Cancidas

Cancidas information, interactions and side effects, CANCIDAS is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS is an echinocandin that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall.

CANCIDAS (caspofungin acetate) is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0 diacetate (salt). CANCIDAS 50 mg also contains: 39 mg sucrose, 26 mg mannitol, glacial acetic acid, and sodium hydroxide. CANCIDAS 70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C52H88N10O15•2C2H4O2 and the formula weight is 1213.42. The structural formula is:

cancidas1

INDICATIONS

CANCIDAS® is indicated in adults and pediatric patients (3 months and older) for:

  • Empirical therapy for presumed fungal infections in febrile, neutropenic patients
  • Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. CANCIDAS has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida.
  • Treatment of esophageal candidiasis [see Clinical Studies]
  • Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole). CANCIDAS has not been studied as initial therapy for invasive aspergillosis.

DOSAGE AND ADMINISTRATION

Instructions for Use in All Patients

CANCIDAS should be administered by slow intravenous (IV) infusion over approximately 1 hour. CANCIDAS should not be administered by IV bolus administration.

Do not mix or co-infuse CANCIDAS with other medications, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as CANCIDAS is not stable in diluents containing dextrose.

Recommended Dosing in Adult Patients [ ≥ 18 years of age]

The usual dose is 50 mg once daily (following a 70-mg loading dose for most indications). The safety and efficacy of a dose of 150 mg daily (range: 1 to 51 days; median: 14 days) have been studied in 100 adult patients with candidemia and other Candida infections. The efficacy of CANCIDAS at this higher dose was not significantly better than the efficacy of the 50-mg daily dose of CANCIDAS. The efficacy of doses higher than 50 mg daily in the other adult patients for whom CANCIDAS is indicated is not known [see Clinical Studies].

Empirical Therapy

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient’s clinical response. Empirical therapy should be continued until resolution of neutropenia. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50-mg dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg.

Candidemia and Other Candida Infections

[see Clinical Studies]

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient’s clinical and microbiological response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia.

Esophageal Candidiasis

The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70-mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered [see Clinical Studies]

Invasive Aspergillosis

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based upon the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.

Recommended Dosing in Pediatric Patients [3 months to 17 years of age]

For all indications, a single 70-mg/m² loading dose should be administered on Day 1, followed by 50 mg/m² once daily thereafter. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient’s calculated dose. Dosing in pediatric patients (3 months to 17 years of age) should be based on the patient’s body surface area (BSA) as calculated by the Mosteller Formula [see REFERENCES]:

BSA(m²) = √Height(cm) xWeight(kg)/3600

Following calculation of the patient’s BSA, the loading dose in milligrams should be calculated as BSA (m²) X 70 mg/m². The maintenance dose in milligrams should be calculated as BSA (m²) X 50 mg/m² .

Duration of treatment should be individualized to the indication, as described for each indication in adults. If the 50-mg/m² daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m² daily (not to exceed 70 mg).

Patients with Hepatic Impairment

Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), CANCIDAS 35 mg once daily is recommended based upon pharmacokinetic data [see CLINICAL PHARMACOLOGY]. However, where recommended, a 70-mg loading dose should still be administered on Day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score > 9) and in pediatric patients with any degree of hepatic impairment.

Patients Receiving Concomitant Inducers of Drug Clearance

Adult patients on rifampin should receive 70 mg of CANCIDAS once daily. Adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin may require an increase in dose to 70 mg of CANCIDAS once daily [see DRUG INTERACTIONS].

When 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 once daily (not to exceed 70 mg) should be considered [see DRUG INTERACTIONS].

Preparation and Reconstitution for Administration

Do not mix or co-infuse CANCIDAS with other medications, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as CANCIDAS is not stable in diluents containing dextrose.

Preparation of CANCIDAS for Infusion

A. Equilibrate the refrigerated vial of CANCIDAS to room temperature.

B. Aseptically add 10.8 mL of 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the vial.

Each vial of CANCIDAS contains an intentional overfill of CANCIDAS. Thus, the drug concentration of the resulting solution is listed in Table 1 below.

Table 1: Information for Preparation of CANCIDAS

 

CANCIDAS vial Total Drug Content (including overfill) Reconstitution Volume to be added Resulting Concentration following Reconstitution
50 mg 54.6 mg 10.8 mL 5 mg/mL
70 mg 75.6 mg 10.8 mL 7 mg/mL

The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained. Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

The reconstituted solution may be stored for up to one hour at ≤ 25°C ( ≤ 77°F).

CANCIDAS vials are for single use only; the remaining solution should be discarded.

C. Aseptically transfer the appropriate volume (mL) of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection. Alternatively, the volume (mL) of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/mL.

This infusion solution must be used within 24 hours if stored at ≤ 25°C ( ≤ 77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).

Special Considerations for Pediatric Patients > 3 Months of Age

Follow the reconstitution procedures described above using either the 70-mg or 50-mg vial to create the reconstituted solution. From the reconstituted solution in the vial, remove the volume of drug equal to the calculated loading dose or calculated maintenance dose based on a concentration of 7 mg/mL (if reconstituted from the 70-mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50-mg vial).

The choice of vial should be based on total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses less than 50 mg that 50mg vials (with a concentration of 5 mg/mL) be used if available. The 70-mg vial should be reserved for pediatric patients requiring doses greater than 50 mg.

The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient’s calculated dose.

