A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cancidas Side Effects, and Drug Interactions - Caspofungin acetate
Cancidas Side Effects, and Drug Interactions - Caspofungin acetate
SIDE EFFECTS
General
Possible histamine-mediated symptoms have been reported in
clinical studies including isolated reports of rash, facial swelling, pruritus,
or sensation of warmth. One case of anaphylaxis characterized by dyspnea, stridor,
and worsening of rash during initial administration of CANCIDAS was reported.
Clinical Adverse Experiences
The overall safety of caspofungin was assessed in 631 individuals
who received single or multiple doses of caspofungin acetate. There were 285 patients with esophageal and/or oropharyngeal
candidiasis and 72 patients with invasive aspergillos enrolled in phase II and phase III clinical studies.
The remaining 274 individuals were enrolled in phase I studies.
Most of the patients in the Candida studies had advanced AIDS (with low CD4 counts <50 mm3). Many of
these patients also had multiple opportunistic infections related to their HIV infection. 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.
Clinical adverse experiences with an incidence ≥
2%, reported in patients treated with CANCIDAS in the noncomparative aspergillosis
study are presented in Table 1.
TABLE 1 :Drug-related Clinical Adverse Experiences in Patients
with Invasive Aspergillosis (open-label, noncomparative study)* Incidence
≥ 2% by Body System
| |
CANCIDAS 50 mg N=69 (percent)
|
|
Body as a Whole
|
|
|
Fever
|
2.9
|
|
Peripheral Vascular System
|
|
|
Infused vein complications
|
2.9
|
|
Digestive System
|
|
|
Nausea
|
2.9
|
|
Vomiting
|
2.9
|
|
Skin & Skin Appendage
|
|
|
Flushing
|
2.9
|
*Relationship to drug was determined by the investigator to
be possibly, probably, or definitely drug related. Patients received CANCIDAS
70 mg on Day 1, then 50 mg daily for the remainder of their treatment.
Also reported infrequently in this patient population were
pulmonary edema, ARDS, and radiographic infiltrates.
Laboratory abnormalities with an incidence ≥
2%, reported in patients treated with CANCIDAS in the noncomparative aspergillosis
study are presented in Table 2.
TABLE 2 :Drug-related Laboratory Abnormalities Reported Among
Patients with Invasive Aspergillosis (open-label, noncomparative study)* Incidence
≥ 2% by Laboratory Test Category
| |
CANCIDAS 50 mg N=69 (percent)
|
|
Blood Chemistry
|
|
|
Serum alkaline phosphatase increased
|
2.9
|
|
Serum potassium decreased
|
2.9
|
|
Hematology
|
|
|
Eosinophils increased
|
3.2
|
|
Urinalysis
|
|
|
Urine protein increased
|
4.9
|
|
Urine RBC’s increased
|
2.2
|
*Relationship to drug was determined by the investigator to
be possibly, probably, or definitely drug related. Patients received CANCIDAS
70 mg on Day 1, then 50 mg daily for the remainder of their treatment.
Drug-related clinical adverse experiences occurring in ≥
2% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 3.
TABLE 3 : 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 200mg ** 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
|
†
|
6.7
|
|
Chills
|
†
|
† |
2.5
|
1.5
|
75.3
|
|
Edema/swelling
|
†
|
† |
†
|
†
|
5.6
|
|
Edema, facial
|
†
|
† |
†
|
3.1
|
†
|
|
Fever
|
3.6
|
1.1 |
21.3
|
26.2
|
69.7
|
|
Flu-like illness
|
†
|
† |
†
|
3.1
|
†
|
|
Malaise
|
†
|
† |
†
|
†
|
5.6
|
|
Pain
|
†
|
† |
1.3
|
4.6
|
5.6
|
|
Pain, abdominal
|
3.6
|
2.1 |
2.5
|
†
|
9.0
|
|
Warm sensation
|
†
|
† |
†
|
1.5
|
4.5
|
|
Peripheral vascular System
|
|
Infused vein complication
|
12.0
|
8.5 |
2.5
|
1.5
|
†
|
|
Phlebitis/thrombophlebitis
|
15.7
|
8.5 |
11.3
|
13.8
|
22.5
|
|
Cardiovascular System
|
|
Tachycardia
|
†
|
† |
1.3
|
†
|
4.5
|
|
Vasculitis
|
†
|
† |
†
|
†
|
3.4
|
|
Digestive System
|
|
Anorexia
|
†
|
† |
1.3
|
†
|
3.4
|
|
Diarrhea
|
3.6
