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Cancidas

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Cancidas

Cancidas

SIDE EFFECTS

The following serious adverse reactions are discussed in detail in another section of the labeling:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of CANCIDAS cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does provide a basis for identifying adverse reactions that appear to be related to drug use and for approximating rates.

Clinical Trials Experience in Adults

The overall safety of CANCIDAS was assessed in 1865 adult individuals who received single or multiple doses of CANCIDAS: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 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 studies 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®(amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the CANCIDAS and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia considered possibly related to CANCIDAS. Adverse reactions occurring in ≥ 7.5% of the patients in either treatment group are presented in Table 2.

Table 2: Adverse Reactions Among Patients with Persistent Fever and Neutropenia* Incidence ≥ 7.5% for at Least One Treatment Group by System Organ Class or Preferred Term

Adverse Reaction CANCIDAS†
N=564
(percent)
AmBisome‡
N=547
(percent)
(MedDRA v10.1 System Organ Class and Preferred Term) All Systems, Any Adverse Reaction 95 97
Investigations 58 63
  Alanine Aminotransferase Increased 18 20
  Blood Alkaline Phosphatase Increased 15 23
  Blood Potassium Decreased 15 23
  Aspartate Aminotransferase Increased 14 17
  Blood Bilirubin Increased 10 14
  Blood Albumin Decreased 7 8
  Blood Magnesium Decreased 7 9
  Blood Glucose Increased 6 9
  Bilirubin Conjugated Increased 5 9
  Blood Urea Increased 4 8
  Blood Creatinine Increased 3 11
General Disorders and Administration Site Conditions 57 63
  Pyrexia 27 29
  Chills 23 31
  Edema Peripheral 11 12
  Mucosal Inflammation 6 8
Gastrointestinal Disorders 50 55
  Diarrhea 20 16
  Nausea 11 20
  Abdominal Pain 9 11
  Vomiting 9 17
Respiratory, Thoracic and Mediastinal Disorders 47 49
  Cough 11 10
  Dyspnea 9 10
  Rales 7 8
  Infections and Infestations 45 42
  Pneumonia 11 10
Skin and Subcutaneous Tissue Disorders    42 37
  Rash 16 14
Nervous System Disorders 25 27
  Headache 11 12
Metabolism and Nutrition Disorders 21 24
  Hypokalemia 6 8
Vascular Disorders 20 23
  Hypotension 6 10
Cardiac Disorders 16 19
  Tachycardia 7 9
Within any system organ class, individuals may experience more than 1 adverse reaction.
* Regardless of causality
†70 mg on Day 1, then 50 mg once daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients.
‡ 3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients

The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with CANCIDAS (35%) than in the group treated with AmBisome (52%).

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 (3%) than in the group treated with AmBisome (12%). Clinical renal events, regardless of causality, were similar between CANCIDAS (75/564, 13%) and AmBisome (85/547, 16%).

Candidemia and Other Candida Infections

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 mg/kg/day. Adverse reactions occurring in ≥ 10% of the patients in either treatment group are presented in Table 3.

Table 3: Adverse Reactions Among Patients with Candidemia or other Candida Infections*, † Incidence ≥ 10% for at Least One Treatment Group by System Organ Class or Preferred Term

Adverse Reaction (MedDRA v10.1 System Organ Class and Preferred Term) CANCIDAS50 mg‡
N=114
(percent)
Amphotericin B
N=125
(percent)
All Systems, Any Adverse Reaction 96 99
Investigations 67 82
  Blood Potassium Decreased 23 32
  Blood Alkaline Phosphatase Increased 21 32
  Hemoglobin Decreased 18 23
  Alanine Aminotransferase Increased 16 15
  Aspartate Aminotransferase Increased 16 14
  Blood Bilirubin Increased 13 17
  Hematocrit Decreased 13 18
  Blood Creatinine Increased 11 28
  Red Blood Cells Urine Positive 10 10
  Blood Urea Increased 9 23
  Bilirubin Conjugated Increased 8 14
Gastrointestinal Disorders 49 53
  Vomiting 17 16
  Diarrhea 14 10
  Nausea 9 17
Infections and Infestations 48 54
  Septic Shock 11 9
  Pneumonia 4 10
General Disorders and Administration Site Conditions 47 63
  Pyrexia 13 33
  Edema Peripheral 11 12
  Chills 9 30
Respiratory, Thoracic and Mediastinal Disorders 40 54
  Respiratory Failure 11 12
  Pleural Effusion 9 14
  Tachypnea 1 11
Cardiac Disorders 26 34
  Tachycardia 8 12
Skin and Subcutaneous Tissue Disorders 25 28
  Rash 4 10
Vascular Disorders 25 38
  Hypotension 10 16
Blood and Lymphatic System Disorders 15 13
  Anemia 11 9
Within any system organ class, individuals may experience more than 1 adverse reaction.
* Intra-abdominal abscesses, peritonitis and pleural space infections.
† Regardless of causality
‡ Patients received CANCIDAS 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with CANCIDAS (20%) than in the group treated with amphotericin B (49%).

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.

