Interim Results from a New Trial of Cancidas (caspofungin acetate) in Pediatric Patients with Documented Fungal Infections

SAN DIEGO--(BUSINESS WIRE)--Oct 5, 2007 - CANCIDAS(R) (caspofungin acetate), given once daily, was evaluated as a treatment for patients three months to 17 years of age with documented or suspected fungal infections. The use of CANCIDAS in pediatric patients is investigational. Interim results from the first Phase II clinical trial to study this therapy in pediatric patients with invasive candidiasis, esophageal candidiasis or invasive aspergillosis (as salvage therapy only) will be presented on Sunday, October 7, at the 45th Annual Meeting of the Infectious Diseases Society of America (IDSA).

Preliminary data from the first 39 patients enrolled in the study found that 74 percent of trial participants treated with CANCIDAS achieved complete or significant improvement in signs and symptoms related to each infection type studied. Favorable response was determined based on complete (in the case of patients with candidemia) or significant clinical and, where appropriate, microbiological or radiographic/endoscopic improvement.

Specifically, 81 percent (22/27) of patients with invasive candidiasis, 100 percent (1/1) of patients with esophageal candidiasis and 50 percent (5/10) of patients with invasive aspergillosis had a favorable response at the end of CANCIDAS therapy. One patient (4 percent) relapsed after four weeks post-therapy. Duration of treatment was individualized for each patient, in accordance with IDSA practice guidelines. The mean duration of treatment for patients with invasive aspergillosis was 42.7 days, 12.3 days for invasive candidiasis and 32 days for esophageal candidiasis.

There were no drug-related serious adverse events and no discontinuations of CANCIDAS therapy due to toxicity. Twenty-eight percent of trial participants experienced clinical drug-related adverse events. Fever (8 percent) and rash (8 percent) were the most frequent clinical drug-related adverse events reported in greater than1 patient. Thirty-one percent of trial participants experienced laboratory drug-related adverse events which included increases in two liver enzymes that measure liver function - aspartate aminotransferase (18 percent) and alanine aminotransferase (10 percent); ï? an increase in a type of white blood cell count - the eosinophil cell (5 percent); and decreases in magnesium and phosphorus levels (5 percent). However, many laboratory abnormalities had returned to prestudy levels or were decreasing by the end of therapy. One systemic infusion-related adverse event of severe intensity (thrombophlebitis) and one event of moderate intensity (fever) were also reported. There were five deaths (13 percent) reported through five weeks posttherapy, all in patients with invasive aspergillosis. None were considered by the investigator to be related to therapy with CANCIDAS.

"These interim results are a preliminary indicator that CANCIDAS may be a therapeutic intervention for pediatric patients with invasive fungal infections," said Dr. Theoklis Zaoutis, assistant professor of Pediatrics and Epidemiology, Division of Infectious Diseases, Children's Hospital, Philadelphia, and lead study investigator.

Study design

This prospective, open-label, multi-center noncomparative study enrolled patients aged three months to 17 years of age with:

-- Proven or probable invasive aspergillosis refractory to or intolerant of standard antifungal therapy

-- Proven esophageal candidiasis (based on clinical, endoscopic and microbiological (or histopathological) criteria)

-- Invasive candidiasis (with clinical and microbiological evidence within 96 hours of study entry)

Study exclusion criteria included invasive aspergillosis in which the disease was limited to allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, or ocular disease; Candida endocarditis, osteomyelitis, or meningitis; prosthetic device at suspected site of infection not removed within 72 hours; esophageal candidiasis limited to oropharynx and other cause of esophagitis or other esophageal pathology.

Participants were followed for 14 days post-treatment to evaluate safety and 28 days post-treatment for relapse. A total of 12 sites in five countries are enrolling patients with a target of approximately 50 participants. CANCIDAS was administered as primary or salvage therapy for esophageal candidiasis and invasive candidiasis and as salvage therapy for invasive aspergillosis. Patients were given CANCIDAS 50 mg/m(2) daily (maximum 70 mg daily) following a 70 mg/m(2 )loading dose on day one. Patients could be dose-escalated to CANCIDAS 70 mg/m(2) daily (maximum 70 mg/day) if not responding.

About fungal infections

Candidemia - a form of invasive candidiasis - is the fourth most common bloodstream infection among hospitalized patients in the United States. Invasive aspergillosis, a fungal infection that originates most commonly in the lungs, often occurs in severely immune-compromised patients and is associated with high mortality. Esophageal candidiasis is a fungal infection that forms in the esophagus and is largely caused by Candida species. It most commonly occurs in immunosuppressed patients and is among the most common opportunistic infection in patients with advanced HIV infection.

Fungal infections resulting from Candida or Aspergillus species are a significant cause of morbidity and mortality, and immunosuppressed patients such as those with persistent fever and neutropenia are at a particularly high risk. In fact, one form of fungal infection, invasive candidiasis, has a mortality rate of 40 to 60 percent with bloodstream and disseminated infection in adults.

About CANCIDAS

CANCIDAS is a member of the echinocandin class of antifungals. CANCIDAS inhibits the synthesis of (beta)(1,3)-D-glucan, an integral component of the fungal cell wall. CANCIDAS is administered via intravenous infusion.

In the United States, CANCIDAS is indicated in adults for:

-- Empirical therapy for presumed fungal infections in febrile, neutropenic patients

-- Treatment of candidemia and the following Candida infections: intraabdominal abscesses, peritonitis, and pleural space infections; CANCIDAS has not been studied in endocarditis, osteomyelitis, or meningitis due to Candida

-- Treatment of esophageal candidiasis

-- Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies.

Selected important risk information

Caspofungin is not currently approved for use in pediatric patients. CANCIDAS is contraindicated in patients with hypersensitivity to any component of the product. Concomitant use of CANCIDAS with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk of increased hepatic enzyme abnormalities.

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with CANCIDAS. In some patients with serious underlying conditions who are receiving multiple concomitant medications along with CANCIDAS, clinical hepatic abnormalities have also occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported in patients; a causal relationship to CANCIDAS has not been established. Patients who develop abnormal liver function tests during therapy with CANCIDAS should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing therapy with CANCIDAS.

Possible histamine-mediated symptoms have been reported including rash, facial swelling, pruritus, sensation of warmth and bronchospasm. Anaphylaxis has been reported during administration of CANCIDAS.

