SAN DIEGO -- CANCIDAS® (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 >1 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); 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/m2 daily (maximum 70 mg daily) following a 70 mg/m2 loading dose on day one. Patients could be dose-escalated to CANCIDAS 70 mg/m2 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 β(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® is a registered trademark of Merck & Co., Inc.
Prescribing information for CANCIDAS® is attached.
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 3.5 8.0
Metabolic/Nutritional/Immune
Hypokalemia 0.9 5.6
Nervous System & Psychiatric
Tremor 1.8 2.4
Respiratory System
Tachypnea 0.0 10.4
Skin & Skin Appendage
Erythema 0.0 2.4
Rash 0.9 3.2
Sweating 0.9 3.2
Urogenital System
Renal insufficiency 0.9 5.6
Renal insufficiency, acute 0.0 5.6
---------------------------------------------- ---------- ------------
* Determined by the investigator to be possibly, probably, or
definitely drug-related.
** Intra-abdominal abscesses, peritonitis and pleural space
infections
*** Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily
for the remainder of their treatment.
The incidence of drug-related clinical adverse experiences was
significantly lower among patients treated with CANCIDAS (28.9%) than
among patients treated with amphotericin B (58.4%). Also, the
proportion of patients who experienced an infusion-related adverse
event was significantly lower in the group treated with CANCIDAS
(20.2%) than in the group treated with amphotericin B (48.8%).
Drug-related laboratory adverse experiences occurring in (greater
than or=)2% of the patients in either treatment group are presented in
Table 11.
TABLE 11
Drug-Related* Laboratory Adverse Experiences Among Patients with
Candidemia or other Candida Infections**
Incidence (greater than=)2% for at least one treatment group by
Laboratory Test
Category
CANCIDAS Amphotericin
50 mg*** B
N=114 N=125
(percent) (percent)
---------------------------------------------- ---------- ------------
Blood Chemistry
ALT increased 3.7 8.1
AST increased 1.9 9.0
Blood urea increased 1.9 15.8
Direct serum bilirubin increased 3.8 8.4
Serum alkaline phosphatase increased 8.3 15.6
Serum bicarbonate decreased 0.0 3.6
Serum creatinine increased 3.7 22.6
Serum phosphate increased 0.0 2.7
Serum potassium decreased 9.9 23.4
Serum potassium increased 0.9 2.4
Total serum bilirubin increased 2.8 8.9
Hematology
Hematocrit decreased 0.9 7.3
Hemoglobin decreased 0.9 10.5
Urinalysis
Urine protein increased 0.0 3.7
---------------------------------------------- ---------- ------------
* Determined by the investigator to be possibly, probably, or
definitely drug-related.
** Intra-abdominal abscesses, peritonitis and pleural space
infections
*** Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily
for the remainder of their treatment.
The incidence of drug-related laboratory adverse experiences was
significantly lower among patients receiving CANCIDAS (24.3%) than
among patients receiving amphotericin B (54.0%).
The percentage of patients with either a drug-related clinical
adverse experience or a drug-related laboratory adverse experience was
significantly lower among patients receiving CANCIDAS (42.1%) than
among patients receiving amphotericin B (75.2%). Furthermore, a
significant difference between the two treatment groups was observed
with regard to incidence of discontinuation due to drug-related
clinical or laboratory adverse experience; incidences were 3/114
(2.6%) in the group treated with CANCIDAS and 29/125 (23.2%) in the
group treated with amphotericin B.
To evaluate the effect of CANCIDAS and amphotericin B 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. In a subgroup of patients whose baseline creatinine
clearance was greater than30 mL/min, the incidence of nephrotoxicity
was significantly lower in the group treated with CANCIDAS than in the
group treated with amphotericin B.
Esophageal Candidiasis and Oropharyngeal Candidiasis
Drug-related clinical adverse experiences occurring in
(greater than=)2% of patients with esophageal and/or oropharyngeal
candidiasis are presented in Table 12.
