SIDE EFFECTS

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

• Hepatic effects [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity [see WARNINGS AND PRECAUTIONS]

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

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

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

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

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

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

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

• Blood and lymphatic system disorders: anemia, coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia
• Cardiac disorders: arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, myocardial infarction, tachycardia
• Gastrointestinal disorders: abdominal distension, abdominal pain upper, constipation, dyspepsia
• General disorders and administration site conditions: asthenia, fatigue, infusion site pain/pruritus/swelling, mucosal inflammation, edema
• Hepatobiliary disorders: hepatic failure, hepatomegaly, hepatotoxicity, hyperbilirubinemia, jaundice
• Infections and infestations: bacteremia, sepsis, urinary tract infection
• Metabolic and nutrition disorders: anorexia, decreased appetite, fluid overload, hypomagnesemia, hypercalcemia, hyperglycemia, hypokalemia
• Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, pain in extremity
• Nervous system disorders: convulsion, dizziness, somnolence, tremor
• Psychiatric disorders: anxiety, confusional state, depression, insomnia
• Renal and urinary disorders: hematuria, renal failure
• Respiratory, thoracic, and mediastinal disorders: dyspnea, epistaxis, hypoxia, tachypnea
• Skin and subcutaneous tissue disorders: erythema, petechiae, skin lesion, urticaria
• Vascular disorders: flushing, hypertension, phlebitis

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 entire FDA prescribing information for Cancidas (Caspofungin Acetate for Injection) »