the amended protocol. Therapy was not
reinstituted until creatinine returned to within 10% of the baseline
value.

Following amendment 3, the overall incidence of renal related AEs was
comparable for zoledronate 4 mg (30.9%) and placebo (31.0%). However,
the incidence of "renal impairment NOS" was 7.2% for zoledronate 4 mg,
3.2% for zoledronate 8/4 mg and 3.6% for placebo. The incidence of renal
failure acute" was 5.2% for zoledronate 4 mg, 4.3% for zoledronate 8/4
mg, and 0 for placebo. "Blood creatinine increased was reported at 0 for
zoledronate 4 mg and 3.6% for placebo (4.3% for zoledronate 8/4 mg).

The incidence of renal function deterioration was higher in the
zoledronate 4 mg group (15.2%) and zoledronate 8m (20.7%) compared with
placebo (11.5%), even following amendment 3.

Cox regression analysis of time to renal function deterioration showed
no difference between the groups. Kaplan-Meier curves of first renal
function deterioration by treatment group showed no difference for
patients treated by 15-minute infusion. The risk ratio between
zoledronate 4 mg and placebo was 1.066 for these patients, but the
difference was not statistically significant.

Reviewer conclusion: Zoledronate 4 mg i.v. over 15 minutes every 3 weeks
has an acceptable risk profile. The risk of renal deterioration with
zoledronate is greater than placebo, but acceptable with clinical
monitoring of renal function before each dose. The risk of renal
toxicity increases with duration of therapy. Caution is indicated for
patients with elevated baseline creatinine, particularly since the study
population excluded patients with creatinine \> 3 and the drug is
excreted unchanged by the kidneys. This study population (prostate
cancer) did not have extensive concomitant exposure to other potentially
renal toxic drugs. As the treatment population is expanded, it will be
necessary to monitor for possible enhancement of renal toxicity in
patients who are treated concomitantly with drugs of known nephrotoxic
potential.

**Appendix 2 Review of** **Zoledronate Safety in Solid Tumors, Study
011**

**Study \# CGP 42446-03-011:** "A randomized, double-blind,
placebo-controlled, multicenter trial to evaluate the safety and
efficacy of zoledronate (4 and 8 mg) administered intravenously as an
adjuvant to anticancer therapy to patients with any cancer with bone
metastases other than breast cancer, multiple myeloma or prostate
cancer."

This is a multicenter, international study (141 sites, in US 72, others
in Europe, Australia/New Zealand). The first patient enrolled 27 August
1998 and the last patient completed therapy 30 January 2001. The study
population consisted of adults with solid tumors other than breast or
prostate cancer. Patients could receive antineoplastic chemotherapy.
Patients were to have objective evidence of at least 1 site of
metastatic disease to bone. ECOG performance status was to be 0.1, or 2.
If ECOG 2, patients needed to have been diagnosed within 6 weeks of the
screening visit.

Criteria for exclusion included creatinine \>3. Corrected calcium \< 8
or [\>]{.underline} 12 at visit 1 was an indication for exclusion.

From December 1998 to May 1999 there were 3 renal failure SAEs in
patients receiving zoledronate 8mg, manifested by progressively rising
serum creatinine. "These 3 cases represent approximately 1% of the
patients who have been exposed to the 8 mg dose in the zoledronate
program." This occurred in 1 patient each of a Phase II myeloma study
(cycle #11), protocol 010 (diagnosis breast cancer, cycle #1), and
protocol 039 (prostate cancer, after cycle #7). The patients were,
respectively, ages 75, 80, and 71, with baseline creatinines of 1.6,
1.9, and 1.4. These events led to Amendment 3 on 25 June 1999 and
Amendment 5 on 7 June 2000.

The duration of therapy was 9 months (36 weeks). Patients were
randomized to receive zoledronate 4 mg or 8 mg or placebo i.v. over 5
minutes q 3 weeks. After amendment 3, the infusion duration was
prolonged to 15 minutes. After amendment 5, all zoledronate patients
received 4 mg per dose. Serum creatinine was to be evaluated before each
dose, and treatment held for deterioration of creatinine, as defined in
the amendment, until the level was within 10% of the baseline
creatinine.

# Applicant assessment and analysis of safety 

Adverse events, serious adverse events, laboratory studies, and survival
data were the main safety variables. Baseline and end of study (week 36)
physical examination, EKG, and laboratory evaluations were done,
including hematology, blood chemistries, urine chemistries and
urinalysis. Interim physical examination, vital signs, assessment for
adverse events, and laboratory studies were repeated every 3 weeks,
except urine studies were approximately every 3 months. After amendment
5, the results of creatinine levels were required prior to each dose of
zoledronate, so that the drug could be held for renal deterioration.

Safety analysis was based on the type and frequency of adverse events
and the laboratory values outside of pre-determined ranges. The data
were tabulated.

The effect on renal function was analyzed according to the number of
patients who experienced renal adverse events using selected terms
suggested by the renal advisory board (RAB) and the number of patients
who met pre-defined criteria of renal deterioration. Kaplan-Meier curves
were used to describe the time course of renal function deterioration.

"For laboratory and adverse event analysis, data were cut at the end of
the study drug period," either at the end of the core study phase or the
last date of study medication plus 28 days. For time to death and renal
deterioration analysis, all available data was included, up to the date
of the data base lock. For other safety parameters, the last visit date
was used.

# Study population

Seven hundred seventy-three patients with osteolytic bone metastases
from solid tumors other than breast and prostate cancer were randomized
to the following groups:

Zoledronate 4 mg #257

Zoledronate 8 mg #266

Placebo #250

Patients were stratified into two groups, patients with non-small cell
lung cancer (NSCLC) and patients with all other types of solid tumors
(except breast and prostate).

The safety population consisted of all randomized patients who received
study medication, and had documented evidence of at least one
post-baseline safety evaluation.

Seven randomized patients were not included in the safety analysis
because they failed to receive any study treatment. The number of
patients in each arm is shown in applicant's table 7-2.

Applicant Table 7-2

![](media/image14.png){width="5.997222222222222in"
height="1.288888888888889in"}***Reviewer's Note**: Analysis of data
provided by the applicant, demonstrates that for patients assigned to
the 8/4 mg group, 391 of 1809* *zoledronate doses administered were
actually 4mg rather than 8 mg, or approximately 22%.*

Thirty-eight patients were randomized to the incorrect stratum.

