CANCIDAS (Brand for CASPOFUNGIN ACETATE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect prepared infusions for particulate matter and discoloration prior to administration.
Intravenous Administration
Reconstitution
-Bring refrigerated vials of caspofungin to room temperature prior to reconstitution.
-Add 10.8 ml of 0.9% sodium chloride, sterile water, bacteriostatic water with methylparaben and propylparaben, or bacteriostatic water with 0.9% benzyl alcohol for injection to the 50-mg vial or 70-mg vial for a resultant concentration of 5 mg/ml or 7 mg/ml, respectively.-For neonates, do not use a solution that contains benzyl alcohol.

-Mix gently until the solution is clear.
-Caspofungin vials are single use only; discard any unused reconstituted solution.
-Storage: Reconstituted caspofungin in the vial may be stored at <= 25 degrees C (<= 77 degrees F) for 1 hour prior to dilution.

Dilution
-Withdraw appropriate volume and dilute in NS, 1/2 NS, or LR to a final concentration not to exceed 0.5 mg/ml.
-Do not use any diluents containing dextrose to prepare caspofungin.
-Storage: The final diluted infusion may be stored for up to 24 hours at <= 25 degrees C (<= 77 degrees F) or for up to 48 hours under refrigeration at 2-8 degrees C.

Intermittent IV Infusion
-Caspofungin should be administered as a slow intravenous (IV) infusion over approximately 1 hour. Do not administer as an IV bolus injection.
-Do not mix or co-infuse caspofungin with other medications or infuse with dextrose containing solutions.

NOTE: Safety in pediatric patients was comparable among age groups and similar to that in adult patients. Most adverse events were mild and transient.

In pediatric clinical trials, edema occurred in 3-4% of patients receiving caspofungin.

Elevated hepatic enzymes have been noted in pediatric patients receiving caspofungin. Overall in pediatric studies, elevated alanine aminotransferase (ALT) has been noted in approximately 5-14% of patients and elevated aspartate aminotransaminase (AST) has occurred in approximately 2-17% of patients. Although not reported in pediatric studies, hyperbilirubinemia was reported in 10-13% of adult patients in clinical studies. In some patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, isolated cases (< 5%) of clinically significant hepatic dysfunction, jaundice, hepatitis, hepatomegaly, and hepatic failure have been reported; a causal relationship to the drug has not been established. Patients who develop abnormal liver function tests during therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing caspofungin. Hepatic necrosis and elevated gamma-glutamyltransferase concentrations have been reported in post-marketing surveillance. Patients who have received cyclosporine in combination with caspofungin have developed transient elevated hepatic enzymes. In some cases, ALT reached 3 times the upper limit of normal. Elevations in AST have paralleled ALT but were of lesser magnitude. Enzyme levels returned to normal upon discontinuation of cyclosporine. The FDA-approved product labeling recommends against the concomitant use of caspofungin with cyclosporine unless the potential benefit outweighs the risk to the patient.

Anaphylactoid reactions have been reported with caspofungin administration. Possible histamine-mediated symptoms that have been reported include rash (6% to 23%), pruritus (6% to 7%), facial swelling, angioedema, bronchospasm, and sensation of warmth. Erythema (4% to 9%) and mucosal inflammation (4% to 10%) have also occurred. Petechiae, skin lesions, and urticaria were reported in less than 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2,036; 171 pediatric patients). Decubitus ulcers (skin ulcer) have been reported in adult clinical trials. Skin exfoliation (exfoliative dermatitis), erythema multiforme, and cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been noted during postmarketing. Discontinue caspofungin at the first symptom of a hypersensitivity reaction and administer appropriate treatment.

In pediatric patients receiving caspofungin during clinical trials, fever (29-30%), headache (5-9%), and chills (10-13%) were common. Flushing was reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients). The incidence of infusion-related reactions was less with caspofungin (22%) compared with liposomal amphotericin B (35%). An infusion-related adverse reaction was defined as a systemic event, such as pyrexia, chills, flushing, rash, changes in blood pressure, increased heart rate, breathing abnormalities, and anaphylaxis, that developed during the study therapy infusion and one hour following infusion.