For details about CANCIDAS, please read the accompanying prescribing information.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programmes that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

CANCIDAS(R) is a registered trademark of Merck & Co., Inc.

Prescribing information for CANCIDAS(R) is attached. -0-

                                                               9344308


    INTRAVENOUS INFUSION (not for IV Bolus Injection)


    CANCIDAS(R)

    (caspofungin acetate) FOR INJECTION


    DESCRIPTION:


    CANCIDAS* is a sterile, lyophilized product for intravenous (IV)

infusion that contains a semisynthetic lipopeptide (echinocandin)

compound synthesized from a fermentation product of Glarea lozoyensis.

CANCIDAS is the first of a new class of antifungal drugs

(echinocandins) that inhibit the synthesis of beta (1,3)-D-glucan, an

integral component of the fungal cell wall.


    CANCIDAS (caspofungin acetate) is 1-((4R,5S)-

5-((2-aminoethyl)amino)-N(2)-(10,12-dimethyl-1-oxotetradecyl)-

4-hydroxy-L-ornithine)-5-((3R)-3-hydroxy-L-ornithine) pneumocandin

B(0) diacetate (salt). CANCIDAS 50 mg also contains: 39 mg sucrose,

26 mg mannitol, glacial acetic acid, and sodium hydroxide. CANCIDAS

70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic

acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic,

white to off-white powder. It is freely soluble in water and methanol,

and slightly soluble in ethanol. The pH of a saturated aqueous

solution of caspofungin acetate is approximately 6.6. The empirical

formula is C(52)H(88)N(10)O(15)--2C(2)H(4)O(2) and the formula weight

is 1213.42. The structural formula is:


    (Graphic Omitted)


    CLINICAL PHARMACOLOGY

    Pharmacokinetics


    Distribution


    Plasma concentrations of caspofungin decline in a polyphasic

manner following single 1-hour IV infusions. A short alpha-phase

occurs immediately postinfusion, followed by a beta-phase (half-life

of 9 to 11 hours) that characterizes much of the profile and exhibits

clear log-linear behavior from 6 to 48 hours postdose during which the

plasma concentration decreases 10-fold. An additional, longer

half-life phase, gamma-phase, (half-life of 40-50 hours), also occurs.

Distribution, rather than excretion or biotransformation, is the

dominant mechanism influencing plasma clearance. Caspofungin is

extensively bound to albumin (tilde97%), and distribution into red

blood cells is minimal. Mass balance results showed that approximately

92% of the administered radioactivity was distributed to tissues by 36

to 48 hours after a single 70-mg dose of ((3)H) caspofungin acetate.

There is little excretion or biotransformation of caspofungin during

the first 30 hours after administration.


    Metabolism


    Caspofungin is slowly metabolized by hydrolysis and N-acetylation.

Caspofungin also undergoes spontaneous chemical degradation to an

open-ring peptide compound, L-747969. At later time points ((greater

than=)5 days postdose), there is a low level ((less than=)7

picomoles/mg protein, or (less than=)1.3% of administered dose) of

covalent binding of radiolabel in plasma following single-dose

administration of ((3)H) caspofungin acetate, which may be due to two

reactive intermediates formed during the chemical degradation of

caspofungin to L-747969. Additional metabolism involves hydrolysis

into constitutive amino acids and their degradates, including

dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two

tyrosine derivatives are found only in urine, suggesting rapid

clearance of these derivatives by the kidneys.


    Excretion


    Two single-dose radiolabeled pharmacokinetic studies were

conducted. In one study, plasma, urine, and feces were collected over

27 days, and in the second study plasma was collected over 6 months.

Plasma concentrations of radioactivity and of caspofungin were similar

during the first 24 to 48 hours postdose; thereafter drug levels fell

more rapidly. In plasma, caspofungin concentrations fell below the

limit of quantitation after 6 to 8 days postdose, while radiolabel

fell below the limit of quantitation at 22.3 weeks postdose. After

single intravenous administration of ((3)H) caspofungin acetate,

excretion of caspofungin and its metabolites in humans was 35% of dose

in feces and 41% of dose in urine. A small amount of caspofungin is

excreted unchanged in urine (tilde1.4% of dose). Renal clearance of

parent drug is low (tilde0.15 mL/min) and total clearance of

caspofungin is 12 mL/min.


    Special Populations

    Gender


    Plasma concentrations of caspofungin in healthy men and women were

similar following a single 70-mg dose. After 13 daily 50-mg doses,

caspofungin plasma concentrations in women were elevated slightly

(approximately 22% in area under the curve (AUC)) relative to men. No

dosage adjustment is necessary based on gender.


    Geriatric


    Plasma concentrations of caspofungin in healthy older men and

women ((greater than=)65 years of age) were increased slightly

(approximately 28% AUC) compared to young healthy men after a single

70-mg dose of caspofungin. In patients who were treated empirically or

who had candidemia or other Candida infections (intra-abdominal

abscesses, peritonitis, or pleural space infections), a similar modest

effect of age was seen in older patients relative to younger patients.

No dosage adjustment is necessary for the elderly (see PRECAUTIONS,

Geriatric Use).


    Race


    Regression analyses of patient pharmacokinetic data indicated that

no clinically significant differences in the pharmacokinetics of

caspofungin were seen among Caucasians, Blacks, and Hispanics. No

dosage adjustment is necessary on the basis of race.


    Renal Insufficiency


    In a clinical study of single 70-mg doses, caspofungin

pharmacokinetics were similar in volunteers with mild renal

insufficiency (creatinine clearance 50 to 80 mL/min) and control

subjects. Moderate (creatinine clearance 31 to 49 mL/min), advanced

(creatinine clearance 5 to 30 mL/min), and end-stage (creatinine

clearance less than 10 mL/min and dialysis dependent) renal

insufficiency moderately increased caspofungin plasma concentrations

after single-dose administration (range: 30 to 49% for AUC). However,

in patients with invasive aspergillosis, candidemia, or other Candida

infections (intra-abdominal abscesses, peritonitis, or pleural space

infections) who received multiple daily doses of CANCIDAS 50 mg, there

was no significant effect of mild to end-stage renal impairment on

caspofungin concentrations. No dosage adjustment is necessary for

patients with renal insufficiency. Caspofungin is not dialyzable, thus

supplementary dosing is not required following hemodialysis.


