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英文药名：CANCIDAS(caspofungin acetate for injection) 中文药名：注射用醋酸卡泊芬净 生产厂家：默克有限公司
E.The reconstituted solution of CANCIDAS 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. F.CANCIDAS vials are for single use only. Discard unused portion. Dilution of the Reconstituted Solution in the Intravenous Bag for Infusion A.Aseptically transfer the appropriate volume (mL) of reconstituted CANCIDAS 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. B.Alternatively, the volume (mL) of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/mL. C.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/mL (if reconstituted from the 70-mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50-mg vial). The choice of vial should be based on total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses less than 50 mg that 50-mg vials (with a concentration of 5 mg/mL) be used if available. The 70-mg vial should be reserved for pediatric patients requiring doses greater than 50 mg. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. 2.7 Drug Incompatibilities Do not mix or co-infuse CANCIDAS with other medications, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. Do not use diluents containing dextrose (α-D-glucose), as CANCIDAS is not stable in diluents containing dextrose. 3 DOSAGE FORMS AND STRENGTHS CANCIDAS 50 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with a red aluminum band and a plastic cap. CANCIDAS 50-mg vial contains 54.6 mg of caspofungin. CANCIDAS 70 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with a yellow/orange aluminum band and a plastic cap. CANCIDAS 70-mg vial contains 75.6 mg of caspofungin. 4 CONTRAINDICATIONS CANCIDAS 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 has been reported during administration of CANCIDAS. If this occurs, discontinue CANCIDAS and administer appropriate treatment. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment. 5.2 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with CANCIDAS. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with CANCIDAS, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to CANCIDAS has not been established. Monitor patients who develop abnormal liver function tests during CANCIDAS therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing CANCIDAS therapy. 5.3 Elevated Liver Enzymes During Concomitant Use With Cyclosporine Elevated liver enzymes have occurred in patients receiving CANCIDAS and cyclosporine concomitantly. Only use CANCIDAS 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 CANCIDAS 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 CANCIDAS was assessed in 1865 adult individuals who received single or multiple doses of CANCIDAS: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications. Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients In the randomized, double-blinded empirical therapy study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or AmBisome® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the CANCIDAS and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. 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
The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with CANCIDAS (35%) than in the group treated with AmBisome (52%).
To evaluate the effect of CANCIDAS and 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 CANCIDAS than in the group treated with amphotericin B. In a second randomized, double-blinded invasive candidiasis study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or CANCIDAS 150 mg/day. The proportion of patients who experienced any adverse reaction was similar in the 2 treatment groups; however, this study was not large enough to detect differences in rare or unexpected adverse 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
Patients received CANCIDAS 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment. Esophageal Candidiasis and Oropharyngeal Candidiasis Adverse reactions occurring in 10% 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
Invasive Aspergillosis In an open-label, noncomparative aspergillosis study, in which 69 patients received CANCIDAS (70-mg loading dose on Day 1 followed by 50 mg daily), the following 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 CANCIDAS was assessed in 171 pediatric patients who received single or multiple doses of CANCIDAS. The distribution among the 153 pediatric patients who were over the age of 3 months was as follows: 104 febrile, neutropenic patients; 38 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of CANCIDAS in pediatric patients is comparable to that in adult patients. Table 6 shows the incidence of adverse reactions reported in 7.5% or greater of pediatric patients in clinical studies. One patient (0.6%) receiving CANCIDAS, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from CANCIDAS and three patients (12%) were discontinued from AmBisome due to a drug-related adverse reaction. The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was 22% in the group treated with CANCIDAS and 35% in the group treated with AmBisome. Table 6: Adverse Reactions Among Pediatric Patients (0 months to 17 years of age) Incidence 7.5% or Greater for at Least One Treatment Group
