Caspofungin Acetate (Page 2 of 7)
2.7 Drug Incompatibilities
Do not mix or co-infuse caspofungin acetate for injection with other medications, as there are no data available on the compatibility of caspofungin acetate for injection with other intravenous substances, additives, or medications. Do not use diluents containing dextrose (α-D-glucose), as caspofungin acetate for injection is not stable in diluents containing dextrose.
3 DOSAGE FORMS AND STRENGTHS
Caspofungin Acetate for Injection 50 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with an aluminum seal and a plastic cap. Caspofungin acetate for injection 50 mg vial contains 50 mg of caspofungin equivalent to 55.5 mg of caspofungin acetate.
Caspofungin Acetate for Injection 70 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with an aluminum seal and a plastic cap. Caspofungin acetate for injection 70 mg vial contains 70 mg of caspofungin equivalent to 77.7 mg of caspofungin acetate.
4 CONTRAINDICATIONS
Caspofungin is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions (6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity
Anaphylaxis and other hypersensitivity reactions have been reported during administration of caspofungin.
Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported.
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of caspofungin [see Adverse Reactions (6.2)].Discontinue caspofungin at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment.
5.2 Hepatic Effects
Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to caspofungin has not been established. Monitor patients who develop abnormal liver function tests during caspofungin therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing caspofungin therapy.
5.3 Elevated Liver Enzymes During Concomitant Use With Cyclosporine
Elevated liver enzymes have occurred in patients receiving caspofungin and cyclosporine concomitantly. Only use caspofungin and cyclosporine in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in detail in another section of the labeling:
• Hypersensitivity [see Warnings and Precautions (5.1)]
• Hepatic Effects [see Warnings and Precautions (5.2)]
• Elevated Liver Enzymes During Concomitant Use with Cyclosporine [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience in Adults
The overall safety of caspofungin was assessed in 1865 adult individuals who received single or multiple doses of caspofungin: 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 for Presumed Fungal Infections in Febrile Neutropenic Patients
In the randomized, double-blinded empirical therapy study, patients received either caspofungin 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 caspofungin and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. Adverse reactions occurring in 7.5% or greater 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% or greater for at Least One Treatment Group
Adverse Reactions | Caspofungin* N=564 (%) | AmBisome† N=547 (%) |
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 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 |
Dyspnea | 9 | 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.* 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 caspofungin (35%) than in the group treated with AmBisome (52%).
To evaluate the effect of caspofungin and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 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 greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin (3%) than in the group treated with AmBisome (12%).
Candidemia and Other Candida Infections In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70 mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in 10% or greater 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% or Greater for at Least One Treatment Group
Adverse Reactions | Caspofungin 50 mg† N=114 (%) | Amphotericin B N=125 (%) |
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 |
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 |
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.† Patients received caspofungin 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 caspofungin (20%) than in the group treated with amphotericin B (49%).
To evaluate the effect of caspofungin and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 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 greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin than in the group treated with amphotericin B.
In a second randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70 mg loading dose) or caspofungin 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 reactions. Adverse reactions occurring in 5% or greater 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% or Greater for at Least One Treatment Group
Adverse Reactions | Caspofungin 50 mg† N=104 (%) | Caspofungin 150 mg N=100 (%) |
All Systems, Any Adverse Reaction | 83 | 83 |
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 |
Vascular Disorders | 19 | 18 |
Hypotension | 7 | 3 |
Hypertension | 5 | 6 |
Within any system organ class, individuals may experience more than 1 adverse event.* Intra-abdominal abscesses, peritonitis and pleural space infections.† Patients received caspofungin 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% or greater 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% or Greater for at Least One Treatment Group
Adverse Reactions | Caspofungin 50 mg* N=83 (%) | Fluconazole IV 200 mg* N=94 (%) |
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.* Derived from a comparator-controlled clinical study. |
Invasive Aspergillosis
In an open-label, noncomparative aspergillosis study, in which 69 patients received caspofungin
(70 mg loading dose on Day 1 followed by 50 mg daily), the following adverse reactions were observed with an incidence of 12.5% or greater: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%). Also reported 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 caspofungin was assessed in 171 pediatric patients who received single or multiple doses of caspofungin. 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 caspofungin in pediatric patients is comparable to that in adult patients. Table 6 shows the incidence of adverse reactions reported in 7.5% or greater of pediatric patients in clinical studies.
One patient (0.6%) receiving caspofungin, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from caspofungin 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 caspofungin 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% or Greater for at Least One Treatment Group
Adverse Reactions | Noncomparative Clinical Studies | Comparator-Controlled Clinical Study of Empirical Therapy | |
Caspofungin Any Dose N=115 (%) | Caspofungin 50 mg/m2 * N=56 (%) | AmBisome 3 mg/kg N=26 (%) | |
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 |
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 |
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 |
Within any system organ class, individuals may experience more than 1 adverse reaction.* 70 mg/m2 on Day 1, then 50 mg/m2 once daily for the remainder of the treatment. |
Overall Safety Experience of Caspofungin in Clinical Trials
The overall safety of caspofungin 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 caspofungin, 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. Adverse reactions which occurred in 5% or greater of all individuals who received caspofungin in these trials are shown in Table 7.
Overall, 1665 of the 1951 (85%) patients/volunteers who received caspofungin experienced an adverse reaction.Table 7: Adverse Reactions* in Patients Who Received Caspofungin in Clinical Trials† Incidence 5% or Greater for at Least One Treatment Group
Adverse Reactions‡ | Caspofungin (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 caspofungin or during the 14-day post- caspofungin follow-up period.† Incidence for each preferred term is 5% or greater among individuals who received at least 1 dose of caspofungin.‡ 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
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