-   3 patients with NSCLC were randomized into the other solid tumors
    stratum, one in each of the 3 treatment groups.

-   35 patients with small cell lung cancer were randomized in the NSCL
    cancer stratum with 12 in the 4 mg group, 10 in the 8/4 mg group and
    13 in the placebo group.

For the efficacy analysis, the patients were not reassigned, but for the
safety analysis, "such patients were reassigned to the correct stratum."

***Reviewer comment:** The protocol (section 3.4.1) describes
stratification for "patients with lung cancer" and "patients with all
other cancers". NSCLC and SCLC are not distinguished in the protocol or
its amendments and, it seems there was no clear distinction between
NSCLC and SCLC until the study report.*

The following table abstracts data from applicant's tables 7-3 and 7-4,
to illustrate baseline age and serum creatinine. These are patient
factors which might increase the susceptibility to the renal toxic
effects of zoledronate.

Reviewer Table 1. Baseline patient age and serum creatinine by treatment
group.

![](media/image15.png){width="5.9944444444444445in"
height="1.9243055555555555in"}

![](media/image16.png){width="5.998611111111111in"
height="0.9791666666666666in"}

This data shows similar age for treatment groups whether viewed as
median age or % older than 60 years of age. The baseline serum
creatinine values are similar, particularly for the zoledronate 4 mg and
placebo groups.

***Reviewer's comment**: The treatment related factors that might
predict for renal toxicity of* *zoledronate include dose, duration of
infusion, exposure over time (# of months of treatment), and concomitant
exposure to renal toxic drugs.*

# Overall exposure

The duration of exposure to the study drug was similar for all treatment
groups (applicant's table 8-1). The mean duration of exposure was 4.51
months for zoledronate 4 mg, 4.45 months for the 8/4 mg group and 4.62
months for placebo. The median duration of exposure was 4.04 months for
zoledronate 4mg, 3.21 months for zoledronate 8/4 mg, and 3.79 months for
placebo.

Most patients in all groups were treated following amendment 3 and,
therefore, were treated by infusion over 15 (rather than 5) minutes.
This was 73% of the zoledronate 4 mg patients, 76% of the 8/4 mg group
and 74.5% of the placebo group. Many patients were treated fewer than 3
months. For the 15 minute infusion patients, this includes 37.1% of the
4mg group, 40.8% of the 8/4 mg group, and 41.8% of the placebo patients.

# Concomitant medication

"Approximately 80% in each group were receiving antineoplastic therapy
at study entry and during the study with the most common agents being
carboplatin, cisplatin, paclitaxel, gemcitabine, fluorouracil,
etoposide, folinic acid, vinorelbine and doxorubicin." Post-text table
8.2-4 shows that the incidence of treatment with the nephrotoxic drug,
cisplatin, concomitant with study medication was similar among the
treatment groups. The incidence of cisplatin therapy was 14.6% for the
zoledronate 4mg group, 17.4% for the 8/4 mg group, and 16.6% for
placebo.

**Overall incidence and severity of adverse events**:

Clinical study reports used the IMN dictionary to code adverse events
(AEs.) The data is summarized in the study report using MedDRA preferred
terms. Adverse events were mapped from the IMN preferred terms to the
corresponding MedDRA terms. The number of patients with AEs is provided
by body system, preferred term, and treatment group. If a patient had
more than one type of event within a body system, the patient was
counted only once.

"Almost all patients in all treatment groups experienced at least one
adverse event." There was a slightly higher incidence among the
zoledronate 4 mg patients of AEs affecting gastrointestinal, nervous,
and respiratory systems, and the eye, compared with the other 2 groups.
Applicant table 10-1 shows the % of patients with adverse events overall
and by system, for events occurring [\>]{.underline} 15% in any group.

Applicant Table 10-1

![](media/image17.png){width="5.995138888888889in" height="5.1875in"}

The patients with renal and urinary disorders include all patients,
regardless of whether they were treated by 5- or 15-minute infusion. The
incidence is similar for zoledronate 4 mg and placebo, slightly higher
for the 8/4 mg group.

The most frequent adverse events were bone pain, nausea, anemia,
vomiting, constipation, dyspnea, fatigue, pyrexia, weakness, anorexia,
lower extremity edema, and malignant neoplasm aggravated. Nausea,
vomiting, and dyspnea were higher in the zoledronate 4 mg group than in
the placebo group. There was no clear dose relationship. This data
appears in applicant table 10-2.

Applicant Table 10-2

![](media/image18.png){width="5.99375in" height="6.468055555555556in"}

***Reviewer comment**: The applicant also presented the number of
patients with the most common AEs by stratum (NSCLC or not) and
treatment group (table 10.3) but this did not seem to add significantly
to the analysis.*

The overall incidence of grade 3 and 4 adverse events, regardless of
cause, is similar for the treatment groups. (Post text table 10.1-4,
volume 95.) The incidence of grade 3 AEs for the zoledronate 4 mg group
was 33.5% and 38.9% for the placebo group. The incidence of grade 4 AEs
was 43.3% and 39.8%, respectively.

# Renal adverse events

#  

A Renal Advisory Board (RAB) was established in November 1999 to monitor
the renal safety of zoledronate, due to concerns about renal toxicity.
Three patients in other studies had renal failure after receiving
zoledronate 8 mg. Applicant table 10-4 shows renal AEs using the
preferred terms specified by the RAB for patients randomized before the
15-minute infusion amendment and in table 10-5 for patients randomized
after the 15-minute infusion amendment. For the pre-amendment patients,
the incidence of renal AEs was 16.2 % in the zoledronate 4 mg group,
20.3% in the 8/4 mg group and 12.7% in the placebo group. The incidence
of acute renal failure was 5.9% (4 patients) and 6.3% for zoledronate 4
mg and 8/4 mg, respectively, and 0 for placebo. The incidence of "renal
impairment NOS" was 2.9% (2 patients) and 3.1% in the zoledronate
groups, and 0 in the placebo group.

Renal AEs decreased in the zoledronate arms after extending the infusion
time to 15 minutes, and was stable for the placebo patients. Applicant
table 5 shows the renal AEs by preferred term and treatment group for
the patients randomized after the 15-minute infusion amendment.

