**NDA 21-740 - OXYPRIM™**

**Arthritis Advisory Committee Briefing Document**

**June 2, 2004**

**Name:** Oxypurinol

**Proposed trade name:** Oxyprim™

**Drug Class:** Xanthine oxidase inhibitor

**Sponsor:** Cardiome Pharma Corp

**Indication:** Hyperuricemia in patients with symptomatic gout who are
intolerant to allopurinol and have failed either rechallenge or
desensitization with allopurinol

**Dosage form/route:** 100 mg oral hard gelatin capsules.

**Dose:** 300 mg to 800 mg daily

**Type of application:** Application has been given Priority Review
status.

> It has been submitted under Subpart H:

-   Uses of a surrogate marker as primary evidence of efficacy: change
    in serum uric acid (SUA) levels.

-   Requires a risk/management program (RMP)

***DISCLAIMER: This is the preliminary summary of an ongoing review.***

**Background information**

Oxypurinol is the major metabolite of allopurinol. Both allopurinol and
oxypurinol inhibit the synthesis of uric acid by action on the enzyme
xanthine oxidase. Allopurinol effectively reduces serum uric acid (SUA)
levels and is generally well tolerated. Target therapeutic long-term
levels for SUA are \< 6 mg/dl. However, others advocate that the optimal
SUA is \< 5 mg/dl. According to the literature, at least 2% of patients
develop hypersensitivity reactions to allopurinol, and 20% of those are
severe. Severe reactions include rashes such as toxic epidermal
necrolysis, hepatitis, interstitial nephritis, and death.

Oxypurinol was not originally developed as a therapeutic agent for gout
because it has less inhibitory activity (on a molar basis) against
xanthine oxidase than allopurinol. However, oxypurinol has been
available to patients with allopurinol intolerance under a compassionate
protocol since 1966 (IND 3,362). According to the literature, up to 40%
of patients treated with oxypurinol develop allergic reactions similar
to those of allopurinol.

Negotiations between a prior sponsor (ILEX Corp.) and the DAAODP
regarding the possibility of marketing oxypurinol started in 1997. The
current application and NDA is being submitted by Cardiome Pharma Co.
Cardiome maintains that oxypurinol is effective in reducing SUA levels
and has the advantage of being safer than allopurinol in terms of
overall hypersensitivity reactions. Cardiome intends to market Oxyprim™
for the treatment of hyperuricemia in patients with symptomatic gout,
intolerant to allopurinol. (See attached articles on hyperuricemia,
gout, hypersensitivity reactions to allopurinol and the allopurinol
desensitization regimen.)

**Clinical data included NDA 21-740**

Cardiome has submitted information (Table 1) on the efficacy and safety
of oxypurinol from three main databases:

-   An open-label (OL) retrospective analysis from 533 patients enrolled
    in the original Compassionate Use Program (CUP); this program is
    ongoing.

-   A prospectively designed 14-week OL study (OXPL-213) involving 79
    patients with an extension (A4) that is also ongoing.

-   A pharmacokinetic (PK) study (AAI-US-175).

Table 1. Clinical data included in the NDA

+------------+----------------------+----+------+-----------+---------+
| Study name | Design               | N  | \%   | Age range | Dose    |
|            |                      |    | M/F  | (mean)    | (mg/d)  |
+------------+----------------------+----+------+-----------+---------+
| CUP        | OL, dose escalation, | 5  | 6    | 4-94      | 100-800 |
|            | ongoing              | 33 | 4/36 | (59.8)    |         |
| O          |                      |    |      |           | 100-800 |
| XPL-213^1^ | OL, dose escalation, | 79 | 5    | 27-83     |         |
|            | 14 week              |    | 2/48 | (61.4)    | 300-800 |
| A4         |                      | 37 |      |           |         |
|            | OL, 14-week          |    | 7    | 18-39     | 300-800 |
| AAI-US-    | extension            | 42 | 1/29 | 26.1      |         |
| 175        |                      |    |      |           |         |
|            | OL, PK               |    |      |           |         |
+------------+----------------------+----+------+-----------+---------+

1\. The 14-week extension to study OXPL-213 is designated A4 in this
review.