Overall Safety Experience of CANCIDAS in Clinical Trials The overall safety of CANCIDAS was assessed in 2036 individuals (including 1642 adult or pediatric patients and 394 volunteers) from 34 clinical studies. These individuals received single or multiple (once daily) doses of CANCIDAS, ranging from 5 mg to 210 mg. Full safety data is available from 1951 individuals, as the safety data from 85 patients enrolled in 2 compassionate use studies was limited solely to serious adverse reactions. Adverse reactions which occurred in 5% or greater of all individuals who received CANCIDAS in these trials are shown in Table 7. Overall, 1665 of the 1951 (85%) patients/volunteers who received CANCIDAS experienced an adverse reaction. Table 7: Adverse Reactions* in Patients Who Received CANCIDAS in Clinical Trials† Incidence 5% or Greater for at Least One Treatment Group
Incidence for each preferred term is 5% or greater among individuals who received at least 1 dose of CANCIDAS. Within any system organ class, individuals may experience more than 1 adverse event. Clinically significant adverse reactions, regardless of causality or incidence which occurred in less than 5% of patients are listed below. Blood and lymphatic system disorders: anemia, coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia Cardiac disorders: arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, myocardial infarction, tachycardia Gastrointestinal disorders: abdominal distension, abdominal pain upper, constipation, dyspepsia General disorders and administration site conditions: asthenia, fatigue, infusion site pain/pruritus/swelling, mucosal inflammation, edema Hepatobiliary disorders: hepatic failure, hepatomegaly, hepatotoxicity, hyperbilirubinemia, jaundice Infections and infestations: bacteremia, sepsis, urinary tract infection Metabolic and nutrition disorders: anorexia, decreased appetite, fluid overload, hypomagnesemia, hypercalcemia, hyperglycemia, hypokalemia Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, pain in extremity Nervous system disorders: convulsion, dizziness, somnolence, tremor Psychiatric disorders: anxiety, confusional state, depression, insomnia Renal and urinary disorders: hematuria, renal failure Respiratory, thoracic, and mediastinal disorders: dyspnea, epistaxis, hypoxia, tachypnea Skin and subcutaneous tissue disorders: erythema, petechiae, skin lesion, urticaria Vascular disorders: flushing, hypertension, phlebitis 6.2 Postmarketing Experience The following additional adverse reactions have been identified during the post-approval use of CANCIDAS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: pancreatitis Hepatobiliary disorders: hepatic necrosis Skin and subcutaneous tissue disorders: erythema multiforme, 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 7 DRUG INTERACTIONS Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of CANCIDAS. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Tacrolimus: For patients receiving CANCIDAS and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Inducers of Hepatic CYP Enzymes Rifampin: Rifampin is a potent CYP3A4 inducer and concomitant administration with CANCIDAS is expected to reduce the plasma concentrations of CANCIDAS. Therefore, adult patients on rifampin should receive 70 mg of CANCIDAS daily and pediatric patients on rifampin should receive 70 mg/m2 of CANCIDAS daily (not to exceed an actual daily dose of 70 mg) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Other Inducers of Hepatic CYP Enzymes Adults: When CANCIDAS is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of CANCIDAS should be considered [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Pediatric Patients: When CANCIDAS is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg/m2 CANCIDAS (not to exceed an actual daily dose of 70 mg) should be considered [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with the use of CANCIDAS in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri-implantation loss, and incomplete ossification at multiple fetal sites. CANCIDAS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In offspring born to pregnant rats treated with caspofungin at doses comparable to the human dose based on body surface area comparisons, there was incomplete ossification of the skull and torso and increased incidences of cervical rib. There was also an increase in resorptions and peri-implantation losses. In pregnant rabbits treated with caspofungin at doses comparable to 2 times the human dose based on body surface area comparisons, there was an increased incidence of incomplete ossification of the talus/calcaneus in offspring and increases in fetal resorptions. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma. 8.3 Nursing Mothers It is not known whether caspofungin is present in human milk. Caspofungin was found in the milk of lactating, drug-treated rats. Because many drugs are excreted in human milk, caution should be exercised when caspofungin is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of CANCIDAS in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications [see Indications and Usage (1)]: Empirical therapy for presumed fungal infections in febrile, neutropenic patients. Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections. Treatment of esophageal candidiasis. Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole). The efficacy and safety of CANCIDAS has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of CANCIDAS to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. CANCIDAS has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. CANCIDAS has also not been studied as initial therapy for invasive aspergillosis in pediatric patients. In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous CANCIDAS. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received CANCIDAS in safety and efficacy studies [see Clinical Pharmacology (12.3) and Clinical Studies (14.5)]. The majority of the pediatric patients received CANCIDAS at a once-daily maintenance dose of 50 mg/m2 for a mean duration of 12 days (median 9, range 1-87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with CANCIDAS were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%) [see Adverse Reactions (6.2)]. Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions [see Warnings and Precautions (5.3)]. 8.5 Geriatric Use Clinical studies of CANCIDAS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% in AUC) compared to young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), CANCIDAS 35 mg once daily is recommended based upon pharmacokinetic data [see Clinical Pharmacology (12.3)]. However, where recommended, a 70-mg loading dose should still be administered on Day 1 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment. 8.7 Patients with Renal Impairment No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable. In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on Day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported. 11 DESCRIPTION CANCIDAS is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS is an echinocandin antifungal that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall. CANCIDAS (caspofungin acetate) is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0 diacetate (salt). CANCIDAS 50 mg also contains: 39 mg sucrose, 26 mg mannitol, glacial acetic acid, and sodium hydroxide. CANCIDAS 70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C52H88N10O15∙2C2H4O2 and the formula weight is 1213.42. The structural formula is:
N=5 for C 1hr and AUC 0-24hr; N=6 for C 24hr N=117 for C 24hr; N=119 for C 1hr Following an initial 70-mg loading dose on day 1 Drug Interactions [see Drug Interactions (7)] Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P (CYP) system. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for CYP enzymes. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Clinical studies in adult healthy volunteers also demonstrated that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate. Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered [see Warnings and Precautions (5.2)]. Tacrolimus: CANCIDAS reduced the blood AUC0-12 of tacrolimus (FK-506, Prograf®) by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus whole blood trough concentrations and appropriate tacrolimus dosage adjustments are recommended. Rifampin: A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations [see Dosage and Administration (2.5)]. Other Inducers of Hepatic CYP Enzymes Adults: Results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other hepatic CYP enzyme inducers (e.g., efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with CANCIDAS may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible [see Dosage and Administration (2.5)]. Pediatric patients: In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with CANCIDAS may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults [see Dosage and Administration (2.5)]. 12.4 Microbiology Mechanism of Action Caspofungin, an echinocandin, inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. Beta (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus. Drug Resistance There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the Fks subunits of the glucan synthase enzyme. These mutations are associated with higher MICs and breakthrough infection. Candida species that exhibit reduced susceptibility to caspofungin as a result of an increase in the chitin content of the fungal cell wall have also been identified, although the significance of this phenomenon in vivo is not well known. Drug Interactions Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either A. fumigatus or C. albicans. The clinical significance of these results is unknown. Activity in Vitro and in Clinical Infections Caspofungin has been shown to be active both in vitro and in clinical infections against most strains of the following microorganisms: Aspergillus fumigatus Aspergillus flavus Aspergillus terreus Candida albicans Candida glabrata Candida guilliermondii Candida krusei Candida parapsilosis Candida tropicalis Susceptibility Testing Methods The interpretive standards for caspofungin against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference methods2,3 for MIC (partial inhibition endpoint) read at 24 hours. No interpretive criteria have been established for Aspergillus species or other filamentous fungi. When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of pathogens. These reports should aid the physician in selecting an antifungal drug product for treatment. The techniques for Broth Microdilution are described below. Broth Microdilution Techniques Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure at 24 hours2,3. Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of caspofungin powder. The MIC values should be interpreted according to the criteria provided in Table 9. Table 9: Susceptibility Interpretive Criteria for Caspofungin
Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard caspofungin powder should provide the following range of values noted in Table 103. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Table 10: Acceptable Quality Control Ranges for caspofungin to be used in Validation of Susceptibility Test Results
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin. Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously. Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients treated with the 70-mg dose. 13.2 Animal Toxicology and/or Pharmacology In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses. No treatment-related findings were seen in a 5-week study in infant monkeys at doses which produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m2 daily. 14 CLINICAL STUDIES 14.1 Empirical Therapy in Febrile, Neutropenic Patients A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm3) patients who were randomized to treatment with daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3 mg/kg/day). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. Twenty-four percent of patients were high risk and 56% had received prior antifungal prophylaxis. Patients who remained febrile or clinically deteriorated following 5 days of therapy could receive 70 mg/day of CANCIDAS or 5 mg/kg/day of AmBisome. Treatment was continued to resolution of neutropenia (but not beyond 28 days unless a fungal infection was documented). An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection. Based on the composite response rates, CANCIDAS was as effective as AmBisome in empirical therapy of persistent febrile neutropenia (see Table 11). Table 11: Favorable Response of Patients with Persistent Fever and Neutropenia
Overall Response: estimated % difference adjusted for strata and expressed as CANCIDAS – AmBisome (95.2% CI); Individual criteria presented above are not mutually exclusive. The percent difference calculated as CANCIDAS – AmBisome. Analysis population excluded subjects who did not have fever or neutropenia at study entry. The rate of successful treatment of documented baseline infections, a component of the primary endpoint, was not statistically different between treatment groups. The response rates did not differ between treatment groups based on either of the stratification variables: risk category or prior antifungal prophylaxis. 14.2 Candidemia and the Following other Candida Infections: Intra-Abdominal Abscesses, Peritonitis and Pleural Space Infections In a randomized, double-blind study, patients with a proven diagnosis of invasive candidiasis received daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non-neutropenic patients and 0.7 to 1 mg/kg/day for neutropenic patients). Patients were stratified by both neutropenic status and APACHE II score. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded from this study. Patients who met the entry criteria and received one or more doses of IV study therapy were included in the modified intention-to-treat [MITT] analysis of response at the end of IV study therapy. A favorable response at this time point required both symptom/sign resolution/improvement and microbiological clearance of the Candida infection. Two hundred thirty-nine patients were enrolled. Patient disposition is shown in Table 12. Table 12: Disposition in Candidemia and Other Candida Infections (Intra-abdominal abscesses, peritonitis, and pleural space infections)
Study defined as study treatment period and 6-8 week follow-up period. Determined by the investigator to be possibly, probably, or definitely drug-related Of the 239 patients enrolled, 224 met the criteria for inclusion in the MITT population (109 treated with CANCIDAS and 115 treated with amphotericin B). Of these 224 patients, 186 patients had candidemia (92 treated with CANCIDAS and 94 treated with amphotericin B). The majority of the patients with candidemia were non-neutropenic (87%) and had an APACHE II score less than or equal to 20 (77%) in both arms. Most candidemia infections were caused by C. albicans (39%), followed by C. parapsilosis (20%), C. tropicalis (17%), C. glabrata (8%), and C. krusei (3%). At the end of IV study therapy, CANCIDAS was comparable to amphotericin B in the treatment of candidemia in the MITT population. For the other efficacy time points (Day 10 of IV study therapy, end of all antifungal therapy, 2-week post-therapy follow-up, and 6- to 8-week post-therapy follow-up), CANCIDAS was as effective as amphotericin B. Outcome, relapse and mortality data are shown in Table 13. Table 13: Outcomes, Relapse, & Mortality in Candidemia and Other Candida Infections (Intra-abdominal abscesses, peritonitis, and pleural space infections)