Applicant Table 10.5

![](media/image19.png){width="5.997916666666667in" height="4.95in"}

Even after institution of the 15-minute amendment, the incidence of
"renal failure acute" is higher for zoledronate (4mg, 2.2 ) compared
with placebo (0.5), but particularly for the 8/4 mg group (3.5). The
category of "blood creatinine increased" is higher in the post 15-minute
group, 5% for 4 mg, 8% for 8/4 mg, and 1% for placebo, compared with the
pre 15-minute incidence of 0, 1.6% and 0 respectively.

***Reviewer comment**: The higher incidence of elevated creatinine post-
compared with pre-amendment 3 may actually be a higher incidence of
discovery, relating to the requirement to assess creatinine prior to
each treatment, following amendment 5 in June 2000.*

In table 10-6 of the study report, the applicant reviews
chemotherapy-associated AEs to determine if these were increased by the
addition of zoledronate. The most common AEs were nausea, vomiting,
anorexia and appetite decrease. Each of these, except anorexia, was more
frequent in the zoledronate groups than in the placebo group.

***Reviewer comment**: Since the incidence of these AEs was higher for*
*zoledronate 4 mg than 8/4 mg, makes it less likely that* *zoledronate
caused the symptoms. Of interest, but probably not of causal
significance, is the fact that stomatitis is present at higher incidence
in the* *zoledronate 4 mg (5.9%) and 8/4 mg (6.4%) groups than for
placebo (3.6%).*

AEs (other than renal) tabulated as "most clinically relevant for
bisphosphonates" showed no overall increased incidence for zoledronate
patients when "any body system" was specified. However, the zoledronate
4 mg group did have excess AEs compared to placebo for "electrolytes"
(20.1% vs. 12.1%) and "eye abnormalities" (12.6% vs. 6.9%). There was no
dose-related increase for the zoledronate 8/4 mg group, which was
similar to the 4 mg group for these AEs (19.2% "electrolytes" and 11.3%
"eye abnormalities."

# Deaths, SAEs and other "significant adverse events"

# 

# In section 3.5.3.2 of the protocol, the applicant defines a serious adverse event (SAE) as an event which:

# 

# Is fatal or life threatening

# 2. Requires or prolongs hospitalization 

> 3\. Is significantly or persistently disabling or incapacitating

4.  Constitutes a congenital anomaly or a birth defect

5.  Encompasses any other clinically significant event

Item 5 is not clearly explained. "Clinically significant AEs" are
defined as events which were no SAEs, but "resulted in withdrawal of
study drug or were considered to be clinically important and required
concomitant therapy.

The applicant's table 10.8 lists "patients who died (up to the end of
the core study phase or within 28 days following last treatment), had
other serious or clinically significant AEs or discontinued because of
them".

Applicant table 10-8

![](media/image20.png){width="5.995138888888889in"
height="2.667361111111111in"}There is a slight excess of SAEs for
zoledronate 4mg compared with placebo, but not for the other events.
There were 261 deaths, with a similar incidence in each treatment group.
The most frequent cause of death was progression of cancer.

Post-text table 10.2-3 summarizes number of patients who discontinued
due to death by body system, preferred term and treatment group. This
shows 10.6% of the zoledronate 4 mg group and 17.4% of the placebo group
dying from "malignant neoplasm aggravated". Death was attributed to
"renal and urinary disorders" for only 1 patient in the zoledronate 4 mg
group, and no patients in the placebo group.

***Reviewer note**: There is a discrepancy between the per cent of
patients in each treatment group for table 10-8 and post-text-table
10.2-3. The latter cites 26.0%, 28.3% and 26.7% incidence of deaths in
the* *zoledronate 4 and 8/4 mg groups, compared with 35.0%, 33.6%, and
33.6% deaths in table 10-8.*

The most frequent SAEs, regardless of study drug relationship, were
anemia, dehydration, malignant neoplasm aggravated and dyspnea. Anemia
occurred in 7.9% of the zoledronate 4 mg group and in 3.6% of the
placebo group. Dyspnea was present in 10.2% and 7.7%, respectively. The
incidence of "renal and urinary disorders" was 5.1% in zoledronate 4mg,
7.2% in 8/4 mg, and 3.6% in placebo. For acute renal failure, the
incidence was 3.1%, 4.2%, and 0.4%, respectively.

Note that the efficacy endpoint of SREs (skeletal related events) was
not to be included in the SAE tabulation.

Applicant's table 10-9 summarizes the number of patients discontinued
from study for an adverse event.

Applicant table 10-9

![](media/image21.png){width="5.999305555555556in"
height="3.7215277777777778in"}

![](media/image22.png){width="5.996527777777778in"
height="1.9395833333333334in"}

There is no increase in discontinuations for zoledronate 4 mg compared
with placebo. Discontinuation for renal and urinary disorders is similar
for the 2 groups, but slightly higher for the zoledronate 8/4 mg group.

# Laboratory parameters

**Hematology**

The treatment groups were similar when hematology tests were analyzed by
number of patients reaching selected "notable" values of neutrophil
count \<0.5 x 10^9^, platelets \< 25 x 10^9^ and hemoglobin \< 6.5 G/dL
(applicant's table 10-12). The percentage of patients with \>25%
decrease in hemoglobin is also similar for the groups.

There was a slightly increased incidence of grade 3, but not grade 4,
post-baseline hemoglobin (\<8 g/dL) for the zoledronate 4 mg group
compared with 8/4 mg and placebo. These percentages were 3.6%, 2.2%, and
1.4% respectively.

# Serum chemistry

The tests performed include sodium, potassium, SGOT, SGPT, alkaline
phosphatase, LDH, creatinine, BUN, calcium, phosphorus and magnesium.
When patients were analyzed for notable biochemistry values (other than
creatinine), there were no major differences between the zoledronate 4
mg and placebo groups. The incidence of phosphorus \< 1.5 mg/dL was 2.7%
for zoledronate 4 mg and 0.9% for placebo (applicant table 10-15). Grade
3 and 4 abnormalities are shown in table 10-17 and reveal little
difference between zoledronate groups and control for chemistry
abnormalities post baseline. except for more hypophosphatemia with
zoledronate. Phosphorus \<2 (grade 3 hypophosphatemia) was present 8.9%,
12.0% and 1.4%, respectively for zolodronate 4 mg, 8/4 mg and placebo.
Grade 3 hypokalemia was slightly higher (4.9%) in the zolodronate 4 mg
group compared with placebo (3.2%).