    Hepatic Insufficiency


    Plasma concentrations of caspofungin after a single 70-mg dose in

patients with mild hepatic insufficiency (Child-Pugh score 5 to 6)

were increased by approximately 55% in AUC compared to healthy control

subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by

50 mg daily thereafter), plasma concentrations in patients with mild

hepatic insufficiency were increased modestly (19 to 25% in AUC) on

Days 7 and 14 relative to healthy control subjects. No dosage

adjustment is recommended for patients with mild hepatic

insufficiency. Patients with moderate hepatic insufficiency

(Child-Pugh score 7 to 9) who received a single 70-mg dose of CANCIDAS

had an average plasma caspofungin increase of 76% in AUC compared to

control subjects. A dosage reduction is recommended for patients with

moderate hepatic insufficiency (see DOSAGE AND ADMINISTRATION). There

is no clinical experience in patients with severe hepatic

insufficiency (Child-Pugh score greater than 9).


    Pediatric Patients


    CANCIDAS has not been adequately studied in patients under

18 years of age.


    MICROBIOLOGY


    Mechanism of Action


    Caspofungin acetate, the active ingredient of CANCIDAS, inhibits

the synthesis of beta (1,3)-D-glucan, an essential component of the

cell wall of susceptible Aspergillus species and Candida species.

beta (1,3)-D-glucan is not present in mammalian cells. Caspofungin has

shown activity against Candida species and in regions of active cell

growth of the hyphae of Aspergillus fumigatus.


    Activity in vitro


    Caspofungin exhibits in vitro activity against Aspergillus species

(Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus)

and Candida species (Candida albicans, Candida glabrata, Candida

guilliermondii, Candida krusei, Candida parapsilosis, and Candida

tropicalis). Susceptibility testing was performed according to the

National Committee for Clinical Laboratory Standards (NCCLS) method

M38-A (for Aspergillus species) and M27-A (for Candida species).

Standardized susceptibility testing methods for echinocandins have not

been established for yeasts and filamentous fungi, and results of

susceptibility studies do not correlate with clinical outcome.


    Activity in vivo


    Caspofungin was active when parenterally administered to

immunocompetent and immunosuppressed mice as long as 24 hours after

disseminated infections with C. albicans, in which the endpoints were

prolonged survival of infected mice and reduction of C. albicans from

target organs. Caspofungin, administered parenterally to

immunocompetent and immunosuppressed rodents, as long as 24 hours

after disseminated or pulmonary infection with Aspergillus fumigatus,

has shown prolonged survival, which has not been consistently

associated with a reduction in mycological burden.


    Drug Resistance


    Mutants of Candida with reduced susceptibility to caspofungin have

been identified in some patients during treatment. Similar

observations were made in a study in mice infected with C. albicans

and treated with orally administered doses of caspofungin. MIC values

for caspofungin should not be used to predict clinical outcome, since

a correlation between MIC values and clinical outcome has not been

established. The incidence of drug resistance by various clinical

isolates of Candida and Aspergillus species is unknown.


    Drug Interactions


    Studies in vitro and in vivo of caspofungin, in combination with

amphotericin B, suggest no antagonism of antifungal activity against

either A. fumigatus or C. albicans. The clinical significance of these

results is unknown.


    CLINICAL STUDIES


    Empirical Therapy in febrile, neutropenic patients


    A double-blind study enrolled 1111 febrile, neutropenic

(less than500 cells/mm(3)) patients who were randomized to treatment

with daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose

on Day 1) or AmBisome((R)1) (amphotericin B liposome for injection,

3.0 mg/kg/day). Patients were stratified based on risk category

(high-risk patients had undergone allogeneic stem cell transplantation

or had relapsed acute leukemia) and on receipt of prior antifungal

prophylaxis. Twenty-four percent of patients were high risk and 56%

had received prior antifungal prophylaxis. Patients who remained

febrile or clinically deteriorated following 5 days of therapy could

receive 70 mg/day of CANCIDAS or 5.0 mg/kg/day of AmBisome. Treatment

was continued to resolution of neutropenia (but not beyond 28 days

unless a fungal infection was documented).


    An overall favorable response required meeting each of the

following criteria: no documented breakthrough fungal infections up to

7 days after completion of treatment, survival for 7 days after

completion of study therapy, no discontinuation of the study drug

because of drug-related toxicity or lack of efficacy, resolution of

fever during the period of neutropenia, and successful treatment of

any documented baseline fungal infection.


    Based on the composite response rates, CANCIDAS was as effective

as AmBisome in empirical therapy of persistent febrile neutropenia

(see Table 1).




                                TABLE 1


       Favorable Response of Patients with Persistent Fever and

                              Neutropenia



                                                        % Difference

                                                        (Confidence

                                CANCIDAS*   AmBisome*    Interval) **

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

Number of Patients (Modified

 Intention-To-Treat)                   556         539

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

Overall Favorable Response     190 (33.9%) 181 (33.7%) 0.2 (-5.6, 6.0)

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

 No documented breakthrough

  fungal infection             527 (94.8%) 515 (95.5%)            -0.8

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

 Survival 7 days after end of

  treatment                    515 (92.6%) 481 (89.2%)             3.4

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

 No discontinuation due to

  toxicity or lack of efficacy 499 (89.7%) 461 (85.5%)             4.2

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

 Resolution of fever during

  neutropenia                  229 (41.2%) 223 (41.4%)            -0.2

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



    * CANCIDAS: 70 mg on Day 1, then 50 mg daily for the remainder of

treatment (daily dose increased to 70 mg for 73 patients);


    AmBisome: 3.0 mg/kg/day (daily dose increased to 5.0 mg/kg for 74

patients).


    ** Overall Response: estimated % difference adjusted for strata

and expressed as CANCIDAS - AmBisome (95.2% CI);


    Individual criteria presented above are not mutually exclusive.

The percent difference calculated as CANCIDAS - AmBisome.


    The rate of successful treatment of documented baseline

infections, a component of the primary endpoint, was not statistically

different between treatment groups.


    The response rates did not differ between treatment groups based

on either of the stratification variables: risk category or prior

antifungal prophylaxis.