TABLE 12
Drug-Related Clinical Adverse Experiences Among Patients with
Esophageal and/or Oropharyngeal Candidiasis*
Incidence (greater than=)2% for at least one treatment dose
(per comparison) by
Body System
CANCIDAS Fluconazole CANCIDAS
50 mg** IV 50 mg***
N=83 200 mg** N=80
(percent) N=94 (percent)
(percent)
------------------------------------- --------- ----------- ----------
Body as a Whole
Asthenia/fatigue 0.0 0.0 0.0
Chills 0.0 0.0 2.5
Edema/swelling 0.0 0.0 0.0
Edema, facial 0.0 0.0 0.0
Fever 3.6 1.1 21.3
Flu-like illness 0.0 0.0 0.0
Malaise 0.0 0.0 0.0
Pain 0.0 0.0 1.3
Pain, abdominal 3.6 2.1 2.5
Warm sensation 0.0 0.0 0.0
Peripheral Vascular System
Infused vein complication 12.0 8.5 2.5
Phlebitis/thrombophlebitis 15.7 8.5 11.3
Cardiovascular System
Tachycardia 0.0 0.0 1.3
Vasculitis 0.0 0.0 0.0
Digestive System
Anorexia 0.0 0.0 1.3
Diarrhea 3.6 2.1 1.3
Gastritis 0.0 2.1 0.0
Nausea 6.0 6.4 2.5
Vomiting 1.2 3.2 1.3
Hemic & Lymphatic System
Anemia 0.0 0.0 3.8
Metabolic/Nutritional/Immune
Anaphylaxis 0.0 0.0 0.0
Musculoskeletal System
Myalgia 1.2 0.0 0.0
Pain, back 0.0 0.0 0.0
Pain, musculoskeletal 0.0 0.0 1.3
Nervous System & Psychiatric
Dizziness 0.0 2.1 0.0
Headache 6.0 1.1 11.3
Insomnia 1.2 0.0 0.0
Paresthesia 0.0 0.0 1.3
Tremor 0.0 0.0 0.0
Respiratory System
Tachypnea 0.0 0.0 1.3
Skin & Skin Appendage
Erythema 1.2 0.0 1.3
Induration 0.0 0.0 0.0
Pruritus 1.2 0.0 2.5
Rash 0.0 0.0 1.3
Sweating 0.0 0.0 1.3
------------------------------------- --------- ----------- ----------
*Relationship to drug was determined by the investigator to be
possibly, probably or definitely drug-related.
** Derived from a Phase III comparator-controlled clinical study.
*** Derived from Phase II comparator-controlled clinical studies.
TABLE 12
Drug-Related Clinical Adverse Experiences Among Patients with
Esophageal and/or Oropharyngeal Candidiasis*
Incidence (greater than=)2% for at least one treatment dose
(per comparison) by
Body System
CANCIDAS Amphotericin
70 mg*** B
N=65 0.5 mg/kg***
(percent) N=89
(percent)
---------------------------------------------- --------- ------------
Body as a Whole
Asthenia/fatigue 0.0 6.7
Chills 1.5 75.3
Edema/swelling 0.0 5.6
Edema, facial 3.1 0.0
Fever 26.2 69.7
Flu-like illness 3.1 0.0
Malaise 0.0 5.6
Pain 4.6 5.6
Pain, abdominal 0.0 9.0
Warm sensation 1.5 4.5
Peripheral Vascular System
Infused vein complication 1.5 0.0
Phlebitis/thrombophlebitis 13.8 22.5
Cardiovascular System
Tachycardia 0.0 4.5
Vasculitis 0.0 3.4
Digestive System
Anorexia 0.0 3.4
Diarrhea 3.1 11.2
Gastritis 0.0 0.0
Nausea 3.1 21.3
Vomiting 3.1 13.5
Hemic & Lymphatic System
Anemia 0.0 9.0
Metabolic/Nutritional/Immune
Anaphylaxis 0.0 2.2
Musculoskeletal System
Myalgia 3.1 2.2
Pain, back 0.0 2.2
Pain, musculoskeletal 0.0 4.5
Nervous System & Psychiatric
Dizziness 1.5 1.1
Headache 7.7 19.1
Insomnia 0.0 2.2
Paresthesia 3.1 1.1
Tremor 0.0 7.9
Respiratory System
Tachypnea 0.0 4.5
Skin & Skin Appendage
Erythema 1.5 7.9
Induration 3.1 6.7
Pruritus 1.5 0.0
Rash 4.6 3.4
Sweating 0.0 3.4
---------------------------------------------- --------- ------------
*Relationship to drug was determined by the investigator to be
possibly, probably or definitely drug-related.
** Derived from a Phase III comparator-controlled clinical study.
*** Derived from Phase II comparator-controlled clinical studies.
Laboratory abnormalities occurring in (greater than=)2% of
patients with esophageal and/or oropharyngeal candidiasis are
presented in Table 13.