In a second randomized, double-blinded invasive candidiasis study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or CANCIDAS 150 mg/day. The proportion of patients who experienced any adverse reaction was similar in the 2 treatment groups; however, this study was not large enough to detect differences in rare or unexpected adverse events. Adverse reactions occurring in ≥ 5% of the patients in either treatment group are presented in Table 4.

Table 4: Adverse Reactions Among Patients with Candidemia or other Candida Infections*, † Incidence ≥ 5% for at Least One Treatment Group by System Organ Class or Preferred Term

Adverse Reaction (MedDRA v11.0 System Organ Class and Preferred Term) CANCIDAS 50 mg‡
N=104 (percent)
CANCIDAS 150 mg
N=100 (percent)
All Systems, Any Adverse Reaction 83 83
Infections and Infestations 44 43
  Septic Shock 13 14
  Pneumonia 5 7
  Sepsis 5 7
General Disorders and Administration Site Conditions 33 27
  Pyrexia 6 6
Gastrointestinal Disorders 30 33
  Vomiting 11 6
  Diarrhea 6 7
  Nausea 5 7
Investigations 28 35
  Alkaline Phosphatase Increased 12 9
  Aspartate Aminotransferase Increased 6 9
  Blood potassium decreased 6 8
  Alanine Aminotransferase Increased 4 7
Respiratory, Thoracic and Mediastinal Disorders 23 26
  Respiratory Failure 6 2
Vascular Disorders 19 18
  Hypotension 7 3
  Hypertension 5 6
Skin and Subcutaneous Tissue Disorders 15 15
  Decubitus Ulcer 3 5
Within any system organ class, individuals may experience more than 1 adverse event
* Intra-abdominal abscesses, peritonitis and pleural space infections.
† Regardless of causality
‡ Patients received CANCIDAS 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

Esophageal Candidiasis and Oropharyngeal Candidiasis

Adverse reactions occurring in ≥ 10% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 5.

Table 5: Adverse Reactions Among Patients with Esophageal and/or Oropharyngeal Candidiasis* Incidence ≥ 10% for at Least One Treatment Group by System Organ Class or Preferred Term

Adverse Reaction (MedDRA v10.1 System Organ Class and Preferred Term) CANCIDAS 50 mg*
N=83
(percent)
Fluconazole IV 200 mg*
N=94
(percent)
All Systems, Any Adverse Reaction 90 93
Gastrointestinal Disorders 58 50
  Diarrhea 27 18
  Nausea 15 15
Investigations 53 61
  Hemoglobin Decreased 21 16
  Hematocrit Decreased 18 16
  Aspartate Aminotransferase Increased 13 19
  Blood Alkaline Phosphatase Increased 13 17
  Alanine Aminotransferase Increased 12 17
  White Blood Cell Count Decreased 12 19
General Disorders and Administration Site Conditions 31 36
  Pyrexia 21 21
Vascular Disorders 19 15
  Phlebitis 18 11
Nervous System Disorders 18 17
  Headache 15 9
Within any system organ class, individuals may experience more than 1 adverse reaction.
*Regardless of causality
†Derived from a comparator-controlled clinical study.

Invasive Aspergillosis

In an 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 treatment-emergent adverse reactions were observed with an incidence of ≥ 12.5%: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), aspergillosis (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%). Also reported infrequently in this patient population were pulmonary edema, ARDS (adult respiratory distress syndrome), and radiographic infiltrates.

Clinical Trials Experience in Pediatric Patients (3 months to 17 years of age)

The overall safety of CANCIDAS was assessed in 171 pediatric patients who received single or multiple doses of CANCIDAS. The distribution among the 153 pediatric patients who were over the age of 3 months was as follows: 104 febrile, neutropenic patients; 38 patients with candidemia and/or intraabdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of CANCIDAS in pediatric patients is comparable to that in adult patients. Table 6 shows the incidence of adverse reactions reported in ≥ 7.5% of pediatric patients in clinical studies.

One patient (0.6%) receiving CANCIDAS, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from CANCIDAS and three patients (12%) were discontinued from AmBisome due to a drug-related adverse reaction. The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was 22% in the group treated with CANCIDAS and 35% in the group treated with AmBisome.

Table 6: Adverse Reactions Among Pediatric Patients (0 months to 17 years of age)* Incidence ≥ 7.5% for at Least One Treatment Group by System Organ Class or Preferred Term