    Candidemia and the following other Candida infections:

intra-abdominal abscesses, peritonitis and pleural space infections


    In a Phase III randomized, double-blind study, patients with a

proven diagnosis of invasive candidiasis received daily doses of

CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or

amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non-neutropenic

patients and 0.7 to 1.0 mg/kg/day for neutropenic patients). Patients

were stratified by both neutropenic status and APACHE II score.

Patients with Candida endocarditis, meningitis, or osteomyelitis were

excluded from this study.


    Patients who met the entry criteria and received one or more doses

of IV study therapy were included in the primary (modified

intention-to-treat (MITT)) analysis of response at the end of IV study

therapy. A favorable response at this time point required both

symptom/sign resolution/improvement and microbiological clearance of

the Candida infection.


    Two hundred thirty-nine patients were enrolled. Patient

disposition is shown in Table 2.




                               TABLE 2

        Disposition in Candidemia and Other Candida Infections

(Intra-abdominal abscesses, peritonitis, and pleural space infections)


                                                CANCIDAS* Amphotericin

                                                                B

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

Randomized patients                                    114         125

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

Patients completing study**                     63 (55.3%)  69 (55.2%)

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

                     DISCONTINUATIONS OF STUDY**

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

All Study Discontinuations                      51 (44.7%)  56 (44.8%)

   Study Discontinuations due to clinical

    adverse events                              39 (34.2%)  43 (34.4%)

   Study Discontinuations due to laboratory

    adverse events                                  0 (0%)    1 (0.8%)

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

                  DISCONTINUATIONS OF STUDY THERAPY

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

All Study Therapy Discontinuations              48 (42.1%)  58 (46.4%)

   Study Therapy Discontinuations due to

    clinical adverse events                     30 (26.3%)  37 (29.6%)

   Study Therapy Discontinuations due to

    laboratory adverse events                     1 (0.9%)    7 (5.6%)

   Study Therapy Discontinuations due to all

    drug-related*** adverse events                3 (2.6%)  29 (23.2%)

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



    * Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily for

the remainder of their treatment.


    **Study defined as study treatment period and 6-8 week follow-up

period.


    ***Determined by the investigator to be possibly, probably, or

definitely drug-related.


    Of the 239 patients enrolled, 224 met the criteria for inclusion

in the MITT population (109 treated with CANCIDAS and 115 treated with

amphotericin B). Of these 224 patients, 186 patients had candidemia

(92 treated with CANCIDAS and 94 treated with amphotericin B). The

majority of the patients with candidemia were non-neutropenic (87%)

and had an APACHE II score less than or equal to 20 (77%) in both

arms. Most candidemia infections were caused by C. albicans (39%),

followed by C. parapsilosis (20%), C. tropicalis (17%), C. glabrata

(8%), and C. krusei (3%).


    At the end of IV study therapy, CANCIDAS was comparable to

amphotericin B in the treatment of candidemia in the MITT population.

For the other efficacy time points (Day 10 of IV study therapy, end of

all antifungal therapy, 2-week post-therapy follow-up, and 6- to

8-week post-therapy follow-up), CANCIDAS was as effective as

amphotericin B.


    Outcome, relapse and mortality data are shown in Table 3.




                               TABLE 3

   Outcomes, Relapse, & Mortality in Candidemia and Other Candida

 Infections (Intra-abdominal abscesses, peritonitis, and pleural space

                              infections)


                                                      % Difference**

                                                       after adjusting

                                                         for strata

                                                        (Confidence

                          CANCIDAS*    Amphotericin B   Interval)***

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

Number of MITT+

 patients                          109            115

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

       FAVORABLE OUTCOMES (MITT) AT THE END OF IV STUDY THERAPY

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

All MITT patients       81/109 (74.3%) 78/115 (67.8%) 7.5 (-5.4, 20.3)

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

Candidemia               67/92 (72.8%)  63/94 (67.0%)

Neutropenic                 6/14 (43%)     5/10 (50%)

Non-neutropenic            61/78 (78%)    58/84 (69%) 7.0 (-7.0, 21.1)

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

Endophthalmitis                    0/1            2/3

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

Multiple Sites                     4/5            4/4

Blood / Pleural                    1/1            1/1

Blood / Peritoneal                 1/1            1/1

Blood / Urine                        -            1/1

Peritoneal / Pleural               1/2              -

Abdominal / Peritoneal               -            1/1

Subphrenic / Peritoneal            1/1              -

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

           DISSEMINATED INFECTIONS, RELAPSES AND MORTALITY

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

Disseminated Infections

 in neutropenic

 patients                 4/14 (28.6%)   3/10 (30.0%)

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

All relapses++             7/81 (8.6%)   8/78 (10.3%)

  Culture-confirmed

   relapse                   5/81 (6%)      2/78 (3%)

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

Overall study+++

 mortality in MITT

Mortality during study

 therapy                36/109 (33.0%) 35/115 (30.4%)

Mortality attributed to   18/109 (17%)   13/115 (11%)

 Candida                    4/109 (4%)     7/115 (6%)

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



    * Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily for

the remainder of their treatment.


    ** Calculated as CANCIDAS - amphotericin B


    *** 95% CI for candidemia, 95.6% for all patients


    + Modified intention-to-treat


    ++ Includes all patients who either developed a culture-confirmed

recurrence of Candida infection or required antifungal therapy for the

treatment of a proven or suspected Candida infection in the follow-up

period.


    +++Study defined as study treatment period and 6-8 week follow-up

period.


    In this study, the efficacy of CANCIDAS in patients with

intra-abdominal abscesses, peritonitis and pleural space Candida

infections was evaluated in 19 non-neutropenic patients. Two of these

patients had concurrent candidemia. Candida was part of a

polymicrobial infection that required adjunctive surgical drainage in

11 of these 19 patients. A favorable response was seen in 9 of

9 patients with peritonitis, 3 of 4 with abscesses (liver,

parasplenic, and urinary bladder abscesses), 2 of 2 with pleural space

infections, 1 of 2 with mixed peritoneal and pleural infection, 1 of 1

with mixed abdominal abscess and peritonitis, and 0 of 1 with Candida

pneumonia.


    Overall, across all sites of infection included in the study, the

efficacy of CANCIDAS was comparable to that of amphotericin B for the

primary endpoint.