# Serum creatinine and renal function deterioration 

Baseline serum creatinine was considered normal if \<1.4 mg/dL and
abnormal if [\>]{.underline} 1.4 mg/dL. Renal function deterioration was
defined as any of the following:

-   Normal baseline with change from baseline [\>]{.underline} 0.5 mg/dL

-   Abnormal baseline with change from baseline [\>]{.underline} 1.0
    mg/dL

-   Post-baseline value [\>]{.underline} 2 time the baseline value.

Applicant table 10-14 shows the incidence of post-baseline notable serum
creatinine. Subsequent to amendment 3 (15 minute infusion), 2 patients
(1.2%) in the zoledronate 4 mg group developed creatinine
[\>]{.underline} 4.5 , 2 patients in the 8/4 mg group, and 0 in the
placebo group. Excluding these patients, the incidence of creatinine
increase [\>]{.underline} 0.5 was 10.3% for zoledronate 4 mg, 11.6% for
zoledronate 8/4 mg and 7.4 % for placebo. This represents an improvement
for the zoledronate groups, compared with pre 15-minute infusion
amendment.

Applicant table 10-14

![](media/image23.png){width="5.993055555555555in"
height="3.953472222222222in"}

Applicant table 10-16 shows the distribution of grade 3 or 4 creatinine
elevations.

Applicant table 10-16

![](media/image24.png){width="5.997916666666667in"
height="3.4229166666666666in"}

For the post amendment patients, the incidence of grade 3 and 4
creatinine elevations was similar across the 3 treatment groups,
representing an increase in incidence for zoledronate 4 mg and placebo
groups compared with pre amendment.

The incidence of renal function deterioration was increased in the
zoledronate treatment groups for patients with normal baseline
creatinine and creatinine [\>]{.underline} 1.4 compared with placebo pre
and post amendment.

***Reviewer comment**: There were too few patients with abnormal
creatinine in the pre amendment group to make quantitative comparisons
with the post amendment group. In the 5-minute infusion group, 3 of 6
patients with abnormal baseline serum creatinine experienced renal
function deterioration after* *zoledronate 4 mg, compared with 2 of 8 in
the 8/4 mg group and 0 of 4 in the placebo group. The following table is
abstracted from applicant's table 10-19, demonstrating renal
deterioration in the patients randomized following amendment 3.*

Reviewer table 2

Patients who experienced renal function deterioration by baseline serum
creatinine (15- minute infusion)

+---------------------+-----------------+-----------------+------------+
|                     | Zoledr 4 mg     | Zoledr 8/4 mg   | Placebo    |
|                     |                 |                 |            |
|                     | N (%)           | N (%)           | N (%)      |
+---------------------+-----------------+-----------------+------------+
| Patients with       | 154             | 160             | 143        |
| normal baseline     |                 |                 |            |
| creatinine          |                 |                 |            |
+---------------------+-----------------+-----------------+------------+
| \-\--with           | 17 (11.0%)      | 19 (11.9%)      | 10 (7.0%)  |
| deterioration       |                 |                 |            |
+---------------------+-----------------+-----------------+------------+
| Patients with       | 11              | 21              | 20         |
| abnormal baseline   |                 |                 |            |
| creatinine          |                 |                 |            |
+---------------------+-----------------+-----------------+------------+
| \-\--with           | 1 (9.1%)        | 2 (9.5%)        | 1 (5.0%)   |
| deterioration       |                 |                 |            |
+---------------------+-----------------+-----------------+------------+
| TOTAL \# patients   | 165             | 181             | 163        |
| at baseline         |                 |                 |            |
+---------------------+-----------------+-----------------+------------+
| \-\--with           | 18 (10.9%)      | 21 (11.6%)      | 11 (6.7%)  |
| deterioration       |                 |                 |            |
+---------------------+-----------------+-----------------+------------+

When time to renal function deterioration was analyzed by Cox regression
for patients treated post amendment 3, there was no statistically
significant difference between

zoledronate and placebo groups. The risk ratio was 1.571 between
zoledronate 4 mg and placebo, indicating a higher risk of renal function
deterioration for zoledronate 4 mg compared with placebo. However, the
p-value was not statistically significant.

Applicant's figure 10-2 is the Kaplan-Meier curve for time to first
renal function deterioration by treatment group for patients randomized
after the 15-minute infusion amendment.

Applicant figure 10-2

![](media/image25.png){width="5.997222222222222in"
height="4.100694444444445in"}

# Urinalysis 

The percentage of patients with elevated urine protein ([\>]{.underline}
2) post-baseline was similar in all groups (6-8%). Post-text table
10.3-2.

# Vital signs

# Systolic and diastolic blood pressure

# 

# The incidence of patients with notably high or low systolic or diastolic blood pressures is similar in all groups.

# 

# Weight 

# 

# The incidence of patients with [\>]{.underline} 10% change in weight was similar for zoledronate 4 mg and placebo groups.

# ECGs

"The proportion of evaluated patients who had an abnormality was similar
at baseline and end of study, but most patients were not evaluated at
the end of the study."

# Special safety topics

The zoledronate 4 mg treatment group had the longest median time to
death (203 days), compared to the 8/4 mg (189 days) and placebo (183)
groups. This date is from post-text table10.2-7.

**Reviewer comment and conclusions**

Increased risk of renal function deterioration is the only significant
safety issue for zoledronate in this and related clinical trials of
long-term treatment for patients with metastatic malignancy to bone.
This toxicity was dose and time-related.

Of the more common adverse events, nausea, vomiting, and dyspnea were
higher in the zoledronate 4 mg group than in the placebo group. There
was no clear dose relationship.

The overall incidence of grade 3 and 4 adverse events, regardless of
cause, is similar for all the treatment groups. The most frequent SAEs,
regardless of study drug relationship, were anemia, dehydration,
malignant neoplasm aggravated and dyspnea. Anemia occurred in 7.9% of
the zoledronate 4 mg group and in 3.6% of the placebo group. Dyspnea was
present in 10.2% and 7.7%, respectively.

Hypophosphatemia was more common with zoledronate than placebo. The
incidence of grade 3 hypophosphatemia was 8.9%, 12.0% and 1.4%,
respectively for zolodronate 4 mg, 8/4 mg and placebo. Grade 3
hypokalemia was slightly higher (4.9%) in the zolodronate 4 mg group
compared with placebo (3.2%).