TABLE 13
Drug-Related Laboratory Abnormalities Reported Among Patients with
Esophageal and/or Oropharyngeal Candidiasis*
Incidence (greater than=)2% (for at least one treatment dose) by
Laboratory Test
Category
CANCIDAS CANCIDAS Fluconazole Amphotericin
50 mg** 70 mg*** IV B 0.5
N=163 N=65 200 mg** mg/kg***
(percent) (percent) N=94 N=89
(percent) (percent)
------------------------- --------- --------- ----------- ------------
Blood Chemistry
ALT increased 10.6 10.8 11.8 22.7
AST increased 13.0 10.8 12.9 22.7
Blood urea increased 0.0 0.0 1.2 10.3
Direct serum bilirubin
increased 0.6 0.0 3.3 2.5
Serum albumin decreased 8.6 4.6 5.4 14.9
Serum alkaline
phosphatase increased 10.5 7.7 11.8 19.3
Serum bicarbonate
decreased 0.9 0.0 0.0 6.6
Serum calcium decreased 1.9 0.0 3.2 1.1
Serum creatinine
increased 0.0 1.5 2.2 28.1
Serum potassium decreased 3.7 10.8 4.3 31.5
Serum potassium increased 0.6 0.0 2.2 1.1
Serum sodium decreased 1.9 1.5 3.2 1.1
Serum uric acid increased 0.6 0.0 0.0 3.4
Total serum bilirubin
increased 0.0 0.0 3.2 4.5
Total serum protein
decreased 3.1 0.0 3.2 3.4
Hematology
Eosinophils increased 3.1 3.1 1.1 1.1
Hematocrit decreased 11.1 1.5 5.4 32.6
Hemoglobin decreased 12.3 3.1 5.4 37.1
Lymphocytes increased 0.0 1.6 2.2 0.0
Neutrophils decreased 1.9 3.1 3.2 1.1
Platelet count decreased 3.1 1.5 2.2 3.4
Prothrombin time
increased 1.3 1.5 0.0 2.3
WBC count decreased 6.2 4.6 8.6 7.9
Urinalysis
Urine blood increased 0.0 0.0 0.0 4.0
Urine casts increased 0.0 0.0 0.0 8.0
Urine pH increased 0.8 0.0 0.0 3.6
Urine protein increased 1.2 0.0 3.3 4.5
Urine RBCs increased 1.1 3.8 5.1 12.0
Urine WBCs increased 0.0 7.7 0.0 24.0
------------------------- --------- --------- ----------- ------------
*Relationship to drug was determined by the investigator to be
possibly, probably or definitely drug-related.
** Derived from Phase II and Phase III comparator-controlled clinical
studies.
*** Derived from Phase II comparator-controlled clinical studies.
Invasive Aspergillosis
In the open-label, noncomparative aspergillosis study, in which
69 patients received CANCIDAS (70-mg loading dose on Day 1 followed by
50 mg daily), the following drug-related clinical adverse experiences
were observed with an incidence of (greater than=)2%: fever (2.9%),
infused-vein complications (2.9%), nausea (2.9%), vomiting (2.9%) and
flushing (2.9%).
Also reported infrequently in this patient population were
pulmonary edema, ARDS, and radiographic infiltrates.
Drug-related laboratory abnormalities reported with an incidence
(greater than=)2% in patients treated with CANCIDAS in the
noncomparative aspergillosis study were: serum alkaline phosphatase
increased (2.9%), serum potassium decreased (2.9%), eosinophils
increased (3.2%), urine protein increased (4.9%), and urine RBCs
increased (2.2%).
Postmarketing Experience:
The following postmarketing adverse events have been reported:
Hepatobiliary: rare cases of clinically significant hepatic
dysfunction
Cardiovascular: swelling and peripheral edema
Metabolic: hypercalcemia
Concomitant Therapy
In one clinical study, 3 of 4 subjects who received CANCIDAS 70 mg
daily 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 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 subjects 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
another clinical study, 2 of 8 healthy men developed transient ALT
elevations of less than 2X ULN. In this study, cyclosporine (4 mg/kg)
was administered on Days 1 and 12, and CANCIDAS was administered
(70 mg) daily on Days 3 through 13. In one subject, the ALT elevation
occurred on Days 7 and 9 and, in the other subject, the ALT elevation
occurred on Day 19. These elevations returned to normal by Day 27. In
all groups, elevations in AST paralleled ALT elevations but were of
lesser magnitude. In these clinical studies, cyclosporine (one 4 mg/kg
dose or two 3 mg/kg doses) increased the AUC of caspofungin by
approximately 35% (see WARNINGS).
OVERDOSAGE
In clinical studies the highest dose was 210 mg, administered as a
single dose to 6 healthy subjects. This dose was generally well
tolerated. In addition, 100 mg once daily for 21 days has been
administered to 15 healthy subjects and was generally well tolerated.
Caspofungin is not dialyzable. The minimum lethal dose of caspofungin
in rats was 50 mg/kg, a dose which is equivalent to 10 times the
recommended daily dose based on relative body surface area comparison.
