Kenyan Health Patient Information Leaflet
Antifungal
1 INDICATIONS AND USAGE Caspofungin acetate for injection is an echinocandin antifungal indicated in adults and pediatric patients (3 months of age and older) for: Empirical therapy for presumed fungal infections in febrile, neutropenic patients. ( 1 ) Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. ( 1 ) Treatment of esophageal candidiasis. ( 1 ) Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. ( 1 ) 1.1 Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients Caspofungin acetate for injection is indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.1 , 14.5 )]. 1.2 Treatment of Candidemia and Other Candida Infections Caspofungin acetate for injection is indicated for the treatment of candidemia and the following candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.2 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida. 1.3 Treatment of Esophageal Candidiasis Caspofungin acetate for injection is indicated for the treatment of esophageal candidiasis in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.3 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of caspofungin in the treatment of esophageal candidiasis, patients with concomitant OPC had higher relapse rate of the OPC [see Clinical Studies ( 14.3 )] . 1.4 Treatment of Invasive Aspergillosis in Patients Who Are Refractory to or Intolerant of Other Therapies Caspofungin acetate for injection is indicated for the treatment of invasive aspergillosis in adult and pediatric patients (3 months of age and older) who are refractory to or intolerant of other therapies [see Clinical Studies ( 14.4 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been studied as initial therapy for invasive aspergillosis.
( 2.1 ): Administer by slow intravenous (IV) infusion over approximately 1 hour. Do not administer by IV bolus administration. Do not mix or co-infuse caspofungin acetate for injection with other medications. Do not use diluents containing dextrose (α-D-glucose). Dosage in Adults [18 years of age and older] ( 2.2 ): Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily for all indications except esophageal candidiasis. For esophageal candidiasis, use 50 mg once daily with no loading dose. Dosage in Pediatric Patients [3 months to 17 years of age] ( 2.3 ): Dosing should be based on the patient's body surface area. For all indications, administer a single 70 mg/m 2 loading dose on Day 1, followed by 50 mg/m 2 once daily thereafter. Maximum loading dose and daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosage Adjustments in Patients with Hepatic Impairment ( 2.4 ): Reduce dosage for adult patients with moderate hepatic impairment (35 mg once daily, with a 70 mg loading dose on Day 1 where appropriate). Dosage Adjustment in Patients Receiving Concomitant Inducers of Hepatic CYP Enzymes ( 2.5 ): Use 70 mg once daily dose for adult patients on rifampin. Consider dose increase to 70 mg once daily for adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin. Pediatric patients receiving these same concomitant medications may also require an increase in dose to 70 mg/m 2 once daily (maximum daily dose not to exceed 70 mg). 2.1 Important Administration Instructions for Use in All Patients Administer caspofungin acetate for injection by slow intravenous (IV) infusion over approximately 1 hour. Do not administer caspofungin acetate for injection by IV bolus administration. 2.2 Recommended Dosage in Adult Patients [18 years of age and older] The dosage and duration of caspofungin acetate for injection treatment for each indication are as follows: Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Continue empirical therapy until resolution of neutropenia. In general, treat patients found to have a fungal infection for a minimum of 14 days after the last positive culture and continue treatment 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 Administer a single 70 mg loading dose 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, continue antifungal therapy for at least 14 days after the last positive culture. Patients with neutropenia 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 ( 14.3 )]. Invasive Aspergillosis Administer a single 70 mg loading dose 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. 2.3 Recommended Dosing in Pediatric Patients [3 months to 17 years of age] For all indications, administer a single 70 mg/m 2 loading dose on Day 1, followed by 50 mg/m 2 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 ( 15 )]: Following calculation of the patient's BSA, the loading dose in milligrams should be calculated as BSA (m 2 ) X 70 mg/m 2 . The maintenance dose in milligrams should be calculated as BSA (m 2 ) X 50 mg/m 2 . Duration of treatment should be individualized to the indication, as described for each indication in adults [see Dosage and Administration ( 2.2 )]. If the 50 mg/m 2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m 2 daily (not to exceed 70 mg). Mosteller Formula 2.4 Dosage Adjustments in 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), caspofungin acetate for injection 35 mg once daily is recommended based upon pharmacokinetic data [see Clinical Pharmacology ( 12.3 )] with a 70 mg loading dose administered on Day 1 where appropriate. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients with any degree of hepatic impairment. 2.5 Dosage Adjustments in Patients Receiving Concomitant Inducers of Hepatic CYP Enzymes Adult Patients : Adult patients on rifampin should receive 70 mg of caspofungin acetate for injection once daily. When caspofungin acetate for injection is co-administered to adult patients with other inducers of hepatic CYP enzymes such as nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin, administration of a daily dose of 70 mg of caspofungin acetate for injection should be considered [see Drug Interactions ( 7 )]. Pediatric Patients : Pediatric patients on rifampin should receive 70 mg/m 2 of caspofungin acetate for injection daily (not to exceed an actual daily dose of 70 mg). When caspofungin acetate for injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin acetate for injection dose of 70 mg/m 2 once daily (not to exceed 70 mg) should be considered [see Drug Interactions ( 7 )]. 2.6 Preparation for Administration Reconstitution of Caspofungin for Intravenous Infusion Equilibrate the refrigerated vial of caspofungin acetate for injection to room temperature. 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 caspofungin acetate for injection contains an intentional overfill of caspofungin acetate for injection. Thus, the volume of diluent to be added to each vial and the drug concentration of the resulting solution is listed in Table 1 below. Table 1: Information for Preparation of Caspofungin Acetate for Injection * Reconstitution volume of diluent to be added is based on the overfill amount of caspofungin (54.6 mg and 75.6 mg, respectively). Caspofungin Acetate for Injection Vial (equivalent to caspofungin) Volume of diluent to be added* Resulting Concentration following Reconstitution 50 mg 10.8 mL 5 mg per mL 70 mg 10.8 mL 7 mg per 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 of caspofungin acetate for injection in the vial may be stored for up to one hour at ≤25°C (≤77°F) prior to the preparation of the infusion solution in the intravenous bag or bottle. Caspofungin acetate for injection vials are for single-dose only. Discard unused portion. Dilution of the Reconstituted Solution in the Intravenous Bag for Infusion Aseptically transfer the appropriate volume (mL) of reconstituted caspofungin acetate for injection to an intravenous (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 caspofungin acetate for injection 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 per mL. This diluted infusion solution in the intravenous bag or bottle 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). Important Reconstitution and Dilution Instructions for Pediatric Patients 3 Months of Age and Older Follow the reconstitution procedures described above using either the 70 mg or 50 mg vial to create the reconstituted solution [see Dosage and Administration ( 2.3 )]. 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 per mL (if reconstituted from the 70 mg vial) or a concentration of 5 mg per 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 50 mg vials (with a concentration of 5 mg per 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 . 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.
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 )] Adults: Most common adverse reactions (incidence 10% or greater) are diarrhea, pyrexia, ALT/AST increased, blood alkaline phosphatase increased, and blood potassium decreased. ( 6.1 ) Pediatric Patients: Most common adverse reactions (incidence ≥10%) are pyrexia, diarrhea, rash, ALT/AST increased, blood potassium decreased, hypotension, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 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. 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 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 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. 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 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 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. 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 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 Within any system organ class, individuals may experience more than 1 adverse reaction. * Derived from a comparator-controlled clinical study. 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 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%)…
16 HOW SUPPLIED/STORAGE AND HANDLING Caspofungin Acetate for Injection is supplied as follows: NDC Caspofungin Acetate for Injection Package Factor 25021-194-10 50 mg Single-Dose Vial 1 vial per carton 25021-195-10 70 mg Single-Dose Vial 1 vial per carton Caspofungin Acetate for Injection is a lyophilized white to off-white powder/cake for intravenous infusion in a vial with an aluminum flip off seal and plastic cap. Storage Conditions Store refrigerated between 2° and 8°C (36° and 46°F). Discard unused portion. Sterile, Nonpyrogenic, Lyophilized. The container closure is not made with natural rubber latex. There are no preservatives or bacteriostatic agents in this product.