Subsequent to the occurrence of acute renal failure in 3 patients
receiving zoledronate 8 mg in related trials for disease metastatic to
bone, several amendments were made to the protocol and a renal advisory
board (RAB) of nephrologists was convened. Prolonging the infusion time
from 5 to 15 minutes (amendment 3), decreased the incidence of renal
function deterioration. Amendment 5 further improved the safety profile
by eliminating the 8 mg dose. The safety of the 4 mg dose was improved
by requiring assessment of serum creatinine before each dose.
Zoledronate was held for renal deterioration, as defined in the amended
protocol, and therapy was not reinstituted until creatinine returned to
within 10% of the baseline value.

Following amendment 3, the overall incidence of renal related AEs was
comparable for zoledronate 4 mg (11.8%) and placebo (12.5%). However,
the incidence of "blood creatinine increased" was 2.7% for zoledronate
4mg and 0.5 for placebo. "Renal failure acute" was 2.2% and 0.5%,
respectively.

The incidence of renal function deterioration was increased in the
zoledronate treatment groups for patients with normal baseline
creatinine and creatinine [\>]{.underline} 1.4 compared with placebo pre
and post amendment. For patients randomized following amendment 3, the
overall incidence of renal deterioration was 10.9% for zoledronate 4 mg,
11.6% for 4/8 mg and 6.7% for placebo. (From applicant table 10-19)

When time to renal function deterioration was analyzed by Cox regression
for patients treated post amendment 3, there was no statistically
significant difference between

zoledronate and placebo groups. The risk ratio was *1.571* between
zoledronate 4 mg and placebo, indicating a higher risk of renal function
deterioration for zoledronate 4 mg compared with placebo. However, the
*p-value* was not statistically significant.

**Reviewer Conclusion:** Zoledronate 4 mg i.v. over 15 minutes every 3
weeks has an acceptable risk profile. The risk of renal deterioration
with zoledronate is greater than placebo, but acceptable with clinical
monitoring of renal function before each dose. Risk of renal toxicity
increases with cumulative time under therapy. Caution is indicated for
patients with elevated baseline creatinine, particularly since the study
population excluded patients with creatinine\>3.0 and the drug is
excreted by the kidneys.

**Appendix 3 Review of** **Zoledronate Safety in Breast Cancer and
Myeloma,**

> **Study 010**

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

                                                            

                                                            

                                                            

                                                            

                                                            

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

**Study \# ZOL42446-03-010:** "A randomized, double-blind, multi-center,
comparative trial of i.v. zoledronic acid (4 mg or 8 mg) versus i.v.
Aredia (90 mg), as an adjunct to standard therapies, in the treatment of
multiple myeloma and breast cancer patients with cancer-related bone
lesions."

This is a multi-center, international study (248 centers in 20
countries). The first patient was enrolled 16 October 1998 and the last
patient completed therapy 12 January 2001. The study duration was 13
months (12 months treatment, 1 month observation), with an optional 12
month extension period.

The study population consisted of adults with Stage III multiple myeloma
or stage IV breast cancer. Patients were to be receiving anti-cancer
therapy at the time of randomization. Breast cancer patients could be
receiving chemotherapy and/or first or second line hormonal therapy.
Myeloma patients were required to have at least one osteolytic bone
lesion on conventional (plain film) radiograph. Breast cancer patients
were required to have a lytic, sclerotic or mixed lesion on plain film.
Patients were to be performance status [\<]{.underline} 2.

Exclusions included serum creatinine \> 3, bilirubin \> 2.5, and
corrected serum calcium \< 8 mg/dL or [\>]{.underline} 12 mg/dL.

Patients were stratified according to the diagnosis of multiple myeloma
or breast cancer on chemotherapy or breast cancer on hormonal therapy.

Patients were randomized to receive zoledronate 4 mg or 8 mg or Aredia
90 mg i.v. every *3* *or 4 weeks* for 12 months. Initially, zoledronate
was to be infused over 5 minutes. Aredia was infused over 2 hours.
Patients were not taken off study for progressive disease.

From December 1998 to May 1999 there were 3 renal failure SAEs in
patients receiving zoledronate 8mg, manifested by progressively rising
serum creatinine. This occurred in 1 patient each of a Phase II myeloma
study (cycle #11), protocol 010 (diagnosis breast cancer, cycle #1), and
protocol 039 (prostate cancer, after cycle #7). The patients were,
respectively, ages 75, 80, and 71, with baseline creatinines of 1.6,
1.9, and 1.4. These events led to Amendment 2 on 25 June 1999 and
Amendment 5 on 7 June 2000 and the formation of a Renal Advisory Board
(RAB) in November 1999.

After amendment 2, the infusion duration was prolonged to 15 minutes for
zoledronate. After amendment 5, all zoledronate patients received 4 mg
per dose. Serum creatinine was to be evaluated before each dose, and
treatment held for deterioration of creatinine, as defined in the
amendment, until the level was within 10% of the baseline creatinine.

# 

# 

# Applicant assessment and analysis of safety

Adverse events, serious adverse events, laboratory studies, and survival
data were the main safety variables. Physical examination, assessment
for adverse events and laboratory studies were done at baseline and then
every 3-4 weeks, and at the end of study. Chemistries were repeated
every 3-4 weeks. Hematology and urine chemistries and urinalyses were
repeated at 3-4 weeks, then at month 3, then every 3 months. Serum
creatinine was measured prior to each dose of study drug following
amendment 5, so that treatment could be held for renal deterioration.
The time to discontinuation of study and duration of survival were
assessed.

Safety analysis was based on the type and frequency of adverse events
and laboratory values outside of pre-determined ranges. The data were
tabulated. Data were cut at the end of the study drug period for
laboratory and adverse event analysis. This was the later of the end of
the core study phase or the last date of study medication plus 28 days.
All data was included up to the date of the data base lock for time to
death and renal deterioration. The last visit date was used for other
safety parameters.

The effect on renal function was analyzed according to the number of
patients who experienced renal adverse events using selected terms
suggested by the renal advisory board (RAB) and the number of patients
who met pre-defined criteria of renal deterioration. Kaplan-Meier curves
were used to describe the time course of renal function deterioration.

# Study population 

There were 1648 patients randomized to the following treatment groups:

Zoledronate 4 mg #564

Zoledronate 8/4 mg #526

Aredia 90 mg #558

Five patients were not included in the safety analysis because they did
not receive study drug. The safety population includes all patents that
were randomized and received study drug. "There were 9, 9, and 10
patients who were randomized to the incorrect stratum" for zoledronate 4
mg, 8/4 mg, and Aredia, respectively. They were re-assigned for safety
analysis.

