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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