The most frequently reported respiratory adverse events associated with caspofungin use during pediatric clinical trials were cough (6-9%) and respiratory distress (8%). Dyspnea, epistaxis, hypoxia, and tachypnea were reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients). Although not reported in pediatric patients, pleural effusion was reported in 9% of adult patients in clinical studies.

Clinically relevant hypokalemia was noted in 5-8% of pediatric patients who received caspofungin in clinical studies; however, some degree of decreased blood potassium was reported in 9-18% of patients. Blood potassium increases were observed in up to 3% of pediatric patients, but the cases were not noted as hyperkalemia. Hyperglycemia, hypomagnesemia, and hypercalcemia were reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

During pediatric clinical trials, anemia was reported in 2% of patients who received caspofungin. Coagulopathy, febrile neutropenia, neutropenia, and thrombocytopenia were reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

An injection site reaction, including infusion site pain, pruritus, and swelling has occurred in < 5% of patients receiving caspofungin during clinical trials. Phlebitis was also reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

In pediatric clinical trials, diarrhea (7-17%), vomiting (8-11%), abdominal pain (4-7%), and nausea (4%) were reported in caspofungin recipients. Abdominal distention, upper abdominal pain, constipation, dyspepsia, decreased appetite, and anorexia were also reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients). Pancreatitis has been reported in post-marketing surveillance. Due to the voluntary nature of post-market reports, neither frequency nor a definitive causal relationship with caspofungin can be established.

In pediatric clinical trials, central line infection occurred in 1-9% of patients receiving caspofungin. Bacteremia, febrile neutropenia, and urinary tract infections were reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

In pediatric caspofungin clinical trials, hypertension (9-10%), hypotension (9-12%) and sinus tachycardia (4-11%) were reported. Arrhythmias/arrhythmia exacerbation, atrial fibrillation, bradycardia, cardiac arrest, and myocardial infarction were also reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

Renal failure (unspecified), fluid retention/overload, and hematuria have been reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients). Post-marketing reports have noted clinically significant renal dysfunction.

In pediatric clinical trials, back pain was reported in 4% of patients who received caspofungin. Arthralgia, extremity pain, asthenia, and fatigue were also reported in < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

Neurologic and psychiatric adverse events, including convulsions (seizures), dizziness, somnolence or drowsiness, tremor, anxiety, confusional state (confusion), depression, and insomnia, were reported by < 5% of patients receiving caspofungin in pooled safety data from 34 adult and pediatric clinical studies (n = 2036; 171 pediatric patients).

Caspofungin is contraindicated for use in patients with known hypersensitivity (e.g., anaphylaxis) to any of the product components. Anaphylaxis and other hypersensitivity reactions, including serious rash like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have been reported during caspofungin therapy. Discontinue caspofungin at the first symptom of a hypersensitivity reaction and administer appropriate treatment.

There is no clinical experience in pediatric patients with any degree of hepatic disease. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), a dosage adjustment for caspofungin is recommended based upon pharmacokinetic data; there is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score more than 9).

Description: Caspofungin is an intravenous antifungal agent belonging to the echinocandin class. Caspofungin has good activity against Candida and Aspergillus species, and is active against many Candida isolates that are resistant to other antifungal agents such as fluconazole and amphotericin B. It has very little or no activity for other fungal infections such as cryptococcosis, zygomycosis, and fusariosis. Caspofungin is used for the treatment of candidemia and invasive candidiasis, for the treatment of invasive aspergillosis that is refractory to or intolerant of other therapies, for empirical treatment of presumed fungal infections in febrile neutropenia, and for the prophylaxis of invasive fungal infections in high-risk patients. Data are lacking for caspofungin use in the neonatal population; therefore, caspofungin use is usually limited to cases where first-line therapies such as fluconazole or amphotericin B cannot be used. Caspofungin is FDA-approved for use in pediatric patients as young as 3 months of age.