A similar % of patients did not complete the study for all treatment
groups: 37.3% for zoledronate 4 mg, 40.3% for 8/4 mg and 39.2% for
Aredia 90 mg. Discontinuation was most frequently due to adverse events
and death. The % of discontinuation for death in each group was 10.8%,
10.7% and 11.5%, respectively.

The number of patients in each arm is shown in applicant's table 7-2.

Applicant table 7-2

![](media/image26.png){width="5.997222222222222in"
height="1.4743055555555555in"}

> **Reviewer Note**: Analysis of data provided by the applicant
> demonstrates that for patients assigned to the 8/4 mg group, 1394 of
> 7072 zoledronate doses delivered were actually 4 mg rather than 8 mg
> doses, or approximately 20% were 4 mg doses.

The following table is an abbreviated, composite version of applicant's
table 7-3 and 7-4, to illustrate baseline age and serum creatinine.
These are some of the patient factors that might affect susceptibility
to the renal toxic effects of treatment.

Reviewer table 1.

Baseline patient age and serum creatinine by treatment group

![](media/image27.png){width="5.997222222222222in"
height="1.6368055555555556in"}

![](media/image28.png){width="5.992361111111111in"
height="0.7847222222222222in"}

This data shows similar age for treatment groups whether viewed as
median age or % older than 60 years of age. The baseline serum
creatinine values are similar for the zoledronate groups, but less
favorable compared with the Aredia patients, of whom only 13.2% had
abnormal creatinine [\>]{.underline} 1.4.

***Reviewer comment**: The treatment related factors that might predict
for renal toxicity include dose, duration of infusion, exposure over
time (# of months of treatment), and concomitant exposure to renal toxic
drugs.*

# Overall exposure 

The duration of exposure to study drug was similar for the treatment
groups. The mean duration of exposure for the multiple myeloma patients
and hormonal breast cancer patients was 10 months. The mean for
chemotherapy breast cancer patients was 9 months. For the overall group,
the mean was approximately 10 months and the median exposure
approximately 12 months for each of the 3 treatment groups. (This
information is found in applicant's table 8-1).

# Concomitant medication 

# 

# Most patients received antineoplastic therapy during the study. The most common chemotherapy drugs were cyclophosphamide and doxorubicin. Post-text table 8.2-2 and 8.2-3 show \# of patients who received antineoplastic therapy prior to and after the start of the study respectively. The incidence of prior therapy with cisplatin was 2%, 1.0% and 0.9% for zoledronate 4, 8/4 and Aredia. The incidence of therapy with cisplatin after the start of the study was 2.0%, 1.0%, and 0.7%, respectively.

# 

# Overall incidence and severity of adverse events: 

# 

# Clinical study reports used the IMN dictionary to code adverse events (AEs). The data is summarized in the study report using MedDRA preferred terms. Adverse events were mapped from the IMN preferred terms to the corresponding MedDRA terms. The number of patients with AEs is provided by body system, preferred term, and treatment group. If a patient had more than one type of event within a body system, the patient was counted only once.

# 

# Most patients experienced at least one adverse event. 

# 

# Applicant table 10-1 shows the % patients with adverse events overall and by system for events occurring [\>]{.underline} 15% in any group. 

# 

# Applicant table 10-1

#  

# ![](media/image29.png){width="5.992361111111111in" height="5.429166666666666in"} 

There is no major imbalance in AEs by system, although the incidence of
"metabolism and nutrition disorders" and "neoplasms benign and
malignant" is slightly higher for zoledronate 4 than Aredia. The
incidence of renal AEs is similar for these treatment groups, including
for patients treated with 5 minute and 15 minute infusion.

The most frequent adverse events were bone pain, nausea, fatigue,
pyrexia, and vomiting. Of these, only pyrexia was present more
frequently in the zoledronate 4 mg and 8/4 mg groups than in the Aredia
group. There was a slight increase in the zoledronate 4 mg group
compared with the Aredia group of cough, arthralgia, weakness and
anorexia. This information is summarized in applicant table 10-2.

Applicant table 10-2

![](media/image30.png){width="5.998611111111111in"
height="5.163194444444445in"}

The overall incidence of grade 3 and 4 AEs was similar for the treatment
groups. Post-text table 10.1-4 was reviewed.

# Renal adverse events

A Renal Advisory Board (RAB) was established in November 1999 to monitor
the renal safety of zoledronate, due to concerns about renal toxicity
when a total of 3 patients in this and other studies developed renal
failure following treatment with zoledronate 8 mg. Renal adverse events
with preferred terms specified by the RAB are presented in applicant
table 10-3 for patients randomized prior to the 15-minute infusion
amendment and table 10-4 for patients randomized following the
amendment. The overall incidence of renal adverse events is similar for
zoledronate 4 mg and Aredia 90 mg both pre and post amendment. The
incidence for zoledronate 8/4 mg is approximately 30% higher than the
other treatment groups for the 5-minute and 15-minute infusions. For the
post amendment patients, the incidence of "blood creatinine increased"
is 2.8% for zoledronate 4 mg, 4.3% for zoledronate 8/4 mg and l.8% for
Aredia 90 mg. The incidence of "renal impairment NOS is identical for
the zoledronate 4 mg and Aredia groups, as it for renal failure acute.
The incidence for both events is higher for zoledronate 8/4 mg. The
incidence of 4.7% "renal failure acute" is significantly higher for the
8/4 mg dose zoledronate, than for the lower dose zoledronate or Aredia,
which are both 0.7%.

Applicant table 10.4

![](media/image31.png){width="5.993055555555555in"
height="6.252777777777778in"}

The sponsor selected and reviewed adverse events previously reported
with bisphosphonates. These are reported in table 10-5. The incidence of
arthralgias and fever was higher for zoledronate 4 mg than Aredia, but
the incidence for zoledronate 8/4 mg was intermediate, suggesting that
there is no causal relationship for these events. The incidence of
electrolyte AEs was higher for both zoledronate groups (15.3% and
19.1%), possibly in a dose-dependant way, compared with Aredia (11.9%)

Applicant table 10-5

![](media/image32.png){width="5.997222222222222in"
height="2.6729166666666666in"}

Events believed to be chemotherapy-associated were not increased in
incidence for zoledronate patients compared with those that received
Aredia.

