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).
|