General dosing information:
Caspofungin use in neonates
-Candida infections in neonates have a higher rate of CNS and multiple organ involvement compared to older patients; the ability of caspofungin to treat meningitis is unknown.
-Echinocandins, including caspofungin, should be used with caution in neonates and generally limited to situations in which resistance or toxicity preclude the use of fluconazole or amphotericin B products.
-Despite the potential concerns regarding caspofungin use, several case reports and small case series and trials describe the use of caspofungin in neonates ranging from 24 weeks gestational age to term.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Aspergillus flavus, Aspergillus fumigatus, Aspergillus sp., Aspergillus terreus, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida sp., Candida tropicalis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Aspergillus niger, Candida lusitaniae
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of candidemia and invasive candidiasis, including chronic disseminated (hepatosplenic) candidiasis*:
-for the treatment of candidemia and invasive candidiasis:
Intravenous dosage:
Neonates*: Very limited data are available; CNS involvement should be presumed in neonates with candidemia. A dose of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. For neonatal candidiasis, amphotericin B or fluconazole is the preferred therapy. Some experts suggest that if an echinocandin is used in neonates, micafungin is the preferred agent.
Infants 1 to 2 months*: Very limited data are available; CNS involvement should be presumed in neonates with candidemia. A dose of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. For neonatal candidiasis, amphotericin B or fluconazole is the preferred therapy. Some experts suggest that if an echinocandin is used in neonates, micafungin is the preferred agent.
Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, followed by 50 mg/m2/dose (Max: 70 mg/dose) IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. May increase dose to 70 mg/m2/dose (Max: 70 mg/dose) if there is an inadequate clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of chronic disseminated (hepatosplenic) candidiasis*:
Intravenous dosage:
Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, then 50 mg/m2/dose (Max: 70 mg/dose) IV once daily for several weeks, followed by oral fluconazole for patients who are unlikely to have a fluconazole-resistant isolate. May increase dose to 70 mg/m2/day (Max: 70 mg/dose) if there is an inadequate clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Neonates* and Infants 1 to 2 months*: No data are available. A dosage of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. Although specific neonatal recommendations are not available, clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.
Infants 3 months and older, Children, and Adolescents: 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

For the treatment of fluconazole-refractory oropharyngeal candidiasis (thrush)*:
Intravenous dosage:
Infants 1 to 2 months: Limited data are available. 25 mg/m2/dose IV once daily for up to 28 days as an alternative. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents 3 months to 17 years: 50 mg/m2/dose IV (Max: 70 mg/dose) once daily for up to 28 days as an alternative. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of esophageal candidiasis, including fluconazole-refractory disease:
Intravenous dosage:
Infants 1 to 2 months*: Limited data are available. 25 mg/m2/dose IV once daily for 14 to 21 days as an alternative. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily for 14 to 21 days as an alternative. The FDA-approved dosage is 50 mg/m2/dose (Max: 70 mg/dose) IV once daily for 7 to 14 days. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of cardiovascular system infections, including endocarditis*, suppurative thrombophlebitis*, and infected pacemaker*, implantable cardiac defibrillator (ICD)*, or ventricular assist devices (VAD)*:
-for the treatment of Candida cardiovascular system infections*:
Intravenous dosage:
Neonates and Infants 1 to 2 months: Very limited data are available; a dose of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. For neonatal candidiasis, amphotericin B or fluconazole is the preferred therapy. Some experts suggest that if an echinocandin is used in neonates, micafungin is the preferred agent. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible, chronic suppressive therapy with fluconazole is recommended after initial treatment. Treat suppurative thrombophlebitis for at least 2 weeks after candidemia (if present) has cleared.
Infants 3 months and older, Children, and Adolescents: 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Although the FDA-approved maximum dose is 70 mg/day, clinical practice guidelines recommend 150 mg IV once daily for adults with cardiac infections. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible, chronic suppressive therapy with fluconazole is recommended after initial treatment. Treat suppurative thrombophlebitis for at least 2 weeks after candidemia (if present) has cleared.
-for the treatment of Aspergillus cardiovascular system infections in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Neonates* and Infants 1 to 2 months*: No data are available. A dosage of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. Although specific neonatal recommendations are not available, clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. After surgical replacement of an infected valve, consider lifelong antifungal therapy.
Infants 3 months and older, Children, and Adolescents: 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. After surgical replacement of an infected valve, consider lifelong antifungal therapy.