# Deaths, SAEs and other significant adverse events

In Section 3.5.3 of the protocol, a serious adverse event (SAE) is
defined as an untoward event which:

1.  Is fatal or life-threatening,

2.  Required or prolonged hospitalization,

3.  Was significantly or permanently disabling or incapacitating,

4.  Constitutes a congenital anomaly or a birth defect,

5.  May jeopardize the subject and may require medical or surgical
    intervention to prevent one of the outcomes listed above.

Applicant table 10-7 lists patients who died, had other SAE or
"clinically significant AEs" or discontinued because of them. Deaths are
included if they occurred up to the end of the core study phase or
within 28 day following the last treatment.

Applicant table 10-7

![](media/image33.png){width="5.996527777777778in"
height="2.8555555555555556in"}

There were 217 deaths during the core study phase or within 28 days of
last study medication. The percentage of deaths in each treatment arm
was similar. The most frequent cause was progression of cancer. There
were no deaths due to renal causes in the zoledronate 4 mg or Aredia 90
groups. There were 4 such deaths in zoledronate 8/4 mg.

SAEs occurred in a similar proportion of patients in each treatment
group (from post-text table 10.2-1, 48.8%, 48.3% and 49.8%). The most
frequent SAE was infection for all groups. The incidence of "renal and
urinary" SAEs was 2.8% for zoledronate 4 mg, 5.7% for 8/4 mg and 2.9%
for Aredia. The incidence for "renal failure acute" was 0.5%, 3.4% and
1.4%, respectively. The incidence for which "renal and urinary" SAEs
were suspected to be treatment related were 0.5%, 1.9% and 0.2%,
respectively.

The study report provides specific information about 27 SAEs that were
not included in the database at the time of the lock, but the SAEs were
not felt to be study drug related. Of these, one breast cancer patient
was treated with Aredia and had unexplained sudden death. One additional
breast patient (zoledronate 4 mg) had azotemia and hypercalcemia at
study day 400, for which she was hospitalized. A myeloma patient
(zoledronate 8/4 mg) had "renal impairment NOS" at study day 80.

In this study, skeletal related events (SRE) were reported as SAEs. The
percentage was 5.0%, 3.8%, and 7.7%, respectively for zoledronate 4 and
8/4 mg and for Aredia.

The incidence of patients discontinuing therapy for adverse events was
10.1% for zoledronate 4 mg, 12.2% for 8/4 mg, and 8.8% for Aredia.
Discontinuations for "renal and urinary disorders" was 0.5% for
zoledronate 4 mg and Aredia 90 mg. It was 2.5% for zoledronate 8/4 mg.

# Laboratory parameters

# Hematology

The treatment groups were similar when hematology tests were analyzed by
number of patients reaching selected "notable" values of neutrophil
count \< 0.5 x 10^9^, platelets \< 25 x 10^9^, and hemoglobin \< 6.5
gm/dL. However, a greater percentage of patients in the zoledronate 4 mg
(10.2%) and 8/4 mg (11.1%) had a decrease of \>25% from baseline
hemoglobin compared with the Aredia group (7.8%). The incidence of grade
3 and grade 4 hematologic toxicity is similar for the treatment groups.

# Serum chemistry 

The tests performed include sodium, potassium, SGOT, SGPT, alkaline
phosphatase, LDH, creatinine, BUN, calcium, phosphorus and magnesium.
When patients were analyzed for notable biochemistry values (other than
creatinine), there were few differences between the treatment groups.
There was a higher incidence of hypercalcemia \> 12.0 mg/dL in the
Aredia group (2.24%) than in the zoledronate 4 (0.37%) or 8/4 mg groups
(0.60%). There was more hypokalemia \< 3 mEq/L in the zoledronate 8/4 mg
group (9.84%) and more hyperkalemia \> 6 mEq/L (4.68%) in the
zoledronate 4 mg group compared with the other 2 treatment groups. The
incidence of grade 3 and grade 4 toxicity was similar for the treatment
groups, except for excess grade 3 hypophosphatemia and grade 3
hypokalemia for zoledronate 8/4 mg. Zoledronate 4 mg patients had 3%
grade 4 hyperkalemia, but only 0.8% for zoledronate 8/4 mg and 1.3% for
Aredia. The following table shows notable chemistry abnormalities by
treatment group.

Applicant table 10-15 (abbreviated)

![](media/image36.png){width="5.995138888888889in"
height="3.089583333333333in"}

***Reviewer comment :*** *There were more electrolyte abnormalities for*
*zoledronate* *8/4 mg. However, comparing* *zoledronate* *4 mg and
Aredia, there are probably no significant differences. The lack of dose
relationship for hyperkalemia in the* *zoledronate* *groups makes it
unlikely to be a treatment--related occurrence.*

# Serum creatinine and renal function deterioration 

Baseline serum creatinine was considered normal if \<1.4 mg/dL and
abnormal if [\>]{.underline} 1.4 mg/dL. Renal function deterioration was
defined as any of the following:

-   Normal baseline with change from baseline [\>]{.underline} 0.5 mg/dL

-   Abnormal baseline with change from baseline [\>]{.underline} 1.0
    mg/dL

-   Post-baseline value [\>]{.underline} 2 time the baseline value.

Applicant table 10-14 shows the incidence of post-baseline notable serum
creatinine for patients randomized before and after the 15-minute
infusion amendment. For post-amendment patients, 10.7%, 18.6% and 7.5%
of zoledronate 4, 8/4 and Aredia patients, respectively, developed
creatinine increase from baseline [\>]{.underline} 0.5. Patients in each
group who developed creatinine [\>]{.underline} 4.5 were 0 for
zoledronate 4 mg, 1.1 % (3 patients) for 8/4 mg and 0.8% (2 patients)
for Aredia.

Applicant table 10-14

![](media/image34.png){width="5.997222222222222in"
height="4.156944444444444in"}There was a decrease in the frequency of
post-baseline notable serum creatinine for both zoledronate groups when
the infusion time was prolonged from 5 minutes to 15 minutes. The
incidence remains significantly elevated for zoledronate 8/4 mg compared
with the two other treatment groups. The incidence of post-baseline
notable serum creatinine elevation is 10.7% for zoledronate 4 mg and
8.3% for Aredia (7.5% + 0.8%). Applicant table 10-16 shows the
distribution of post-baseline grade 3 or 4 creatinine by treatment
group.