**Compassionate Use Program**

Cardiome has conducted several analyses from the CUP database. However,
several features of this program as listed below render this database
inadequate for assessing the efficacy or safety of oxypurinol in
allopurinol intolerant patients:

-   The protocol for compassionate use was not originally designed to
    formally evaluate the safety or efficacy or oxypurinol. It was
    open-label, uncontrolled with flexible follow-up visits. Laboratory
    measurements were not collected systematically. The data analysis
    plan for this program was not written until October, 2003.

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-   There is inadequate documentation of allopurinol intolerance before
    entry.

-   There is inadequate documentation of clinical response to therapy

-   Baseline data are missing in a substantial number of patients:

    -   SUA levels missing in 172 patients (32%)

    -   Age and ethnicity are missing in 41% and 31% of patients,
        respectively

-   Post-baseline SUA levels are missing in 127 (24%) of patients.

-   The final dose level was not document in 126 (24%) of patients. For
    analyses, they were assigned a dose category of 300 mg.

-   There were 148 patients (28%) that were lost to follow up.

**OXPL-213 and extension (A4)**

**Design/patients:**

Open-label, 14-week, uncontrolled study of oxypurinol in 79 patients
with symptomatic gout with mild to moderate intolerance to allopurinol.
The study has an ongoing extension (A4).

**Treatment:**

Fixed, dose-escalation, starting with oxypurinol 100 mg/day for the
first week, 200 mg/day for the second week, and 300 mg/day up to week 6.
At this point, patients who had achieved 2 mg/dL change in SUA would
continue on 300 mg/day. Those who did not, would increase to 400, and
then 500 mg/day until week 9. Patients who did not achieve the targeted
change, would increase up to 800 mg/day by week 10. Completers were
offered to continue into the extension (at the same final dose that they
were in the base study).

**Primary Objectives:**

1\) To demonstrate the efficacy of oxypurinol in lowering serum uric
acid by at least 2 mg/dL after 14 weeks of its administration to
symptomatic, hyperuricemic patients who previously developed an
intolerance to allopurinol.

2\) To describe the toxicity profile of oxypurinol.

**Eligibility:**

1\) **Inclusion**: male and female, ≥18 years of age, with symptomatic
gout and documented intolerance to allopurinol. Laboratories: Hgb \> 10
g/dL, WBC \> 3.5x 10^9^/L, platelets \> 100x 10^9^/L, ANC \> 2.0x
10^9^/L; creatinine \< 2.0 mg/dL, ALT \< 3x ULN (upper limit of normal),
AST \< 3x ULN, Alk Phos \< 5 x ULN, conjugated bilirubin \< 1.5 x ULN

2\) **Exclusion**: Patients with history of severe allopurinol cutaneous
reactions such as Stevens-Johnson (SJS) and Toxic Epidermal Necrolysis
(TEN), or severe hepatic or renal reactions such as hepatic necrosis and
renal failure, allopurinol hypersensitivity syndrome and those with any
\> grade 2 hematologic intolerance. Pregnancy. Prior use of oxypurinol.
Patients currently receiving thiazide diuretics or uricosurics. Patients
were allowed colchicine, NSAIDs, corticosteroids and acetaminophen.

**Outcome measures:**

**Efficacy:** Serum uric acid (SUA) levels as a surrogate endpoint for
efficacy measured at entry, 6 weeks, 9 weeks (only for those who had not
achieved 2 mg/dL at 6 weeks) and at the end of study (weeks 12, 13 and
14).

**Safety:** Clinical and laboratory evaluations at baseline, 6 weeks and
end of study. Patients might be discontinued from the study because of :
skin rash, \> grade 2 hematologic toxicity, creatinine \>2x ULN, AST/ALT
\>5x ULN, alkaline phosphatase \>10x ULN. Patient request.

**Primary efficacy analysis:**

Change in mean SUA level from baseline (three baseline levels
approximately 1 week apart) to the end of study (weeks 12, 13 and 14) in
the Intent to Treat (ITT) population. The study would be declared
successful if it showed at least a 2 mg/dL change from baseline
(including lower bound of the 95% CI) in the ITT population.