Calculated as CANCIDAS – amphotericin B 95% CI for candidemia, 95.6% for all patients Modified intention-to-treat Includes all patients who either developed a culture-confirmed recurrence of Candida infection or required antifungal therapy for the treatment of a proven or suspected Candida infection in the follow-up period. Study defined as study treatment period and 6-8 week follow-up period. In this study, the efficacy of CANCIDAS in patients with intra-abdominal abscesses, peritonitis and pleural space Candida infections was evaluated in 19 non-neutropenic patients. Two of these patients had concurrent candidemia. Candida was part of a polymicrobial infection that required adjunctive surgical drainage in 11 of these 19 patients. A favorable response was seen in 9 of 9 patients with peritonitis, 3 of 4 with abscesses (liver, parasplenic, and urinary bladder abscesses), 2 of 2 with pleural space infections, 1 of 2 with mixed peritoneal and pleural infection, 1 of 1 with mixed abdominal abscess and peritonitis, and 0 of 1 with Candida pneumonia. Overall, across all sites of infection included in the study, the efficacy of CANCIDAS was comparable to that of amphotericin B for the primary endpoint. In this study, the efficacy data for CANCIDAS in neutropenic patients with candidemia were limited. In a separate compassionate use study, 4 patients with hepatosplenic candidiasis received prolonged therapy with CANCIDAS following other long-term antifungal therapy; three of these patients had a favorable response. In a second randomized, double-blind study, 197 patients with proven invasive candidiasis received CANCIDAS 50 mg/day (following a 70-mg loading dose on Day 1) or CANCIDAS 150 mg/day. The diagnostic criteria, evaluation time points, and efficacy endpoints were similar to those employed in the prior study. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded. Although this study was designed to compare the safety of the two doses, it was not large enough to detect differences in rare or unexpected adverse events [see Adverse Reactions (6.1)]. The efficacy of CANCIDAS at the 150 mg daily dose was not significantly better than the efficacy of the 50-mg daily dose of CANCIDAS. The efficacy of doses higher than 50 mg daily in the other adult patients for whom CANCIDAS is indicated has not been evaluated. 14.3 Esophageal Candidiasis (and information on oropharyngeal candidiasis) The safety and efficacy of CANCIDAS in the treatment of esophageal candidiasis was evaluated in one large, controlled, noninferiority, clinical trial and two smaller dose-response studies. In all 3 studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis; most patients had advanced AIDS (with CD4 counts <50/mm3). Of the 166 patients in the large study who had culture-confirmed esophageal candidiasis at baseline, 120 had Candida albicans and 2 had Candida tropicalis as the sole baseline pathogen whereas 44 had mixed baseline cultures containing C. albicans and one or more additional Candida species. In the large, randomized, double-blind study comparing CANCIDAS 50 mg/day versus intravenous fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7-21 days). Favorable overall response at 5 to 7 days following discontinuation of study therapy required both complete resolution of symptoms and significant endoscopic improvement. The definition of endoscopic response was based on severity of disease at baseline using a 4-grade scale and required at least a two-grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less. The proportion of patients with a favorable overall response was comparable for CANCIDAS and fluconazole as shown in Table 14. Table 14: Favorable Response Rates for Patients with Esophageal Candidiasis*
Calculated as CANCIDAS – fluconazole The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for CANCIDAS and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response was comparable (85.2% and 86.2% for CANCIDAS and fluconazole, respectively). As shown in Table 15, the esophageal candidiasis relapse rates at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with CANCIDAS had a numerically higher incidence of relapse; however, the difference was not statistically significant. Table 15: Relapse Rates at 14 and 28 Days Post-Therapy in Patients with Esophageal Candidiasis at Baseline
Table 16: Oropharyngeal Candidiasis Response Rates at 5 to 7 Days Post-Therapy and Relapse Rates at 14 and 28 Days Post-Therapy in Patients with Oropharyngeal and Esophageal Candidiasis at Baseline
The results from the two smaller dose-ranging studies corroborate the efficacy of CANCIDAS for esophageal candidiasis that was demonstrated in the larger study. CANCIDAS was associated with favorable outcomes in 7 of 10 esophageal C. albicans infections refractory to at least 200 mg of fluconazole given for 7 days, although the in vitro susceptibility of the infecting isolates to fluconazole was not known. 14.4 Invasive Aspergillosis Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open-label, noncomparative study to evaluate the safety, tolerability, and efficacy of CANCIDAS. Enrolled patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients were classified as those who had disease progression or failed to improve despite therapy for at least 7 days with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of creatinine (or creatinine ≥2.5 mg/dL while on therapy), other acute reactions, or infusion-related toxicity. To be included in the study, patients with pulmonary disease must have had definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis. Patients were administered a single 70-mg loading dose of CANCIDAS and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days. An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on CANCIDAS, and clinical outcome. A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, nonprogressive disease was considered to be an unfavorable response. Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for greater than 7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and CANCIDAS concomitantly, of whom 8 also received mycophenolate mofetil. Overall, the expert panel determined that 41% (26/63) of patients receiving at least one dose of CANCIDAS had a favorable response. For those patients who received greater than 7 days of therapy with CANCIDAS, 50% (26/52) had a favorable response. The favorable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10), respectively. The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement had a favorable response. Two of these 8 patients had progression of disease and manifested CNS involvement while on therapy. CANCIDAS is effective for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, amphotericin B, and/or lipid formulations of amphotericin B. However, the efficacy of CANCIDAS for initial treatment of invasive aspergillosis has not been evaluated in comparator-controlled clinical studies. 14.5 Pediatric Patients The safety and efficacy of CANCIDAS were evaluated in pediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials. The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing CANCIDAS (50 mg/m2 IV once daily following a 70-mg/m2 loading dose on Day 1 [not to exceed 70 mg daily]) to AmBisome (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on AmBisome) as empirical therapy in pediatric patients with persistent fever and neutropenia. The study design and criteria for efficacy assessment were similar to the study in adult patients [see Clinical Studies (14.1)]. Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk. Favorable overall response rates of pediatric patients with persistent fever and neutropenia are presented in Table 17. Table 17: Favorable Overall Response Rates of Pediatric Patients with Persistent Fever and Neutropenia
The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in pediatric patients (ages 3 months to 17 years) with candidemia and other Candida infections, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). The study employed diagnostic criteria which were based on established EORTC/MSG criteria of proven or probable infection; these criteria were similar to those criteria employed in the adult studies for these various indications. Similarly, the efficacy time points and endpoints used in this study were similar to those employed in the corresponding adult studies [see Clinical Studies (14.2, 14.3, and 14.4)]. All patients received CANCIDAS at 50 mg/m2 IV once daily following a 70-mg/m2 loading dose on Day 1 (not to exceed 70 mg daily). Among the 49 enrolled patients who received CANCIDAS, 48 were included in the efficacy analysis (one patient excluded due to not having a baseline Aspergillus or Candida infection). Of these 48 patients, 37 had candidemia or other Candida infections, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. Most candidemia and other Candida infections were caused by C. albicans (35%), followed by C. parapsilosis (22%), C. tropicalis (14%), and C. glabrata (11%). The favorable response rate, by indication, at the end of caspofungin therapy was as follows: 30/37 (81%) in candidemia or other Candida infections, 5/10 (50%) in invasive aspergillosis, and 1/1 in esophageal candidiasis. 15 REFERENCES 1.Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17): 1098 (letter). 2.Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI document M27-A3. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087, USA, 2008. 3.Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Third Informational Supplement. CLSI document M27-S3. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087, USA, 2008. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied CANCIDAS 50 mg is a lyophilized white to off-white cake or powder for intravenous infusion supplied in single-dose vials with a red aluminum band and a plastic cap. NDC 0006-3822-10 supplied as one single-use vial. CANCIDAS 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap. NDC 0006-3823-10 supplied as one single-use vial. Storage and Handling The lyophilized vials should be stored refrigerated at 2° to 8°C (36° to 46°F). 17 PATIENT COUNSELING INFORMATION 17.1 Hypersensitivity Inform patients that anaphylactic reactions have been reported during administration of CANCIDAS. CANCIDAS can cause hypersensitivity reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm. Inform patients to report these signs or symptoms to their healthcare providers. 17.2 Hepatic Effects Inform patients that there have been isolated reports of serious hepatic effects from CANCIDAS therapy. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3BAD23A6-09A6-4194-9182-093ED61BC71C | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