    In this study, the efficacy data for CANCIDAS in neutropenic

patients with candidemia were limited. In a separate compassionate use

study, 4 patients with hepatosplenic candidiasis received prolonged

therapy with CANCIDAS following other long-term antifungal therapy;

three of these patients had a favorable response.


    Esophageal Candidiasis (and information on oropharyngeal

candidiasis)


    The safety and efficacy of CANCIDAS in the treatment of esophageal

candidiasis was evaluated in one large, controlled, noninferiority,

clinical trial and two smaller dose-response studies.


    In all 3 studies, patients were required to have symptoms and

microbiological documentation of esophageal candidiasis; most patients

had advanced AIDS (with CD4 counts less than50/mm(3)).


    Of the 166 patients in the large study who had culture-confirmed

esophageal candidiasis at baseline, 120 had Candida albicans and 2 had

Candida tropicalis as the sole baseline pathogen whereas 44 had mixed

baseline cultures containing C. albicans and one or more additional

Candida species.


    In the large, randomized, double-blind study comparing CANCIDAS

50 mg/day versus intravenous fluconazole 200 mg/day for the treatment

of esophageal candidiasis, patients were treated for an average of

9 days (range 7-21 days). The primary endpoint was favorable overall

response at 5 to 7 days following discontinuation of study therapy,

which required both complete resolution of symptoms and significant

endoscopic improvement. The definition of endoscopic response was

based on severity of disease at baseline using a 4-grade scale and

required at least a two-grade reduction from baseline endoscopic score

or reduction to grade 0 for patients with a baseline score of 2 or

less.


    The proportion of patients with a favorable overall response for

the primary endpoint was comparable for CANCIDAS and fluconazole as

shown in Table 4.




                               TABLE 4

  Favorable Response Rates for Patients with Esophageal Candidiasis


                                                      % Difference*

                         CANCIDAS      Fluconazole      (95% CI)

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

Day 5-7 post-treatment  66/81 (81.5%)  80/94 (85.1%)-3.6 (-14.7, 7.5)

=====================================================================



    * calculated as CANCIDAS - fluconazole


    The proportion of patients with a favorable symptom response was

also comparable (90.1% and 89.4% for CANCIDAS and fluconazole,

respectively). In addition, the proportion of patients with a

favorable endoscopic response was comparable (85.2% and 86.2% for

CANCIDAS and fluconazole, respectively).


    As shown in Table 5, the esophageal candidiasis relapse rates at

the Day 14 post-treatment visit were similar for the two groups. At

the Day 28 post-treatment visit, the group treated with CANCIDAS had a

numerically higher incidence of relapse, however, the difference was

not statistically significant.




                               TABLE 5

   Relapse Rates at 14 and 28 Days Post-Therapy in Patients with

                  Esophageal Candidiasis at Baseline


                                                      % Difference*

                         CANCIDAS      Fluconazole      (95% CI)

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

Day 14 post-treatment    7/66 (10.6%)    6/76 (7.9%) 2.7 (-6.9, 12.3)

Day 28 post-treatment   18/64 (28.1%)  12/72 (16.7%)11.5 (-2.5, 25.4)

=====================================================================



    * calculated as CANCIDAS - fluconazole


    In this trial, which was designed to establish noninferiority of

CANCIDAS to fluconazole for the treatment of esophageal candidiasis,

122 (70%) patients also had oropharyngeal candidiasis. A favorable

response was defined as complete resolution of all symptoms of

oropharyngeal disease and all visible oropharyngeal lesions. The

proportion of patients with a favorable oropharyngeal response at the

5- to 7-day post-treatment visit was numerically lower for CANCIDAS,

however, the difference was not statistically significant. The results

are shown in Table 6.




                               TABLE 6

Oropharyngeal Candidiasis Response Rates at 5 to 7 Days Post-Therapy

 in Patients with Oropharyngeal and Esophageal Candidiasis at Baseline


                                                      % Difference*

                         CANCIDAS      Fluconazole      (95% CI)

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

Day 5-7 post-treatment  40/56 (71.4%)  55/66 (83.3%)-11.9 (-26.8, 3.0)

======================================================================



    * calculated as CANCIDAS - fluconazole


    As shown in Table 7, the oropharyngeal candidiasis relapse rates

at the Day 14 and the Day 28 post-treatment visits were statistically

significantly higher for CANCIDAS than for fluconazole.




                               TABLE 7

Oropharyngeal Candidiasis Relapse Rates at 14 and 28 Days Post-Therapy

 in Patients with Oropharyngeal and Esophageal Candidiasis at Baseline


                                                      % Difference*

                         CANCIDAS      Fluconazole      (95% CI)

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

Day 14 post-treatment   17/40 (42.5%)   7/53 (13.2%) 29.3 (11.5, 47.1)

Day 28 post-treatment   23/39 (59.0%)  18/51 (35.3%)  23.7 (3.4, 43.9)

======================================================================



    * calculated as CANCIDAS - fluconazole


    The results from the two smaller dose-ranging studies corroborate

the efficacy of CANCIDAS for esophageal candidiasis that was

demonstrated in the larger study.


    CANCIDAS was associated with favorable outcomes in 7 of 10

esophageal C. albicans infections refractory to at least 200 mg of

fluconazole given for 7 days, although the in vitro susceptibility of

the infecting isolates to fluconazole was not known.


    Invasive Aspergillosis


    Sixty-nine patients between the ages of 18 and 80 with invasive

aspergillosis (IA) were enrolled in an open-label, noncomparative

study to evaluate the safety, tolerability, and efficacy of CANCIDAS.

Enrolled patients had previously been refractory to or intolerant of

other antifungal therapy(ies). Refractory patients were classified as

those who had disease progression or failed to improve despite therapy

for at least 7 days with amphotericin B, lipid formulations of

amphotericin B, itraconazole, or an investigational azole with

reported activity against Aspergillus. Intolerance to previous therapy

was defined as a doubling of creatinine (or creatinine

(greater than=)2.5 mg/dL while on therapy), other acute reactions, or

infusion-related toxicity. To be included in the study, patients with

pulmonary disease must have had definite (positive tissue

histopathology or positive culture from tissue obtained by an invasive

procedure) or probable (positive radiographic or computed tomography

evidence with supporting culture from bronchoalveolar lavage or

sputum, galactomannan enzyme-linked immunosorbent assay, and/or

polymerase chain reaction) invasive aspergillosis. Patients with

extrapulmonary disease had to have definite invasive aspergillosis.