|
2.1 |
1.3
|
3.1
|
11.2
|
| Gastritis |
† |
2.1 |
† |
† |
† |
|
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
|
†
|
† |
3.8
|
†
|
9.0
|
|
Metabolic/Nutritional/Immune
|
|
Anaphylaxis
|
†
|
† |
†
|
†
|
2.2
|
|
Musculoskeletal System
|
|
Myalgia
|
1.2
|
† |
†
|
3.1
|
2.2
|
|
Pain, back
|
†
|
† |
†
|
†
|
2.2
|
|
Pain, musculoskeletal
|
†
|
† |
1.3
|
†
|
4.5
|
|
Nervous System & Psychiatric
|
| Dizziness |
† |
2.1 |
† |
1.5 |
1.1 |
|
Headache
|
6.0
|
1.1 |
11.3
|
7.7
|
19.1
|
|
Insomnia
|
1.2
|
† |
†
|
†
|
2.2
|
|
Paresthesia
|
†
|
† |
1.3
|
3.1
|
1.1
|
|
Tremor
|
†
|
† |
†
|
†
|
7.9
|
|
Respiratory System
|
|
Tachypnea
|
†
|
† |
1.3
|
†
|
4.5
|
|
Skin & Skin Appendage
|
|
Erythema
|
1.2
|
† |
1.3
|
1.5
|
7.9
|
|
Induration
|
†
|
† |
†
|
3.1
|
6.7
|
|
Pruritus
|
1.2
|
† |
2.5
|
1.5
|
†
|
|
Rash
|
†
|
† |
1.3
|
4.6
|
3.4
|
|
Sweating
|
†
|
† |
1.3
|
†
|
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.
† Incidence 0.0%.
|
Laboratory abnormalities occurring in ≥
2% of patients in with esophageal and/or oropharyngeal candidiasis are presented in Table 4.
TABLE 4:
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
|
†
|
†
|
1.2 |
10.3
|
|
Direct serum bilirubin increased
|
0.6
|
†
|
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
|
†
|
† |
6.6
|
|
Serum calcium decreased |
1.9 |
† |
3.2 |
1.1 |
|
Serum creatinine increased
|
†
|
1.5
|
2.2 |
28.1
|
|
Serum potassium decreased
|
3.7
|
10.8
|
4.3 |
31.5
|
|
Serum potassium increased |
0.6 |
† |
2.2 |
1.1 |
|
Serum sodium decreased |
1.9 |
1.5 |
3.2 |
1.1 |
|
Serum uric acid increased
|
0.6
|
†
|
† |
3.4
|
|
Total serum bilirubin increased
|
†
|
†
|
3.2 |
4.5
|
|
Total serum protein decreased
|
3.1
|
†
|
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 |
† |
1.6 |
2.2 |
† |
|
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
|
† |
2.3
|
|
WBC count decreased
|
6.2
|
4.6
|
8.6 |
7.9
|
|
Urinalysis
|
|
Urine blood increased
|
†
|
†
|
† |
4.0
|
|
Urine casts increased
|
†
|
†
|
† |
8.0
|
|
Urine pH increased
|
0.8
|
†
|
† |
3.6
|
|
Urine protein increased
|
1.2
|
†
|
3.3 |
4.5
|
|
Urine RBCs increased
|
1.1
|
3.8
|
5.1 |
12.0
|
|
Urine WBCs increased
|
†
|
7.7
|
† |
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.
† Incidence 0.0%.
|
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).
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, 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®2) 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 coadministered (see
WARNINGS and ADVERSE
EFFECTS, Laboratory Abnormalities).
The results from regression analyses of patient pharmacokinetic data suggest that coadministration of inducers of drug clearance and/or mixed inducer/inhibitors with CANCIDAS may result in clinically meaningful reductions in caspofungin concentrations. This is based on results from a small number of patients who were administered the inducers and/or mixed inducer/inhibitors efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine prior to and/or concomitant with caspofungin. There are presently no data from formal drug interaction studies to evaluate these regression analyses of patient pharmacokinetic data, and it is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When coadministering CANCIDAS with efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine, an increase in the daily dose of CANCIDAS to 70 mg, following the usual 70-mg loading dose, should be considered in patients who are not clinically responding.
Carcinogenesis, Mutagenesis, and 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), after the initial 70-mg loading dose, CANCIDAS 35 mg daily is recommended. 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. No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.
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