Extensive negotiations took place between the Sponsor and the DAAODP
regarding this study. Considerations included:

> 1\. This product could potentially fulfill an unmet medical need.
>
> 2\. Investigators were reluctant to use an allopurinol comparator arm.
>
> 3\. If successful in demonstrating a reduction in at least 2 mg/dl in
> SUA and a safety profile that suggested that oxypurinol was safer than
> allopurinol, the sponsor would carry out a phase 4 study for
> evaluation of clinically meaningful endpoints (See Appendix 1). This
> was the rationale for a subpart H submission*.*

**Study Results:**

Baseline demographics are presented in Table 1. Most patients also had
concomitant medical conditions such as hypertension and
hypercholesterolemia and were taking multiple concomitant medications.
Of note, 44 % of patients were on prophylactic colchicine. Prior
allopurinol intolerance in patients who entered OXPL-213 is presented in
Table 2.

Table 2. Prior history of allopurinol intolerance among patients in
OXPL-213.

+------------+---+-----------------------------------------------------+
| Event      | N | Adverse Reactions                                   |
| Category   |   |                                                     |
+------------+---+-----------------------------------------------------+
| Cutaneous  | 2 | Erythroderma with or without pruritus or other      |
|            | 4 | associated symptoms                                 |
| ^(invo     |   |                                                     |
| lved\ 63\  | 1 | Maculopapular or morbilliform rash without          |
| patients)^ | 7 | desquamation and not associated with clinical       |
|            |   | symptoms                                            |
|            | 1 |                                                     |
|            | 1 | Maculopapular or morbilliform rash with localized   |
|            |   | desquamation, covering \<50% body surface area      |
|            | 5 | (BSA).                                              |
|            |   |                                                     |
|            | 7 | Maculopapular or morbilliform rash with localized   |
|            |   | desquamation, covering \>50% BSA.                   |
|            | 1 |                                                     |
|            |   | Exfoliative, eczematoid or vesicular/bullous rash   |
|            | 5 | covering \<50% BSA.                                 |
|            |   |                                                     |
|            |   | Urticarial rash with pruritus and covering \<50% of |
|            |   | BSA requiring PO or topical treatment or IV         |
|            |   | medications or steroids for \< 24 hours.            |
|            |   |                                                     |
|            |   | Urticarial rash with pruritus and covering \> 50%   |
|            |   | of BSA requiring PO or topical treatment or IV      |
|            |   | medications or steroids for more than 24 hours.     |
+------------+---+-----------------------------------------------------+
| Liver      | 7 | ALT/AST or ALT up to 5x ULN                         |
|            |   |                                                     |
|            |   | (four patients also had prior skin reactions)       |
+------------+---+-----------------------------------------------------+
| Renal      | 4 | BUN up to 3x ULN and or Creatinine up to 3x ULN     |
|            |   |                                                     |
|            |   | (two patients also had prior skin react)            |
+------------+---+-----------------------------------------------------+
| Malaise    | 6 | Including asthenia, fatigue, lethargy -- moderate   |
|            |   | causing difficulty performing some activities       |
|            |   |                                                     |
|            |   | (three patients also had prior skin reactions)      |
+------------+---+-----------------------------------------------------+
| Fever      | 1 | Fever in the absence of neutropenia & temperature   |
|            |   | \>40 C for \<24 Hours.                              |
|            |   |                                                     |
|            |   | (this patient also had prior skin reaction)         |
+------------+---+-----------------------------------------------------+
| Mixed      | 1 | BUN up to 3x ULN and or Creatinine up to 3x ULN;    |
|            |   | ALT/AST or ALT up to 2.5 x ULN and malaise.         |
+------------+---+-----------------------------------------------------+

As seen in Table 2, 80% (63/79) of patients had prior mild to moderate
cutaneous reactions to allopurinol, while an additional 24% of patients
had other reactions (alone or in association with cutaneous reactions).
The non-cutaneous reactions (liver, renal, malaise and isolated fever),
were relatively mild. No patient with prior hematologic reaction to
allopurinol was included in the study. Although most patients had a
single episode of allopurinol intolerance, a few had more than one type
of skin reactions or cutaneous and non-cutaneous reactions.