The definitions were modeled after the Mycoses Study Group Criteria.

(2) Patients were administered a single 70-mg loading dose of CANCIDAS

and subsequently dosed with 50 mg daily. The mean duration of therapy

was 33.7 days, with a range of 1 to 162 days.


    An independent expert panel evaluated patient data, including

diagnosis of invasive aspergillosis, response and tolerability to

previous antifungal therapy, treatment course on CANCIDAS, and

clinical outcome.


    A favorable response was defined as either complete resolution

(complete response) or clinically meaningful improvement (partial

response) of all signs and symptoms and attributable radiographic

findings. Stable, nonprogressive disease was considered to be an

unfavorable response.


    Among the 69 patients enrolled in the study, 63 met entry

diagnostic criteria and had outcome data; and of these, 52 patients

received treatment for greater than7 days. Fifty-three (84%) were

refractory to previous antifungal therapy and 10 (16%) were

intolerant. Forty-five patients had pulmonary disease and 18 had

extrapulmonary disease. Underlying conditions were hematologic

malignancy (N=24), allogeneic bone marrow transplant or stem cell

transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other

conditions (N=10). All patients in the study received concomitant

therapies for their other underlying conditions. Eighteen patients

received tacrolimus and CANCIDAS concomitantly, of whom 8 also

received mycophenolate mofetil.


    Overall, the expert panel determined that 41% (26/63) of patients

receiving at least one dose of CANCIDAS had a favorable response. For

those patients who received greater than7 days of therapy with

CANCIDAS, 50% (26/52) had a favorable response. The favorable response

rates for patients who were either refractory to or intolerant of

previous therapies were 36% (19/53) and 70% (7/10), respectively. The

response rates among patients with pulmonary disease and

extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively.

Among patients with extrapulmonary disease, 2 of 8 patients who also

had definite, probable, or possible CNS involvement had a favorable

response. Two of these 8 patients had progression of disease and

manifested CNS involvement while on therapy.


    There is substantial evidence that CANCIDAS is well tolerated and

effective for the treatment of invasive aspergillosis in patients who

are refractory to or intolerant of itraconazole, amphotericin B,

and/or lipid formulations of amphotericin B. However, the efficacy of

CANCIDAS has not been evaluated in concurrently controlled clinical

studies, with other antifungal therapies.


    INDICATIONS AND USAGE


    CANCIDAS is indicated for:


    --  Empirical therapy for presumed fungal infections in febrile,

        neutropenic patients.


    --  Treatment of Candidemia and the following Candida infections:

        intra-abdominal abscesses, peritonitis and pleural space

        infections. CANCIDAS has not been studied in endocarditis,

        osteomyelitis, and meningitis due to Candida.


    --  Treatment of Esophageal Candidiasis (see CLINICAL STUDIES).


    --  Treatment of Invasive Aspergillosis in patients who are

        refractory to or intolerant of other therapies (i.e.,

        amphotericin B, lipid formulations of amphotericin B, and/or

        itraconazole). CANCIDAS has not been studied as initial

        therapy for invasive aspergillosis.


    CONTRAINDICATIONS


    CANCIDAS is contraindicated in patients with hypersensitivity to

any component of this product.


    WARNINGS


    Concomitant use of CANCIDAS with cyclosporine should be limited to

patients for whom the potential benefit outweighs the potential risk.

In one clinical study, 3 of 4 healthy subjects who received CANCIDAS

70 mg on Days 1 through 10, and also received two 3 mg/kg doses of

cyclosporine 12 hours apart on Day 10, developed transient elevations

of alanine transaminase (ALT) on Day 11 that were 2 to 3 times the

upper limit of normal (ULN). In a separate panel of subjects in the

same study, 2 of 8 who received CANCIDAS 35 mg daily for 3 days and

cyclosporine (two 3 mg/kg doses administered 12 hours apart) on Day 1

had small increases in ALT (slightly above the ULN) on Day 2. In both

groups, elevations in aspartate transaminase (AST) paralleled ALT

elevations, but were of lesser magnitude (see ADVERSE REACTIONS).


    In a retrospective study, 40 immunocompromised patients, including

37 transplant recipients, were treated during marketed use with

CANCIDAS and cyclosporine for 1 to 290 days (median 17.5 days).

Fourteen patients (35%) developed transaminase elevations greater than

5X upper limit of normal or greater than 3X baseline during

concomitant therapy or the 14-day follow-up period; five were

considered possibly related to concomitant therapy. One patient had

elevated bilirubin considered possibly related to concomitant therapy.

No patient developed clinical evidence of hepatotoxicity or serious

hepatic events. Discontinuations due to laboratory abnormalities in

hepatic enzymes from any cause occurred in four patients. Of these, 2

were considered possibly related to therapy with CANCIDAS and/or

cyclosporine as well as to other possible causes.


    In the prospective invasive aspergillosis and compassionate use

studies, there were 4 patients treated with CANCIDAS (50 mg/day) and

cyclosporine for 2 to 56 days. None of these patients experienced

increases in hepatic enzymes.


    Given the limitations of these data, CANCIDAS and cyclosporine

should only be used concomitantly in those patients for whom the

potential benefit outweighs the potential risk. Patients who develop

abnormal liver function tests during concomitant therapy should be

monitored and the risk/benefit of continuing therapy should be

evaluated.


    PRECAUTIONS


    General


    The efficacy of a 70-mg dose regimen in patients with invasive

aspergillosis who are not clinically responding to the 50-mg daily

dose is not known. Limited safety data suggest that an increase in

dose to 70 mg daily is well tolerated. The safety and efficacy of

doses above 70 mg have not been adequately studied in patients with

Candida infections. However, CANCIDAS was generally well tolerated at

a dose of 100 mg once daily for 21 days when administered to

15 healthy subjects.


    The safety information on treatment durations longer than 4 weeks

is limited; however, available data suggest that CANCIDAS continues to

be well tolerated with longer courses of therapy (up to 162 days).