ANIMAL PHARMACOLOGY AND TOXICOLOGY
In one 5-week study in monkeys at doses which produced exposures
approximately 4 to 6 times those seen in patients treated with a 70-mg
dose, scattered small foci of subcapsular necrosis were observed
microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg
and 4/8 monkeys at 8 mg/kg); however, this histopathological finding
was not seen in another study of 27 weeks duration at similar doses.
DOSAGE AND ADMINISTRATION
Do not mix or co-infuse CANCIDAS with other medications, as there
are no data available on the compatibility of CANCIDAS with other
intravenous substances, additives, or medications. DO NOT USE DILUENTS
CONTAINING DEXTROSE (A-D-GLUCOSE), as CANCIDAS is not stable in
diluents containing dextrose. CANCIDAS should be administered by slow
IV infusion over approximately 1 hour.
Empirical Therapy
A single 70-mg loading dose should be administered on Day 1,
followed by 50 mg daily thereafter. Duration of treatment should be
based on the patient's clinical response. Empirical therapy should be
continued until resolution of neutropenia. Patients found to have a
fungal infection should be treated for a minimum of 14 days; treatment
should continue for at least 7 days after both neutropenia and
clinical symptoms are resolved. If the 50-mg dose is well tolerated
but does not provide an adequate clinical response, the daily dose can
be increased to 70 mg. Although an increase in efficacy with 70 mg
daily has not been demonstrated, limited safety data suggest that an
increase in dose to 70 mg daily is well tolerated.
Candidemia and other Candida infections (see CLINICAL STUDIES)
A single 70-mg loading dose should be administered on Day 1,
followed by 50 mg daily thereafter. Duration of treatment should be
dictated by the patient's clinical and microbiological response. In
general, antifungal therapy should continue for at least 14 days after
the last positive culture. Patients who remain persistently
neutropenic may warrant a longer course of therapy pending resolution
of the neutropenia.
Esophageal Candidiasis
The dose should be 50 mg daily. Because of the risk of relapse of
oropharyngeal candidiasis in patients with HIV infections, suppressive
oral therapy could be considered (see CLINICAL STUDIES). A 70-mg
loading dose has not been studied with this indication.
Invasive Aspergillosis
A single 70-mg loading dose should be administered on Day 1,
followed by 50 mg daily thereafter. Duration of treatment should be
based upon the severity of the patient's underlying disease, recovery
from immunosuppression, and clinical response. The efficacy of a 70-mg
dose regimen in patients 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.
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. There is no clinical experience in
patients with severe hepatic insufficiency (Child-Pugh score greater
than9).
Concomitant Medication with Inducers of Drug Clearance
Patients on rifampin should receive 70 mg of CANCIDAS daily.
Patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or
phenytoin may require an increase in dose to 70 mg of CANCIDAS daily
(see PRECAUTIONS, Drug Interactions).
Preparation of CANCIDAS for use:
Do not mix or co-infuse CANCIDAS with other medications, as there
are no data available on the compatibility of CANCIDAS with other
intravenous substances, additives, or medications. DO NOT USE DILUENTS
CONTAINING DEXTROSE (A-D-GLUCOSE), as CANCIDAS is not stable in
diluents containing dextrose.
Preparation of the 70-mg infusion
1. Equilibrate the refrigerated vial of CANCIDAS to room
temperature.
2. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection,
Sterile Water for Injection, Bacteriostatic Water for Injection with
methylparaben and propylparaben, or Bacteriostatic Water for Injection
with 0.9% benzyl alcohol to the vial.(a) This reconstituted solution
may be stored for up to one hour at (less than=)25 degrees C
((less than=)77 degrees F).(b)
3. Aseptically transfer 10 mL(c) of reconstituted CANCIDAS to an
IV bag (or bottle) containing 250 mL 0.9%, 0.45%, or 0.225% Sodium
Chloride Injection, or Lactated Ringer's Injection. This infusion
solution must be used within 24 hours if stored at (less than or=)25
degrees C ((less than or=)77 degrees F) or within 48 hours if stored
refrigerated at 2 to 8 degrees C (36 to 46 degrees F). (If a 70-mg
vial is unavailable, see below: Alternative Infusion Preparation
Methods, Preparation of 70-mg dose from two 50-mg vials.)
Preparation of the daily 50-mg infusion
1. Equilibrate the refrigerated vial of CANCIDAS to room
temperature.
2. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection,
Sterile Water for Injection, Bacteriostatic Water for Injection with
methylparaben and propylparaben, or Bacteriostatic Water for Injection
with 0.9% benzyl alcohol to the vial.(a) This reconstituted solution
may be stored for up to one hour at (less than or=)25 degrees C ((less
than or=)77 degrees F).(b)
3. Aseptically transfer 10 mL(c) of reconstituted CANCIDAS to an
IV bag (or bottle) containing 250 mL 0.9%, 0.45%, or 0.225% Sodium
Chloride Injection, or Lactated Ringer's Injection. This infusion
solution must be used within 24 hours if stored at (less than=)25
degrees C ((less than=)77 degrees F) or within 48 hours if stored
refrigerated at 2 to 8 degrees C (36 to 46 degrees F). (If a reduced
infusion volume is medically necessary, see below: Alternative
Infusion Preparation Methods, Preparation of 50-mg daily doses at
reduced volume.)
Alternative Infusion Preparation Methods
Preparation of 70-mg dose from two 50-mg vials
Reconstitute two 50-mg vials with 10.5 mL of diluent each (see
Preparation of the daily 50-mg infusion). Aseptically transfer a total
of 14 mL of the reconstituted CANCIDAS from the two vials to 250 mL of
0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringer's
Injection.
Preparation of 50-mg daily doses at reduced volume
When medically necessary, the 50-mg daily doses can be prepared by
adding 10 mL of reconstituted CANCIDAS to 100 mL of 0.9%, 0.45%, or
0.225% Sodium Chloride Injection, or Lactated Ringer's Injection (see
Preparation of the daily 50-mg infusion).
Preparation of a 35-mg daily dose for patients with moderate
Hepatic Insufficiency
Reconstitute one 50-mg vial (see above: Preparation of the daily
50-mg infusion). Aseptically transfer 7 mL of the reconstituted
CANCIDAS from the vial to 250 mL or, if medically necessary, to 100 mL
of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated
Ringer's Injection.
Preparation notes:
a The white to off-white cake will dissolve completely. Mix gently
until a clear solution is obtained.
b Visually inspect the reconstituted solution for particulate
matter or discoloration during reconstitution and prior to infusion.
Do not use if the solution is cloudy or has precipitated.
c CANCIDAS is formulated to provide the full labeled vial dose
(70 mg or 50 mg) when 10 mL is withdrawn from the vial.
TABLE 14
CANCIDAS Concentrations
Dose Reconstituted Infusion Infusion
Solution Volume Solution
Concentration Concentration
------------------------------- -------------- -------- --------------
70-mg initial dose 7.2 mg/mL 260 mL 0.28 mg/mL
50-mg daily dose 5.2 mg/mL 260 mL 0.20 mg/mL
70-mg initial dose* 5.2 mg/mL 264 mL 0.28 mg/mL
(from two 50 mg vials)
50-mg daily dose* 5.2 mg/mL 110 mL 0.47 mg/mL
(reduced volume)
35-mg daily dose* 5.2 mg/mL 257 mL 0.14 mg/mL
(from one 50 mg vial) for or or or
Moderate Hepatic Insufficiency 5.2 mg/mL 107 mL 0.34 mg/mL
------------------------------- -------------- -------- --------------
*See preceding text for these special situations.
HOW SUPPLIED
No. 3822 -- CANCIDAS 50 mg is a white to off-white powder/cake for
infusion in a vial with a red aluminum band and a plastic cap.
NDC 0006-3822-10 supplied as one single-use vial.
No. 3823 -- CANCIDAS 70 mg is a white to off-white powder/cake for
infusion in a vial with a yellow/orange aluminum band and a plastic
cap.
NDC 0006-3823-10 supplied as one single-use vial.
Storage
Vials
The lyophilized vials should be stored refrigerated at 2 degrees
to 8 degrees C (36 degrees to 46 degrees F).
Reconstituted Concentrate
Reconstituted CANCIDAS may be stored at (less than=)25 degrees C
((less than=)77 degrees F) for one hour prior to the preparation of
the patient infusion solution.
Diluted Product
The final patient infusion solution in the IV bag or bottle can be
stored at (less than=)25 degrees C ((less than=)77 degrees F) for 24
hours or at 2 to 8 degrees C (36 to 46 degrees F) for 48 hours.
Distributed by:
Issued July 2007
*Registered trademark of MERCK & CO., Inc. COPYRIGHT (C) MERCK &
CO., Inc., 2001 All rights reserved
(1) Registered trademark of Gilead Sciences, Inc.
(2) Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses Study
Group multicenter trial of oral itraconazole therapy for invasive
aspergillosis. Am J Med 1994; 97:135-144.
(3) Registered trademark of Fujisawa Healthcare, Inc.