**Patient disposition:** The study enrolled 79 patients. Of those
enrolled, 54 completed the study. As per review of case report
tabulations and case report forms, it appears that 24 patients
discontinued due to adverse events and one due to a protocol violation.

**Efficacy results:**

A comparison of the analyses of the 14-week base study (OXPL-213)
conducted by the sponsor and FDA are presented below in Table 3. As can
be seen, two patients were excluded from the ITT analysis conducted by
the sponsor, but were included in the analysis conducted by FDA; both
analyses imputed missing data with the last observation carried forward
(LOCF).

Table 3. Changes from baseline in SUA levels in patients taking
oxypurinol.

+-----------------------------------------------------------------------+
| SUA Mean decrease                                                     |
|                                                                       |
| \(N\) from baseline^1^ 95% CI                                         |
+-----------------------------------------------------------------------+
| **Sponsor**                                                           |
+-----------------------------------------------------------------------+
| ITT 77 1.90 1.61, 2.18                                                |
|                                                                       |
| Completers 54 2.32 2.07, 2.57                                         |
+-----------------------------------------------------------------------+
| **FDA**                                                               |
+-----------------------------------------------------------------------+
| ITT 79 1.78 1.47, 2.08                                                |
+-----------------------------------------------------------------------+
| Patients who achieved SUA of:                                         |
+-----------------------------------------------------------------------+
| ≤6 mg/dL N (%)                                                        |
|                                                                       |
| ITT 10 (13)                                                           |
|                                                                       |
| Completers 9 (17)                                                     |
+-----------------------------------------------------------------------+
| ≤ 5 mg/dL                                                             |
|                                                                       |
| ITT 2 (3)                                                             |
|                                                                       |
| Completers 2 (4)                                                      |
+-----------------------------------------------------------------------+

1\. The Sponsor's reported p-values (0.0001) test the hypothesis of mean
reduction of zero, that is, the study rejects the hypothesis that
oxypurinol reduces SUA levels by zero. The issue is whether this
statistically significant change is clinically meaningful. In this case
the confidence interval is more informative than the p value.

**Analyses of gout attacks during the OXPL-213 and extension study A4:**

Fourteen patients (18%) had gout flares during these combined studies as
follows:

-   Seven had flares during OXPL-213

-   Six had flares during the extension study (A4)

-   One had flares during both the base and extension phase.

All of these patients experienced a decrease in SUA during the study;
two achieved levels ≤ 6 mg/dL. None of these patients discontinued from
the study due to their gouty flares. This was undoubtedly influenced by
the fact that they were treated with local or systemic corticosteroids
and/or NSAIDs or colchicine as needed. Additionally, three patients
(with no gouty attacks) had tophi complications such as draining, pain
and infection (two patients during the base study and one during the
extension study). Characteristics of the patients with gout attacks
during the base portion are presented in Table 4.

***^Table\ 4.\ Patients\ with\ gout\ flares\ during\ OXPL-2131^***

+--------+-----------------+-------------+-----------+--------+------+
| *Age/* | *Baseline*      | *Final*     | *Taking*  | *Day*  | *Oxy |
|        |                 |             |           |        | d    |
| *g     | *UA level*      | *UA level*  | *co       | *of*   | ose* |
| ender* |                 |             | lchicine* |        |      |
|        |                 |             |           | *      | *(mg |
|        |                 |             |           | Flare* | /d)* |
+--------+-----------------+-------------+-----------+--------+------+
| *29 M* | *9.3- 9- 10.3*  | *8.1- 7.9-  | *Y*       | *39*   | *    |
|        |                 | 8.1*        |           |        | 300* |
| *48 M* | *10.8- 11.9-    |             | *Y*       | *      |      |
|        | 11.5*           | *9.6-10.5-  |           | 14-21* | *    |
| *49 M* |                 | 9.2*        | *Y*       |        | 300* |
|        | *10.7- 12.4-    |             |           | *42-   |      |
| *60 M* | 10.6*           | *9.6-10.5-  | *N*       | 90^2^* | *    |
|        |                 | 8.0*        |           |        | 300* |
| *77 F* | *10.1- 10.2-    |             | *N*       | *26-   |      |
|        | 9.6*            | *6.4- 6.6-  |           | 56^2^* | *    |
| *77 F* |                 | 6.0*        | *N*       |        | 300* |
|        | *8- 8.5- 8.6*   |             |           | *      |      |
| *68 F* |                 | *6.2- 5.9-  | *Y*       | 26-27* | *    |
|        | *9.3- 9.6- 9.6* | 6*          |           |        | 300* |
| *59 F* |                 |             | *N*       | *7-    |      |
|        | *11.3- 10.3-    | *7.6- 8.1-  |           | 23^3^* | *    |
|        | 11*             | 7.1*        |           |        | 200* |
|        |                 |             |           | *      |      |
|        | *8.0- 8.4- 8.5* | *7.3- 8.7-  |           | 68-73* | *    |
|        |                 | 8.2*        |           |        | 300* |
|        |                 |             |           | *15*   |      |
|        |                 | *3.6- 4.8-  |           |        | *    |
|        |                 | 4.7*        |           | *      | 200* |
|        |                 |             |           | 26-31* |      |
|        |                 |             |           |        | *    |
|        |                 |             |           |        | 300* |
+--------+-----------------+-------------+-----------+--------+------+