    Hepatic Effects


    Laboratory abnormalities in liver function tests have been seen in

healthy volunteers and patients treated with CANCIDAS. In some

patients with serious underlying conditions who were receiving

multiple concomitant medications along with CANCIDAS, clinical hepatic

abnormalities have also occurred. Isolated cases of significant

hepatic dysfunction, hepatitis, or worsening hepatic failure have been

reported in patients; a causal relationship to CANCIDAS has not been

established. Patients who develop abnormal liver function tests during

CANCIDAS therapy should be monitored for evidence of worsening hepatic

function and evaluated for risk/benefit of continuing CANCIDAS

therapy.


    Drug Interactions


    Studies in vitro show that caspofungin acetate is not an inhibitor

of any enzyme in the cytochrome P450 (CYP) system. In clinical

studies, caspofungin did not induce the CYP3A4 metabolism of other

drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor

substrate for cytochrome P450 enzymes.


    Clinical studies in healthy volunteers show that the

pharmacokinetics of CANCIDAS are not altered by itraconazole,

amphotericin B, mycophenolate, nelfinavir, or tacrolimus. CANCIDAS has

no effect on the pharmacokinetics of itraconazole, amphotericin B, or

the active metabolite of mycophenolate.


    CANCIDAS reduced the blood AUC(0-12) of tacrolimus (FK-506,

Prograf((R)3)) by approximately 20%, peak blood concentration (C(max))

by 16%, and 12-hour blood concentration (C(12hr)) by 26% in healthy

subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was

administered on the 10th day of CANCIDAS 70 mg daily, as compared to

results from a control period in which tacrolimus was administered

alone. For patients receiving both therapies, standard monitoring of

tacrolimus blood concentrations and appropriate tacrolimus dosage

adjustments are recommended.


    In two clinical studies, cyclosporine (one 4 mg/kg dose or two

3 mg/kg doses) increased the AUC of caspofungin by approximately 35%.

CANCIDAS did not increase the plasma levels of cyclosporine. There

were transient increases in liver ALT and AST when CANCIDAS and

cyclosporine were co-administered (see WARNINGS and ADVERSE

REACTIONS).


    A drug-drug interaction study with rifampin in healthy volunteers

has shown a 30% decrease in caspofungin trough concentrations.

Patients on rifampin should receive 70 mg of CANCIDAS daily. In

addition, results from regression analyses of patient pharmacokinetic

data suggest that co-administration of other inducers of drug

clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or

carbamazepine) with CANCIDAS may result in clinically meaningful

reductions in caspofungin concentrations. It is not known which drug

clearance mechanism involved in caspofungin disposition may be

inducible. When CANCIDAS is co-administered with inducers of drug

clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or

carbamazepine, use of a daily dose of 70 mg of CANCIDAS should be

considered.


    Carcinogenesis, Mutagenesis, Impairment of Fertility


    No long-term studies in animals have been performed to evaluate

the carcinogenic potential of caspofungin.


    Caspofungin did not show evidence of mutagenic or genotoxic

potential when evaluated in the following in vitro assays: bacterial

(Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts)

mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand

break test, and the chromosome aberration assay in Chinese hamster

ovary cells. Caspofungin was not genotoxic when assessed in the mouse

bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to

a human dose of 1 mg/kg based on body surface area comparisons),

administered intravenously.


    Fertility and reproductive performance were not affected by the

intravenous administration of caspofungin to rats at doses up to

5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients

treated with the 70-mg dose.


    Pregnancy


    Pregnancy Category C. CANCIDAS was shown to be embryotoxic in rats

and rabbits. Findings included incomplete ossification of the skull

and torso and an increased incidence of cervical rib in rats. An

increased incidence of incomplete ossifications of the talus/calcaneus

was seen in rabbits. Caspofungin also produced increases in

resorptions in rats and rabbits and periimplantation losses in rats.

These findings were observed at doses which produced exposures similar

to those seen in patients treated with a 70-mg dose. Caspofungin

crossed the placental barrier in rats and rabbits and was detected in

the plasma of fetuses of pregnant animals dosed with CANCIDAS. There

are no adequate and well-controlled studies in pregnant women.

CANCIDAS should be used during pregnancy only if the potential benefit

justifies the potential risk to the fetus.


    Nursing Mothers


    Caspofungin was found in the milk of lactating, drug-treated rats.

It is not known whether caspofungin is excreted in human milk. Because

many drugs are excreted in human milk, caution should be exercised

when caspofungin is administered to a nursing woman.


    Patients with Hepatic Insufficiency


    Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6)

do not need a dosage adjustment. For patients with moderate hepatic

insufficiency (Child-Pugh score 7 to 9), CANCIDAS 35 mg daily is

recommended. However, where recommended, a 70-mg loading dose should

still be administered on Day 1 (see DOSAGE AND ADMINISTRATION). There

is no clinical experience in patients with severe hepatic

insufficiency (Child-Pugh score greater than9).


    Pediatric Use


    Safety and effectiveness in pediatric patients have not been

established.


    Geriatric Use


    Clinical studies of CANCIDAS did not include sufficient numbers of

patients aged 65 and over to determine whether they respond

differently from younger patients. Although the number of elderly

patients was not large enough for a statistical analysis, no overall

differences in safety or efficacy were observed between these and

younger patients. Plasma concentrations of caspofungin in healthy

older men and women ((greater than or=)65 years of age) were increased

slightly (approximately 28% in AUC) compared to young healthy men. A

similar effect of age on pharmacokinetics was seen in patients with

candidemia or other Candida infections (intra-abdominal abscesses,

peritonitis, or pleural space infections). No dose adjustment is

recommended for the elderly; however, greater sensitivity of some

older individuals cannot be ruled out.


    ADVERSE REACTIONS


    General


    Possible histamine-mediated symptoms have been reported including

reports of rash, facial swelling, pruritus, sensation of warmth, or

bronchospasm. Anaphylaxis has been reported during administration of

CANCIDAS.


    Clinical Adverse Experiences


    The overall safety of caspofungin was assessed in 1440 individuals

who received single or multiple doses of caspofungin acetate:

564 febrile, neutropenic patients (empirical therapy study);

125 patients with candidemia and/or intra-abdominal abscesses,

peritonitis, or pleural space infections (including 4 patients with

chronic disseminated candidiasis); 285 patients with esophageal and/or

oropharyngeal candidiasis; 72 patients with invasive aspergillosis;

and 394 individuals in phase I studies. In the empirical therapy study

patients had undergone hematopoietic stem-cell transplantation or

chemotherapy. In the studies involving patients with documented

Candida infections, the majority of the patients had serious

underlying medical conditions (e.g., hematologic or other malignancy,

recent major surgery, HIV) requiring multiple concomitant medications.

