cancidas
Generic Name: (
caspofungin acetate)
Dosage Type: injection, powder, lyophilized, for solution Organization: Merck & Co., Inc.
DESCRIPTION
CANCIDAS1 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 ß(1,3)-D-glucan, an integral component
of the fungal cell wall.
CANCIDAS (caspofungin
acetate) is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]
pneumocandin B0 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 C52H88N10O15•2C2H4O2 and the formula weight is 1213.42.
The structural formula is:
CLINICAL PHARMACOLOGY
Pharmacokinetics
Distribution
Plasma concentrations of caspofungin decline in a
polyphasic manner following single 1-hour IV infusions. A shorta-phase occurs immediately postinfusion, followed by a ß-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, ?-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 (~97%), 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 [3H] 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 (=5 days postdose), there is a low level
(=7 picomoles/mg protein, or =1.3% of administered dose)
of covalent binding of radiolabel in plasma following single-dose
administration of [3H] 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 [3H] 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 (~1.4% of dose). Renal clearance of
parent drug is low (~0.15 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 (=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<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 >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 ß (1,3)-D-glucan, an essential component
of the cell wall of susceptible Aspergillus species and Candida species.ß (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
(<500 cells/mm3) 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®2(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
|
|
|
|
CANCIDAS* |
AmBisome* |
% Difference (Confidence 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 |
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%) |
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)
|
|
|
|
CANCIDAS* |
Amphotericin B |
% Difference† after adjusting for strata (Confidence
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%) |
7.0 (-7.0, 21.1) |
| Neutropenic |
6/14 (43%) |
5/10 (50%) |
|
| Non-neutropenic |
61/78 (78%) |
58/84 (69%) |
|
| 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 |
36/109 (33.0%) |
35/115 (30.4%) |
|
| Mortality during study therapy |
18/109 (17%) |
13/115 (11%) |
|
| Mortality attributed to Candida |
4/109 (4%) |
7/115 (6%) |
|
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 <50/mm3).
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
|
|
|
|
CANCIDAS |
Fluconazole |
%Difference* (95% CI) |
| Day 5-7 post-treatment |
66/81 (81.5%) |
80/94 (85.1%) |
-3.6 (-14.7, 7.5) |
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
|
|
|
|
CANCIDAS |
Fluconazole |
% Difference*
(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) |
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
|
|
|
|
CANCIDAS |
Fluconazole |
% Difference*
(95% CI) |
| Day 5-7 post-treatment |
40/56 (71.4%) |
55/66 (83.3%) |
-11.9 (-26.8, 3.0) |
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
|
|
|
|
CANCIDAS |
Fluconazole |
% Difference*
(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) |
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 =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.3 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 >7 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 >7 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 >5X upper
limit of normal or >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 AUC0-12 of tacrolimus (FK-506,
Prograf®4) by approximately 20%, peak
blood concentration (Cmax) by 16%, and 12-hour blood concentration
(C12hr) 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 >9).
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 (=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 =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 =2% for at least
one treatment group by Body System |
|
|
CANCIDAS†
N=564 (percent) |
AmBisome‡
N=547
(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 |
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 =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 =2% for at least one
treatment group by Laboratory Test Category |
|
|
CANCIDAS†
N=564 (percent) |
AmBisome‡
N=547
(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 |
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 =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 >30
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 =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 =2% for at least
one treatment group by Body System |
|
|
CANCIDAS 50 mg‡
N=114 (percent) |
Amphotericin B
N=125 (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 |
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 =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 =2% for at least one
treatment group by Laboratory Test Category |
|
|
CANCIDAS 50 mg‡
N=114 (percent) |
