Cancidas (Caspofungin Acetate) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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 ¹ Incidence ≥7.5% 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 2 N=564 (percent)	AmBisome 3 N=547 (percent)
Within any system organ class, individuals may experience more than 1 adverse reaction.
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

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 ^{1 , 2} 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 3 N=114 (percent)	Amphotericin B N=125 (percent)
Within any system organ class, individuals may experience more than 1 adverse reaction.
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

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 ^{1 , 2} 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 3 N=104 (percent)	CANCIDAS 150 mg N=100 (percent)
Within any system organ class, individuals may experience more than 1 adverse event
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

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 ¹ 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 2 N=83 (percent)	Fluconazole IV 200 mg N=94 (percent)
Within any system organ class, individuals may experience more than 1 adverse reaction.
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

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 intra-abdominal 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) ¹ Incidence ≥7.5% for at Least One Treatment Group by System Organ Class or Preferred Term

	Noncomparative Clinical Studies	Comparator-Controlled Clinical Study of Empirical Therapy
Adverse Reaction (MedDRA v10.0 System Organ Class and Preferred Term)	CANCIDAS Any Dose N=115 (percent)	CANCIDAS 50 mg/m2 2 N=56 (percent)	AmBisome 3 mg/kg N=26 (percent)
Within any system organ class, individuals may experience more than 1 adverse reaction.
All Systems, Any Adverse Reaction	95	96	89
Investigations	55	41	50
Blood Potassium Decreased	18	9	27
Aspartate Aminotransferase Increased	17	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

REPORTS OF SUSPECTED CANCIDAS SIDE EFFECTS / ADVERSE REACTIONS

Possible Cancidas side effects / adverse reactions in 50 year old male

Reported by a health professional (non-physician/pharmacist) from Spain on 2011-10-05

Patient: 50 year old male

Reactions: Hepatotoxicity, Transaminases Increased

Suspect drug(s):
Amikacin
    Indication: Febrile Neutropenia
    Start date: 2011-04-17
    End date: 2011-04-20

Teicoplanin
    Indication: Febrile Neutropenia
    Start date: 2011-04-08
    End date: 2011-04-15

Teicoplanin
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-04-08
    End date: 2011-04-15

Cancidas
    Indication: Febrile Neutropenia
    Start date: 2011-04-10
    End date: 2011-04-20

Acyclovir
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-04-13
    End date: 2011-04-17

Meropenem
    Indication: Febrile Neutropenia
    Start date: 2011-03-23
    End date: 2011-04-22

Amikacin
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-04-17
    End date: 2011-04-20

Acyclovir
    Indication: Febrile Neutropenia
    Start date: 2011-04-13
    End date: 2011-04-17

Meropenem
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-03-23
    End date: 2011-04-22

Possible Cancidas side effects / adverse reactions in 30 month old female

Reported by a physician from Greece on 2011-10-07

Patient: 30 month old female

Reactions: Drug Ineffective

Adverse event resulted in: hospitalization

Suspect drug(s):
Cancidas

Other drugs received by patient: Meropenem; Cytarabine; Idarubicin Hydrochloride; Etoposide; Amphotericin B; Teicoplanin

Possible Cancidas side effects / adverse reactions in 57 year old female

Reported by a physician from Belgium on 2011-10-10

Patient: 57 year old female

Reactions: Death, Relapsing Fever, Fungal Infection, Pathogen Resistance, Abdominal Compartment Syndrome

Adverse event resulted in: death

Suspect drug(s):
Cancidas

Other drugs received by patient: Teicoplanin; Ceftazidime; Cytarabine; Meropenem; Amsacrine