Patients in the noncomparative Aspergillus study often had serious

predisposing medical conditions (e.g., bone marrow or peripheral stem

cell transplants, hematologic malignancy, solid tumors or organ

transplants) requiring multiple concomitant medications.


    Empirical Therapy


    In the randomized, double-blinded empirical therapy study,

patients received either CANCIDAS 50 mg/day (following a 70-mg loading

dose) or AmBisome (3.0 mg/kg/day). In this study clinical or

laboratory hepatic adverse events were reported in 39% and 45% of

patients in the CANCIDAS and AmBisome groups, respectively, regardless

of causality. Also reported was an isolated, serious adverse

experience of hyperbilirubinemia considered possibly related to

CANCIDAS. Drug-related clinical adverse experiences occurring in

(greater than=)2% of the patients in either treatment group are

presented in Table 8.




                               TABLE 8

   Drug-Related* Clinical Adverse Experiences Among Patients with

                   Persistent Fever and Neutropenia

 Incidence (greater than or=)2% for at least one treatment group by

                              Body System


                                                CANCIDAS** AmBisome***

                                                  N=564      N=547

                                                 (percent)  (percent)

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

Body as a Whole

Abdominal Pain                                         1.4         2.4

Chills                                                13.8        24.7

Fever                                                 17.0        19.4

Flushing                                               1.8         4.2

Perspiration/Diaphoresis                               2.8         2.2

Cardiovascular System

Hypertension                                           1.1         2.0

Tachycardia                                            1.4         2.4

Digestive System

Diarrhea                                               2.7         2.4

Nausea                                                 3.5        11.3

Vomiting                                               3.5         8.6

Metabolism and Nutrition

Hypokalemia                                            3.7         4.2

Musculoskeletal System

Back Pain                                              0.7         2.7

Nervous System & Psychiatric

Headache                                               4.3         5.7

Respiratory System

Dyspnea                                                2.0         4.2

Tachypnea                                              0.4         2.0

Skin & Skin Appendage

Rash                                                   6.2         5.3

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



    * Determined by the investigator to be possibly, probably, or

definitely drug-related.


    ** 70 mg on Day 1, then 50 mg daily for the remainder of

treatment; daily dose was increased to 70 mg for 73 patients.


    *** 3.0 mg/kg/day; daily dose was increased to 5.0 mg/kg for 74

patients.


    The proportion of patients who experienced an infusion-related

adverse event was significantly lower in the group treated with

CANCIDAS (35.1%) than in the group treated with AmBisome (51.6%).


    Drug-related laboratory adverse experiences occurring in (greater

than=)2% of the patients in either treatment group are presented in

Table 9.




                               TABLE 9

  Drug-Related* Laboratory Adverse Experiences Among Patients with

                   Persistent Fever and Neutropenia

Incidence (greater than=)2% for at least one treatment group by

                            Laboratory Test

                               Category


                                                CANCIDAS** AmBisome***

                                                  N=564      N=547

                                                 (percent)  (percent)

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

Blood Chemistry

Alanine aminotransferase increased                     8.7         8.9

Alkaline phosphatase increased                         7.0        12.0

Aspartate aminotransferase increased                   7.0         7.6

Direct serum bilirubin increased                       2.6         5.2

Total serum bilirubin increased                        3.0         5.2

Hypokalemia                                            7.3        11.8

Hypomagnesemia                                         2.3         2.6

Serum creatinine increased                             1.2         5.5

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



    * Determined by the investigator to be possibly, probably, or

definitely drug-related.


    ** 70 mg on Day 1, then 50 mg daily for the remainder of

treatment; daily dose was increased to 70 mg for 73 patients.


    *** 3.0 mg/kg/day; daily dose was increased to 5.0 mg/kg for 74

patients.


    The percentage of patients with either a drug-related clinical or

a drug-related laboratory adverse experience was significantly lower

among patients receiving CANCIDAS (54.4%) than among patients

receiving AmBisome (69.3%). Furthermore, the incidence of

discontinuation due to a drug-related clinical or laboratory adverse

experience was significantly lower among patients treated with

CANCIDAS (5.0%) than among patients treated with AmBisome (8.0%).


    To evaluate the effect of CANCIDAS and AmBisome on renal function,

nephrotoxicity was defined as doubling of serum creatinine relative to

baseline or an increase of (greater than=)1 mg/dL in serum creatinine

if baseline serum creatinine was above the upper limit of the normal

range. Among patients whose baseline creatinine clearance was greater

than30 mL/min, the incidence of nephrotoxicity was significantly lower

in the group treated with CANCIDAS (2.6%) than in the group treated

with AmBisome (11.5%). Serious clinical renal events, regardless of

causality, were similar between CANCIDAS (11/564, 2.0%) and AmBisome

(12/547, 2.2%).


    Candidemia and other Candida infections (see CLINICAL STUDIES)


    In the randomized, double-blinded invasive candidiasis study,

patients received either CANCIDAS 50 mg/day (following a 70-mg loading

dose) or amphotericin B 0.6 to 1.0 mg/kg/day. Drug-related clinical

adverse experiences occurring in (greater than or=)2% of the patients

in either treatment group are presented in Table 10.




                               TABLE 10

   Drug-Related* Clinical Adverse Experiences Among Patients with

               Candidemia or other Candida Infections**

   Incidence (greater than=)2% for at least one treatment group by

                              Body System


                                               CANCIDAS   Amphotericin

                                                50 mg***        B

                                                 N=114       N=125

                                                (percent)   (percent)

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

Body as a Whole

Chills                                                5.3         26.4

Fever                                                 7.0         23.2

Cardiovascular System

Hypertension                                          1.8          6.4

Hypotension                                           0.9          2.4

Tachycardia                                           1.8         10.4

Peripheral Vascular System

Phlebitis/thrombophlebitis                            3.5          4.8

Digestive System

Diarrhea                                              2.6          0.8

Jaundice                                              0.9          3.2

Nausea                                                1.8          5.6

Vomiting     

Posted: October 2007

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