HOW SUPPLIED

Dosage Forms And Strengths

CANCIDAS 50 mg is a white to off-white powder/cake for infusion in a vial with a red aluminum band and a plastic cap. CANCIDAS 50-mg vial contains 54.6 mg of caspofungin.

CANCIDAS 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap. CANCIDAS 70-mg vial contains 75.6 mg of caspofungin.

CANCIDAS 50 mg is a white to off-white powder/cake for infusion in a vial with a red aluminum band and a plastic cap.

NDC 0006-3822-10 supplied as one single-use vial.

CANCIDAS 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap.

NDC 0006-3823-10 supplied as one single-use vial.

Storage and Handling

Vials

The lyophilized vials should be stored refrigerated at 2° to 8°C (36° to 46°F).

Reconstituted Concentrate

Reconstituted CANCIDAS in the vial may be stored at ≤ 25°C ( ≤ 77°F) for one hour prior to the preparation of the patient infusion solution.

Diluted Product

The final patient infusion solution in the IV bag or bottle can be stored at ≤ 25°C ( ≤ 77°F) for 24 hours or at 2 to 8°C (36 to 46°F) for 48 hours.

REFERENCES

1. Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17): 1098 (letter).

2. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI document M27-A3. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, W ayne, Pennsylvania 19087, USA, 2008.

3. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Third Informational Supplement. CLSI document M27-S3. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, W ayne, Pennsylvania 19087 USA, 2008.

4. Denning DW , Lee JY, Hostetler JS, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994; 97:135-144.

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

 

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.

  • 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

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.

PRECAUTIONS

Hypersensitivity

Anaphylaxis has been reported during administration of CANCIDAS. If this occurs, CANCIDAS should be discontinued and appropriate treatment administered.

Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment.

Concomitant Use with Cyclosporine

Concomitant use of CANCIDAS with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk. In one clinical study, 3 of 4 healthy adult subjects who received CANCIDAS 70 mg 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 alanine transaminase (ALT) on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of adult subjects in the same study, 2 of 8 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 both groups, elevations in aspartate transaminase (AST) paralleled ALT elevations, but were of lesser magnitude. 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%.

In a retrospective postmarketing study, 40 immunocompromised patients, including 37 transplant recipients, were treated with CANCIDAS and cyclosporine for 1 to 290 days (median 17.5 days). Fourteen patients (35%) developed transaminase elevations > 5X upper limit of normal or > 3X baseline during concomitant therapy or the 14-day follow-up period; five were considered possibly related to concomitant therapy. One patient had elevated bilirubin considered possibly related to concomitant therapy. No patient developed clinical evidence of hepatotoxicity or serious hepatic events. Discontinuations due to laboratory abnormalities in hepatic enzymes from any cause occurred in four patients. Of these, 2 were considered possibly related to therapy with CANCIDAS and/or cyclosporine as well as to other possible causes.

In the prospective invasive aspergillosis and compassionate use studies, there were 4 adult patients treated with CANCIDAS (50 mg/day) and cyclosporine for 2 to 56 days. None of these patients experienced increases in hepatic enzymes.

Given the limitations of these data, CANCIDAS and cyclosporine should only be used concomitantly in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver function tests during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.

Hepatic Effects

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with CANCIDAS. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with CANCIDAS, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to CANCIDAS has not been established. Patients who develop abnormal liver function tests during CANCIDAS therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing CANCIDAS therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with the use of CANCIDAS in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased periimplantation loss, and incomplete ossification at multiple fetal sites. CANCIDAS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In offspring born to pregnant rats treated with caspofungin at doses comparable to the human dose based on body surface area comparisons, there was incomplete ossification of the skull and torso and increased incidences of cervical rib. There was also an increase in resorptions and peri-implantation losses. In pregnant rabbits treated with caspofungin at doses comparable to 2 times the human dose based on body surface area comparisons, there was an increased incidence of incomplete ossification of the talus/calcaneus in offspring and increases in fetal resorptions. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma.

Nursing Mothers

It is not known whether caspofungin is present in human milk. Caspofungin was found in the milk of lactating, drug-treated rats. Because many drugs are excreted in human milk, caution should be exercised when caspofungin is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of CANCIDAS in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications [see INDICATIONS AND USAGE]:

  • Empirical therapy for presumed fungal infections in febrile, neutropenic patients.
  • Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections.
  • Treatment of esophageal candidiasis.
  • Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole).

The efficacy and safety of CANCIDAS has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of CANCIDAS to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown.

CANCIDAS has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. CANCIDAS has also not been studied as initial therapy for invasive aspergillosis in pediatric patients.

In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous CANCIDAS. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received CANCIDAS in safety and efficacy studies [see CLINICAL PHARMACOLOGY and Clinical Studies]. The majority of the pediatric patients received CANCIDAS at a once-daily maintenance dose of 50 mg/m² for a mean duration of 12 days (median 9, range 1-87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with CANCIDAS were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%) [see ADVERSE REACTIONS].

Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions [see WARNINGS AND PRECAUTIONS].

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. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment

Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), CANCIDAS 35 mg once daily is recommended based upon pharmacokinetic data [see CLINICAL PHARMACOLOGY]. However, where recommended, a 70-mg loading dose should still be administered on Day 1 [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score > 9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment.

Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis [see CLINICAL PHARMACOLOGY].

OVERDOSE

In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable. The minimum lethal dose of caspofungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose based on relative body surface area comparison.

In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on Day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported.

CONTRAINDICATIONS

CANCIDAS is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to any component of this product [see ADVERSE REACTIONS].

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