Applicant table 10-16

![](media/image35.png){width="5.9944444444444445in"
height="3.5694444444444446in"}

For the patients randomized post amendment, the incidence of grade 3 and
4 creatinine was least in the zoledronate 4 mg group. The incidence of
grade 3 plus grade 4 creatinine is slightly higher for zoledronate 8/4
mg (2.7%) than Aredia (1.9%).

For the pre 15-minute infusion amendment patients, renal function
deterioration was experience by 13.2% of the zoledronate 4 mg patients,
20.4% of the zoledronate 8/4 mg patients, and by 6.7% of the Aredia
patients. Extending the time of the infusion significantly decreased the
incidence of creatinine deterioration for the zoledronate 4 mg patients.
The following table is abstracted from applicant's table 10-19 and shows
renal function deterioration by baseline creatinine for post 15-minute
infusion amendment patients.

Reviewer table 2

Patients who experienced renal function deterioration by baseline serum
creatinine (15-minute infusion)

+----------------------+----------------+---------------+-------------+
|                      | Zoledr 4 mg    | Zoledr 8/4 mg | Aredia 90   |
|                      |                |               | mg          |
|                      | N (%)          | N (%)         |             |
|                      |                |               | N (%)       |
+----------------------+----------------+---------------+-------------+
| Patients with normal | 246            | 242           | 246         |
| baseline creatinine  |                |               |             |
+----------------------+----------------+---------------+-------------+
| \-\--with            | 23 (9.3%)      | 43 (17.8%)    | 20 (8.1%)   |
| deterioration        |                |               |             |
+----------------------+----------------+---------------+-------------+
| Patients with        | 26             | 21            | 22          |
| abnormal baseline    |                |               |             |
| creatinine           |                |               |             |
+----------------------+----------------+---------------+-------------+
| \-\--with            | 1 (3.8%)       | 6 (28.6%)     | 2 (9.1%)    |
| deterioration        |                |               |             |
+----------------------+----------------+---------------+-------------+
| TOTAL \# patients at | 272            | 263           | 268         |
| baseline             |                |               |             |
+----------------------+----------------+---------------+-------------+
| \-\--with            | 24 (8.8%)      | 49 (18.6%)    | 22 (8.2%)   |
| deterioration        |                |               |             |
+----------------------+----------------+---------------+-------------+

Zoledronate 4 mg was comparable to Aredia 90 mg for the entire
population and for patients with normal baseline creatinine. For the
small number of patients with abnormal baseline creatinine, zoledronate
4 mg had a lower incidence of creatinine deterioration (3.8%) than
Aredia 90 mg (9.1%). Zoledronate 8/4 mg was more renal toxic than either
zoledronate 4 mg or Aredia 90 mg for patients with normal and abnormal
baseline creatinine.

When time to renal function deterioration was analyzed by Cox regression
for patients randomized after the 15-minute infusion amendment, there
was no statistically significant difference between zoledronate 4 mg and
Aredia 90 mg. The risk ratio was 0.984 between zoledronate 4 mg and
Aredia 90 mg groups. However, there was a statistically significant
difference in terms of time to renal function deterioration for each of
zoledronate 4 mg and Aredia 90 mg compared with zoledronate 8/4 mg. The
risk ratios were 2.372 and 2.379, respectively.

Applicant's figure 10-2 is the Kaplan-Meier curve for time to first
renal function deterioration by treatment group for patients randomized
after the 15-minute infusion amendment.

Applicant figure 10-2

# ![](media/image37.png){width="5.993055555555555in" height="3.4604166666666667in"}

# Urinalysis

The percentage of patients with elevated post-baseline urine protein was
similar for zoledronate 4 mg and Aredia 90 mg.

# Vital signs, other safety evaluations, special safety topics

Vital signs were not collected. There were no other clinically relevant
findings.

# Reviewer comment and conclusions

Increased risk of renal function deterioration is the only significant
safety issue for zoledronate in this and related clinical trials of
long-term treatment for patients with metastatic malignancy to bone.
Toxicity was dose-related and exposure over time-related.

The more common adverse events were bone pain, nausea, fatigue, pyrexia,
and vomiting. Pyrexia, cough, arthralgia, weakness and anorexia were
slightly increased in the Zoledronate 4 mg group compared with the
Aredia 90 mg group. The incidence of grade 3 and 4 AEs was similar.

More patients in the zoledronate 4 mg group had a decrease of \> 25%
from baseline hemoglobin compared with the Aredia patients, although
there was no difference in notable hematology values or grade 3 and 4
hematologic toxicity.

There were no major differences in blood chemistry abnormalities for
zoledronate 4 mg, compared with Aredia.

Subsequent to the occurrence of acute renal failure in 3 patients
receiving zoledronate 8 mg in trials for malignancy metastatic to bone,
several amendments were made to the protocol, which improved safety. The
infusion time of zoledronate was increased from 5 to 15 minutes
(amendment 2), which decreased the incidence of renal function
deterioration in the zoledronate groups. Amendment 5 further improved
the safety profile by eliminating the 8 mg dose. The safety of the 4 mg
dose was improved by requiring assessment of serum creatinine before
each dose. Zoledronate was held for renal deterioration, as defined in
the amended protocol, and therapy was not reinstituted until creatinine
returned to within 10% of the baseline value.

The overall incidence of renal adverse events was similar for
zoledronate 4 mg and Aredia 90 mg both pre and post the amendment which
prolonged the infusion time. The incidence of renal function
deterioration with zoledronate 4 mg was higher than Aredia
pre-amendment, but was similar (8.8% and 8.2%, respectively) when
zoledronate was infused over 15 minutes. Zoledronate was comparable to
Aredia for the entire population of patients and for patients with
normal baseline creatinine. For the small number of patients with
abnormal baseline creatinine, zoledronate 4 mg had a lower incidence of
creatinine deterioration (3.8%) than Aredia 90 mg (9.1%). There was no
statistically significant difference in time to first renal function
deterioration for zoledronate 4 mg compared with Aredia 90 mg.

**Reviewer conclusions**: Zoledronate 4 mg i.v. over 15 minutes every
3-4 weeks has an acceptable risk profile that is comparable to Aredia.
To minimize renal risk, zoledronate must be infused over 15 minutes and
clinical monitoring of serum creatinine should be performed before each
dose. Caution is indicated for patient with elevated serum creatinine,
particularly since the study population excluded patients with
creatinine \> 3.0 and the drug is excreted unchanged by the kidneys.