Adverse Reaction (MedDRA v10.0 System Organ Class and Preferred Term) Noncomparative Clinical Studies Comparator-Controlled Clinical Study of Empirical Therapy
CANCIDAS Any Dose
N=115
(percent)
CANCIDAS 50 mg/m²†
N=56
(percent)
AmBisome 3 mg/kg
N=26
(percent)
All Systems, Any Adverse Reaction 95 96 89
Investigations 55 41 50
  Blood Potassium Decreased 18 9 27
  Aspartate Aminotransferase Increased 1 7 2 12
  Alanine Aminotransferase Increased 14 5 12
  Blood Potassium Increased 3 0 8
  Protein Total Decreased 0 0 8
General Disorders and Administration Site Conditions 47 59 42
  Pyrexia 29 30 23
  Chills 10 13 8
  Mucosal Inflammation 10 4 4
  Edema 3 4 8
Respiratory, Thoracic and Mediastinal Disorders 43 32 27
  Respiratory Distress 8 0 4
  Cough 6 9 8
Gastrointestinal Disorders 42 41 35
  Diarrhea 17 7 15
  Vomiting 8 11 12
  Abdominal Pain 7 4 12
  Nausea 4 4 8
Infections and Infestations 40 30 35
  Central Line Infection 1 9 0
Skin and Subcutaneous Tissue Disorders 33 41 39
  Pruritus 7 6 8
  Rash 6 23 8
  Erythema 4 9 0
Vascular Disorders 24 21 19
  Hypotension 12 9 8
  Hypertension 10 9 4
Metabolism and Nutrition Disorders 22 11 23
  Hypokalemia 8 5 4
Cardiac Disorders 17 13 19
  Tachycardia 4 11 19
Nervous System Disorders 13 16 8
  Headache 5 9 4
Musculoskeletal and Connective Tissue Disorders 11 14 12
  Back Pain 4 0 8
Blood and Lymphatic System Disorders 10 2 15
  Anemia 2 0 8
Immune System Disorders 7 7 12
  Graft Versus Host Disease 1 4 8
† 70 mg/m² on Day 1, then 50 mg/m² once daily for the remainder of the treatment.
Within any system organ class, individuals may experience more than 1 adverse reaction.
* Regardless of causality

Overall Safety Experience of CANCIDAS in Clinical Trials

The overall safety of CANCIDAS was assessed in 2036 individuals (including 1642 adult or pediatric patients and 394 volunteers) from 34 clinical studies. These individuals received single or multiple (once daily) doses of CANCIDAS, ranging from 5 mg to 210 mg. Full safety data is available from 1951 individuals, as the safety data from 85 patients enrolled in 2 compassionate use studies was limited solely to serious adverse reactions. Treatment emergent adverse reactions, regardless of causality, which occurred in ≥ 5% of all individuals who received CANCIDAS in these trials, are shown in Table 7.

Overall, 1665 of the 1951 (85%) patients/volunteers who received CANCIDAS experienced an adverse reaction.

Table 7: Treatment-Emergent* Adverse Reactions in Patients Who Received CANCIDAS in Clinical Trials†Incidence ≥ 5% for at Least One Treatment Group by System Organ Class or Preferred Term

Adverse Reaction‡ (MedDRA v10 System Organ Class and Preferred Term) CANCIDAS
(N = 1951)
n (%)
All Systems, Any Adverse Reaction 1665 (85)
Investigations 901 (46)
  Alanine Aminotransferase Increased 258 (13)
  Aspartate Aminotransferase Increased 233 (12)
  Blood Alkaline Phosphatase Increased 232 (12)
  Blood Potassium Decreased 220 (11)
  Blood Bilirubin Increased 117 (6)
General Disorders and Administration Site Conditions 843 (43)
  Pyrexia 381 (20)
  Chills 192 (10)
  Edema Peripheral 110 (6)
Gastrointestinal Disorders 754 (39)
  Diarrhea 273 (14)
  Nausea 166 (9)
  Vomiting 146 (8)
  Abdominal Pain 112 (6)
Infections and Infestations 730 (37)
  Pneumonia 115 (6)
Respiratory, Thoracic, and Mediastinal Disorders 613 (31)
  Cough 111 (6)
Skin and Subcutaneous Tissue Disorders 520 (27)
  Rash 159 (8)
  Erythema 98 (5)
Nervous System Disorders 412 (21)
  Headache 193 (10)
Vascular Disorders 344 (18)
  Hypotension 118 (6)
* Defined as an adverse reaction, regardless of causality, while on CANCIDAS or during the 14-day post-CANCIDAS follow-up period.
† Incidence for each preferred term is ≥ 5% among individuals who received at least 1 dose of CANCIDAS.
‡ Within any system organ class, individuals may experience more than 1 adverse event.

Clinically significant adverse reactions, regardless of causality or incidence which occurred in less than 5% of patients are listed below.

Postmarketing Experience

The following additional adverse reactions have been identified during the post-approval use of CANCIDAS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Gastrointestinal disorders: pancreatitis
  • Hepatobiliary disorders: hepatic necrosis
  • Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-Johnson, skin exfoliation
  • Renal and urinary disorders: clinically significant renal dysfunction
  • General disorders and administration site conditions: swelling and peripheral edema

Read the Cancidas (caspofungin acetate for injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

[See CLINICAL PHARMACOLOGY.]

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 adult 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.

Cyclosporine: In two adult 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 PRECAUTIONS].

Tacrolimus: For patients receiving CANCIDAS and tacrolimus, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Rifampin: Adult patients on rifampin should receive 70 mg of CANCIDAS daily.

Other inducers of drug clearance

Adults: W hen CANCIDAS is co-administered to adult patients 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.

Pediatric Patients: W hen CANCIDAS is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a CANCIDAS dose of 70 mg/m² daily (not to exceed an actual daily dose of 70 mg) should be considered.

Read the Cancidas Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/12/2013
This monograph has been modified to include the generic and brand name in many instances.

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