1.  No patients were described in CRF as having tophi. Analyses from the
    extension study are pending.

2.  Intermittent flares throughout the study.

3.  Had two separate episodes.

While gout attacks are known to occur at the beginning of UA lowering
treatment (supposedly because of rapid changes in SUA levels), the exact
incidence of this event is unknown. As per a published retrospective
review of 354 patients with gout treated with either allopurinol or
uricosuric agents, 15% of patients on allopurinol and 8% of patients
treated with probenecid had gout attacks within the first 3 months of
treatment \[Grahame and Scott, 1970\]. In another article, 10-24% of
patients with gout are reported to have gout flares within the first
year of treatment with allopurinol or uricosuric agents \[Fam, 1995\]

The lack of a placebo-control arm in OXPL-213 makes these finding
difficult to interpret whether were related to the flares the oxypurinol
therapy or ongoing disease. CRFs for this study did not mention the
frequency of gout attacks before study entry.

While it makes intuitive sense that reduction of SUA levels will lead to
reduction of gout attacks, a reduction of SUA of only 2 mg/dl may be
insufficient to decrease the number of gout flares long-term in
patients. By the most favorable analysis in this study (Completers at
the end of 14-week study) mean serum UA levels among 54 completers went
from **9.94** (±1.20) to **7.53** (±1.49) mg/dL, a level that is still
above the normal range and above the desired 6 m/dL level. Only 9
patients achieved SUA ≤ 6 mg/dL (Table 3).

**Safety**

[\
]{.underline}**Deaths:**

There was one death during study OXPL-213 and four during the extension
phase (Table 5). Deaths did not appear to be related to oxypurinol.
Additional data for patient 005.003 are pending.

**Table 5. OXPL-213** and extension A4 - Deaths

+-----------------------------------------------------------------------+
| 14-week base study                                                    |
+-----------------------------------------------------------------------+
| Pancreatic carcinoma                                                  |
+-----------------------------------------------------------------------+
| Extension study                                                       |
+-----------------------------------------------------------------------+
| -Died of end stage liver disease by the time of, before, visit 1 of   |
| the extension. Pt had mild LFT elevation during base study.           |
|                                                                       |
| -Anemia, cellulitis, sepsis sepsis after hip surgery, aspiration      |
| pneumonia (visit 4)                                                   |
|                                                                       |
| -GI bleed, worsening COPD, (during base study had CHF and MI^2^)      |
|                                                                       |
| -Listed as Multi-organ failure (visit 2). CRF consistent with sudden  |
| death                                                                 |
+-----------------------------------------------------------------------+

**Serious adverse events:**

Non-fatal serious adverse events (SAE) during the OXPL-213 and the
extension study A4 are presented in Table 6 and 7, respectively.

**Table 6. Serious adverse events in study OXPL-213**

**Table 7. Serious adverse events in extension study A4**

Most of the serious adverse events appear unrelated to study drug. Of
note, there were three MIs in the base study and one MI and one unstable
angina during the extension study. It is likely these cardiovascular are
not drug related but reflect associated co-morbid conditions such as
hypertension, diabetes, obesity and hypercholesterolemia. The lack of a
placebo arm precludes more definitive conclusions relating to the safety
of oxypurinol.