Amphotericin B
N=125 (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 |
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 =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 >30 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 =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 =2% for at least
one treatment dose (per comparison) by Body System |
|
|
CANCIDAS
50 mg†
N=83
(percent) |
Fluconazole IV
200 mg†
N=94
(percent) |
CANCIDAS
50 mg‡
N=80
(percent) |
CANCIDAS
70 mg‡
N=65
(percent) |
Amphotericin B
0.5 mg/kg‡
N=89
(percent) |
| Body as a Whole |
|
|
|
|
|
| Asthenia/fatigue |
0.0 |
0.0 |
0.0 |
0.0 |
6.7 |
| Chills |
0.0 |
0.0 |
2.5 |
1.5 |
75.3 |
| Edema/swelling |
0.0 |
0.0 |
0.0 |
0.0 |
5.6 |
| Edema, facial |
0.0 |
0.0 |
0.0 |
3.1 |
0.0 |
| Fever |
3.6 |
1.1 |
21.3 |
26.2 |
69.7 |
| Flu-like illness |
0.0 |
0.0 |
0.0 |
3.1 |
0.0 |
| Malaise |
0.0 |
0.0 |
0.0 |
0.0 |
5.6 |
| Pain |
0.0 |
0.0 |
1.3 |
4.6 |
5.6 |
| Pain, abdominal |
3.6 |
2.1 |
2.5 |
0.0 |
9.0 |
| Warm sensation |
0.0 |
0.0 |
0.0 |
1.5 |
4.5 |
| Peripheral Vascular System |
|
|
|
|
|
| Infused vein complication |
12.0 |
8.5 |
2.5 |
1.5 |
0.0 |
| Phlebitis/thrombophlebitis |
15.7 |
8.5 |
11.3 |
13.8 |
22.5 |
| Cardiovascular System |
|
|
|
|
|
| Tachycardia |
0.0 |
0.0 |
1.3 |
0.0 |
4.5 |
| Vasculitis |
0.0 |
0.0 |
0.0 |
0.0 |
3.4 |
| Digestive System |
|
|
|
|
|
| Anorexia |
0.0 |
0.0 |
1.3 |
0.0 |
3.4 |
| Diarrhea |
3.6 |
2.1 |
1.3 |
3.1 |
11.2 |
| Gastritis |
0.0 |
2.1 |
0.0 |
0.0 |
0.0 |
| Nausea |
6.0 |
6.4 |
2.5 |
3.1 |
21.3 |
| Vomiting |
1.2 |
3.2 |
1.3 |
3.1 |
13.5 |
| Hemic & Lymphatic System |
|
|
|
|
|
| Anemia |
0.0 |
0.0 |
3.8 |
0.0 |
9.0 |
| Metabolic/Nutritional/Immune |
|
|
|
|
|
| Anaphylaxis |
0.0 |
0.0 |
0.0 |
0.0 |
2.2 |
| Musculoskeletal System |
|
|
|
|
|
| Myalgia |
1.2 |
0.0 |
0.0 |
3.1 |
2.2 |
| Pain, back |
0.0 |
0.0 |
0.0 |
0.0 |
2.2 |
| Pain, musculoskeletal |
0.0 |
0.0 |
1.3 |
0.0 |
4.5 |
| Nervous System & Psychiatric |
|
|
|
|
|
| Dizziness |
0.0 |
2.1 |
0.0 |
1.5 |
1.1 |
| Headache |
6.0 |
1.1 |
11.3 |
7.7 |
19.1 |
| Insomnia |
1.2 |
0.0 |
0.0 |
0.0 |
2.2 |
| Paresthesia |
0.0 |
0.0 |
1.3 |
3.1 |
1.1 |
| Tremor |
0.0 |
0.0 |
0.0 |
0.0 |
7.9 |
| Respiratory System |
|
|
|
|
|
| Tachypnea |
0.0 |
0.0 |
1.3 |
0.0 |
4.5 |
| Skin & Skin Appendage |
|
|
|
|
|
| Erythema |
1.2 |
0.0 |
1.3 |
1.5 |
7.9 |
| Induration |
0.0 |
0.0 |
0.0 |
3.1 |
6.7 |
| Pruritus |
1.2 |
0.0 |
2.5 |
1.5 |
0.0 |
| Rash |
0.0 |
0.0 |
1.3 |
4.6 |
3.4 |
| Sweating |
0.0 |
0.0 |
1.3 |
0.0 |
3.4 |
Laboratory abnormalities occurring in =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 =2% (for at least
one treatment dose) by Laboratory Test Category |
|
|
CANCIDAS
50 mg†
N=163
(percent) |
CANCIDAS
70 mg‡
N=65
(percent) |
Fluconazole IV
200 mg†
N=94
(percent) |
Amphotericin B
0.5 mg/kg‡
N=89
(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 |
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 =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 =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 >9).
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
-
Equilibrate the refrigerated vial of CANCIDAS to
room temperature.
-
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.5 This reconstituted solution may be stored for up to one hour at=25°C (=77°F).6
-
Aseptically transfer 10 mL7 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 =25°C (=77°F)
or within 48 hours if stored refrigerated at 2 to 8°C (36 to
46°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
-
Equilibrate the refrigerated vial of CANCIDAS to
room temperature.
-
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.5 This reconstituted
solution may be stored for up to one hour at =25°C (=77°F).6
-
Aseptically transfer 10 mL7 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 =25°C (=77°F) or within 48 hours
if stored refrigerated at 2 to 8°C (36 to 46°F). (If a reduced
infusion volume is medically necessary, see below: Alternative Infusion Preparation Methods, Preparation of 50-mg daily
doses at reduced volume.)
Preparation notes:
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.
TABLE
14: CANCIDAS Concentrations
|
|
| Dose |
Reconstituted Solution Concentration |
Infusion Volume |
Infusion Solution 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* (from two 50 mg vials) |
5.2 mg/mL |
264 mL |
0.28 mg/mL |
| 50-mg daily dose* (reduced
volume) |
5.2 mg/mL |
110 mL |
0.47 mg/mL |
| 35-mg daily dose* (from one
50 mg vial) for Moderate Hepatic Insufficiency |
5.2 mg/mL
or
5.2 mg/mL |
257 mL
or
107 mL |
0.14 mg/mL
or
0.34 mg/mL |
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° to 8°C (36° to 46°F).
Reconstituted Concentrate
Reconstituted CANCIDAS may be stored at =25°C
(=77°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 =25°C (=77°F) for
24 hours or at 2 to 8°C (36 to 46°F) for 48 hours.
Manufactured for:
Merck &
Co., Inc., Whitehouse Station, NJ 08889, USA
Manufactured by:
Merck & Co., Inc., Whitehouse
Station, NJ 08889, USA
or
Cardinal Health
Albuquerque, NM 87109
Issued February 2005
Printed
in USA
9344307