Special Warning : אזהרת שימוש

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 labelling:
• 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 Reaction                            Caspofungin         AmBisome† *
N=564               N=547
(percent)            (percent)
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              57                   63 Site Conditions
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             47                   49 Disorders

Dyspnea                                          9                    10 

Skin     and    Subcutaneous         Tissue        42                   37 Disorders
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   Amphotericin B 50 mg† N=114      N=125
(percent)      (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 


General    Disorders    and   Administration    Site        47              63 Conditions
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 
Adverse Reactions                                                  Caspofungin            Amphotericin B 50 mg† N=114               N=125
(percent)               (percent)
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†    Caspofungin 150 N=104 (percent)            mg
N=100 (percent)

All Systems, Any Adverse Reaction                           83                   83 


General Disorders and Administration Site                   33                   27 Conditions
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    Fluconazole IV 50 mg*         200 mg*
N=83           N=94
(percent)      (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.

*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
Noncomparative Comparator-Controlled
Clinical Studies    Clinical Study of
Adverse Reactions                                           Empirical Therapy Caspofungin Caspofungin AmBisome
Any Dose      50 mg/m2*      3 mg/kg
N=115         N=56          N=26
(percent)    (percent)     (percent)
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           47            59           42 Site Conditions
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                   33            41           39 Disorders
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 
Noncomparative Comparator-Controlled
Clinical Studies    Clinical Study of
Adverse Reactions                                        Empirical Therapy Caspofungin Caspofungin AmBisome
Any Dose      50 mg/m2*      3 mg/kg
N=115         N=56          N=26
(percent)    (percent)     (percent)
Headache                                    5            9             4 Musculoskeletal and Connective Tissue        11           14            12 Disorders
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                 843                      (43) Conditions
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

6.2 Postmarketing Experience
The following additional adverse reactions have been identified during the post-approval use of caspofungin. 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, toxic epidermal necrolysis, Stevens-Johnson syndrome, and skin exfoliation
• Renal and urinary disorders: clinically significant renal dysfunction • General disorders and administration site conditions: swelling and peripheral edema
• Laboratory abnormalities: gamma-glutamyltransferase increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(https://sideeffects.health.gov.il/).

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