**Discontinuations due to adverse events**

There were 23 patients that discontinued the 14-week base study due to
non-fatal adverse events; these are presented in Table 8.

Table 8. Discontinuations due to Adverse Events in study OXPL-213

+-----------------+--------+-----------------------------+------------+
| Event           | Prior  | Description of oxypurinol   | A          |
|                 |        | intolerance                 | pproximate |
|                 | allop  |                             | day of     |
|                 | urinol |                             | onset      |
|                 | intol  |                             |            |
|                 | erance |                             |            |
+-----------------+--------+-----------------------------+------------+
| **Skin          | Skin   | Erythematous rash           | Day 3      |
| reaction**      |        |                             |            |
|                 | "      | " "                         | Day 5      |
| 1\.             |        |                             |            |
|                 | " +    | Maculopapular rash          | Day2       |
| 2\.             | M      | arms/chest/back             |            |
|                 | alaise |                             | Day 2      |
| 3\.             |        | Erythematous rash           |            |
|                 | "      |                             | Day 3      |
| 4\.             |        | ""                          |            |
|                 | "      |                             | Day 4      |
| 5\.             |        | Diffuse erythema/ facial    |            |
|                 | "      | swelling                    | Day 2      |
| 6\.             |        |                             |            |
|                 | "      | Diffuse erythema/ pruritus  | Day 23     |
| 7\.             |        |                             |            |
|                 | "      | Diffuse acneiform           | Day 2      |
| 8\.             |        | rash/gastroenteritis        |            |
|                 | "      |                             | Day 6      |
| 9\.             | +Renal | Macular erythematous        |            |
|                 |        |                             | Day 6      |
| 10\.            | "      | Erythematous-itchy          |            |
|                 |        |                             | First dose |
| 11\.            | "      | Maculopapular, itchy        |            |
|                 |        |                             | 1 month    |
| 12\.            | "      | Urticarial/macular/bullous  |            |
|                 |        | rash                        | Day 3      |
| 13\.            | "      |                             |            |
|                 |        | Follicular diffuse rash     | Day 9      |
| 14\.            | "      |                             |            |
|                 |        | Erythematous,               | Day 2      |
| 15\.            | "      | macular,pruritic rash       |            |
|                 |        |                             |            |
| 16\.            | "      | Petechial rash-legs         |            |
|                 |        |                             |            |
|                 |        | Pruritus, Erythematous rash |            |
+-----------------+--------+-----------------------------+------------+
| **Thr           | Skin   | Thrombocytopenia            | Day 20     |
| ombocytopenia** |        |                             |            |
|                 |        |                             |            |
| 17\.            |        |                             |            |
+-----------------+--------+-----------------------------+------------+
| **Liver         | Skin   | ↑ALT/ AST/ AlkPhosphatase   | Day 12     |
| reaction**      | /Liver |                             |            |
|                 |        |                             |            |
| 18\.            |        |                             |            |
+-----------------+--------+-----------------------------+------------+
| **              | Skin   | Fever, chills,              | 3 days     |
| Miscellaneous** | /Liver | polyarthralgia, "viral      |            |
|                 |        | syndrome" Early term as per | Day 54     |
| 19\.            | Skin   | medical monitor decision    |            |
|                 |        | **^1^**                     | First dose |
| 20\.            | M      |                             |            |
|                 | alaise | ↑ALT/ AST/ BUN. Listed as   | First dose |
| 21\.            |        | discontinued due to         |            |
|                 | Liver  | protocol violation,         | 2 months   |
| 22\.            | /Renal | non-compliance. Hx of       |            |
|                 |        | preexisting Hepatitis C.    |            |
| 23\.            | Skin   | **^1^**                     |            |
|                 |        |                             |            |
|                 | "      | Listed as discontinued due  |            |
|                 |        | to nausea/malaise **^1^**   |            |
|                 |        |                             |            |
|                 |        | Hypersensitivity to         |            |
|                 |        | oxypurinol (NOS)            |            |
|                 |        |                             |            |
|                 |        | HA, chills, allergic        |            |
|                 |        | rhinitis                    |            |
+-----------------+--------+-----------------------------+------------+

1\. Information to the IND suggests these patients had hepatic
intolerance.

The hypersensitivity reactions attributed to oxypurinol were very
similar to those previously attributed to allopurinol. Most were
cutaneous reaction in patients with prior history of cutaneous
intolerance (n=18) and most occurred early in the trial (16 cases within
the first week, including three cases after the first dose).

Review of case report tabulations and case report forms suggests that
hepatic intolerance was developed by more than one patient. As per Table
8, in addition to the patient reported by the sponsor as having hepatic
intolerance, three patients who discontinued from the study may have had
hepatic intolerance. Additionally, two patients had mild transaminase
elevation and completed the study OXPL-213 but did not continue into the
extension. One of these was a patient who had had mild LFT elevation at
baseline and throughout the base study, and was reported to have died of
"end stage liver disease" before entering the extension study.
Additional information on this patient is pending. Therefore, there
could be six liver reactions among 79 patients who received oxypurinol.
Although the case report forms are not very helpful in determining
causality, four of the six occurred in patients with a prior history of
liver intolerance to allopurinol. Eosinophil counts were not
consistently obtained in these patients. Those patients who had
available eosinophil counts did not show increase in eosinophil levels.

One patient with prior history of cutaneous intolerance developed
thrombocytopenia.

Four patients discontinued during the extension study A4; they are
listed in Table 9. Overall, the patient disposition for the extension
study is unclear at the time of preparation of this background document.
The sponsor states that 48 patients entered the extension study,
however, case report tabulations include data for 37 patients only.

**Table 9: Discontinuations due to adverse events in A4 extension
study**

\- Rash arms/legs/trunk

\- Adverse event related to oxypurinol (rash versus MI)

\- Right foot infection (after surgical procedure to remove tophi)

\- Left foot surgery, hematuria

Two of these discontinuations appear related to oxypurinol therapy. This
table does not include patients who had abnormal laboratories at the end
of the base study and therefore did not continue into the extension.
Additionally, three patients refused further treatment, one was lost to
follow-up and for one the reason is unclear.

**Adverse events among patients with documented allopurinol re-challenge
or desensitization in study OXPL-213:**

According the Sponsor, there were 26 patients with documented
re-challenge or desensitization of allopurinol. Among the patients, the
following adverse events occurred:

-   1/26 died of pancreatic carcinoma at week 6

-   7/26 developed intolerance to oxypurinol (same as to allopurinol: 5
    skin; 1 liver;1 malaise)

-   18/26 completed 14 weeks of treatment. One of them had a mild skin
    rash and did not enter the extension study. The other 17 entered the
    extension study A4.

Therefore, 18 of 26 patients (69%) who had failed documented allopurinol
re-challenge or desensitization were able to tolerate oxypurinol without
further allergic reactions for up to 14 weeks. However, the cause of
discontinuation is unclear for three patients. Additionally, it is
unclear whether three other patients actually entered the extension
study or not. Additional information is pending at the time of this
review.

**[AAI-US- 175 (Pharmacokinetic study):]{.underline}**

Oxypurinol has non-linear pharmacokinetics. The dose of oxypurinol can
not be easily correlated with that of allopurinol. The following
summarizes oxypurinol PK characteristics:

-   Oral administration of single-doses of 100 and 800 mg doses
    increases systemic exposure only about 2-fold.

-   A high-fat meal increases systemic availability about 2-fold.

-   Relative bioavailability of oxypurinol is about 30% of that from
    allopurinol. Based on oxypurinol exposure, equivalent allopurinol
    doses from oxypurinol doses of 100, 300, 600 and 800 mg are
    approximately 58, 78, 81, and 112 mg, respectively.

**[SUMMARY]{.underline}**

1\) Oxypurinol treatment is associated with a modest reduction in SUA
levels in 79 patients with hyperuricemia after 14 weeks of treatment
(mean change 1.7 mg/dL, 1.47, 2.08 95% CI in the ITT population).

2\) Oxyprim™ appears to provide a subtherapeutic lowering of SUA for the
majority of symptomatic hyperuricemic patients.

3\) Fourteen patients experienced gouty flares and three other patients
had tophi complications during OXPL-213 and its extension. The lack of a
placebo control or an allopurinol comparator arm hampers an adequate
interpretation of these findings.

4\) In OXPL-213, up to one third of the patients developed intolerance
to oxypurinol. Most patients developed the same kind of reaction that
they had experienced with allopurinol; the majority were skin reactions
and occurred early in treatment. However, six patients developed LFT
elevation (four of them had a prior hepatic reaction to allopurinol) and
there was one patient who developed thrombocytopenia.

**Appendix 1**

**Proposal for a Phase 4 Oxypurinol Study (modified from sponsor)**

**1. Design/patients:** Multi-center, double-blind, randomized, placebo
controlled, two-year study in 240 patients with symptomatic gout, with
documented allopurinol intolerance and at least 6 gout attacks in the
year before enrollment.

**2. Treatment:** dose titration: 100 mg/day x 2 weeks, dose gradually
escalated by 100 mg/day every 2 weeks, if indicated, to achieve a SUA of
\<6 mg/dL (supervised by a blinded 3^rd^ party physician based on
adverse events and laboratory data) up to a maximum daily dose of 800
mg.

![](media/image1.png){width="6.010416666666667in"
height="1.5104166666666667in"}

> Oxypurinol 100 mg\-\--800 mg

Or Placebo

(2:1 randomization)

**3. Objective:** Primary: To evaluate efficacy and safety of oxypurinol
therapy, over at least a 2-year period, in reducing the number of acute
attacks.

Secondary: Reducing SUA from baseline

SUA \<6mg/dL

Size and number of swollen joints

Size and number of tophi

Decreasing hospital admissions for gout

Emergency visits for gout flares

Frequency of symptomatic nephrolithiasis

Reducing use of anti-inflammatory and other rescue medications

Improving overall quality of life (SF-36)

**4. Eligibility**: Inclusion: M or F, 18 to 80 years. Mild to moderate
skin or other allergic

> reactions to allopurinol with recurrence of symptoms on re-exposure to
> allopurinol, on a stable treatment for gout for at least 3 weeks prior
> to study entry.

Exclusion: patients with severe or serious adverse events related to

> allopurinol. Pregnancy or lactation.
>
> Concomitant medications. Permitted:
>
> Analgesics, NSAIDS, colchicine, steroids and uricosuric agents. Low
> dose aspirin if benefits are believed to outweigh the risk of
> increasing SUA. Ethanol consumption should be discouraged.
>
> Concomitant medications. Prohibited: Ampicillin and related
> semi-synthetic penicillins; thiazide and loop diuretics because they
> can reduce renal uric acid excretion and increase SUA.

**5. Safety outcomes:** History and physical, vital signs, documentation
of adverse reactions and SUA levels at baseline, every two weeks until
week 18, then every two months until final assessment at 30 months.
Laboratories: Hematology, renal function and liver function tests at
baseline, at weeks 4 and every two weeks until week 18, then every six
months until month 30.

**6. Statistical Considerations and statistical plan**

**6.1 Efficacy Endpoints**

***Primary Efficacy Endpoint***

> The primary efficacy endpoint will be the number of documented acute
> gout attacks, requiring additional treatment and reported by the
> patient to the investigator, during the 2-year study period.

***Secondary Efficacy Endpoints***

> • Reduction in SUA
>
> • Proportion of patients with SUA levels \< 6mg/dL
>
> • Size of swollen joints
>
> • Number of swollen joints
>
> • Size of tophi
>
> • Number of tophi
>
> • Number of hospital admissions for gout
>
> • Number of emergency room visits for gout flares
>
> • Number of episodes of symptomatic nephrolithiasis
>
> • Use of anti-inflammatory and other rescue medications for acute gout
> flares
>
> • SF-36 Quality-of-Life Questionnaire

**6.2 Safety Endpoints**

> • Adverse events,

• Vital signs,

> • Laboratory data (CBC , Liver function tests, and SUA).

**7. Statistical and analytical methods**.

The primary efficacy analysis will consist of a comparison between the
mean number of

documented acute gout attacks (requiring additional treatment and
reported by the patient

to the investigator, during the 2-year study period) between the
oxypurinol and placebo

groups.