For the treatment of respiratory infections (i.e., pneumonia and pleural space infections):
-for the treatment of Candida pneumonia and pleural space infections:
Intravenous dosage:
Neonates* and Infants 1 to 2 months*: Growth of Candida sp. from the respiratory tract typically reflects colonization and rarely requires antifungal therapy. Restrict treatment to pneumonia associated with disseminated infection. Very limited data are available. A dose of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. For neonatal candidiasis, amphotericin B or fluconazole is the preferred therapy. Some experts suggest that if an echinocandin is used in neonates, micafungin is the preferred agent.
Infants 3 months and older, Children, and Adolescents: Growth of Candida sp. from the respiratory tract typically reflects colonization and rarely requires antifungal therapy. In cases where pneumonia is associated with disseminated infection, 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of Aspergillus pneumonia and pleural space infections in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Neonates* and Infants 1 to 2 months*: No data are available. A dosage of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. Although specific neonatal recommendations are not available, clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. In lung transplant recipients with tracheobronchial aspergillosis (TBA) associated with anastomotic endobronchial ischemia or ischemic reperfusion injury, inhaled amphotericin B deoxycholate is suggested in addition to systemic therapy; treat for at least 3 months or until TBA is resolved, whichever is longer. Surgery alone may be used to treat Aspergillus fungal ball of the paranasal sinus.
Infants 3 months and older, Children, and Adolescents: 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. In lung transplant recipients with tracheobronchial aspergillosis (TBA) associated with anastomotic endobronchial ischemia or ischemic reperfusion injury, inhaled amphotericin B deoxycholate is suggested in addition to systemic therapy; treat for at least 3 months or until TBA is resolved, whichever is longer. Surgery alone may be used to treat Aspergillus fungal ball of the paranasal sinus.

For the treatment of intraabdominal infections (i.e., peritonitis, intraabdominal abscess) including intraabdominal candidiasis and peritoneal dialysis-related peritonitis*:
-for the treatment of intraabdominal candidiasis:
Intravenous dosage:
Neonates* and Infants 1 to 2 months*: Very limited data are available; a dose of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants 3 months and older, Children, and Adolescents: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, then 50 mg/m2/dose (Max: 70 mg/dose) IV once daily. If the 50 mg/m2 daily dose is well tolerated but the clinical response is inadequate, the maintenance dose may be increased to 70 mg/m2/day (Max: 70 mg/dose) IV once daily. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of peritoneal dialysis-related peritonitis*:
Intravenous dosage:
Infants 3 months and older, Children, and Adolescents: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, then 50 mg/m2/dose (Max: 70 mg/dose) IV once daily for at least 14 days after catheter removal for Candida and as salvage therapy for Aspergillus. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of bone and joint infections, including osteomyelitis and infectious arthritis:
-for the treatment of Candida osteomyelitis* or infectious arthritis*:
Intravenous dosage:
Neonates and Infants 1 to 2 months: Very limited data are available. A dose of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. For neonatal candidiasis, amphotericin B or fluconazole is the preferred therapy. Some experts suggest that if an echinocandin is used in neonates, micafungin is the preferred agent. Treat for at least 2 weeks followed by fluconazole for 6 to 12 months for osteomyelitis or 4 weeks for infectious arthritis. Surgical debridement may be helpful in some cases of osteomyelitis and is recommended for all cases of septic arthritis.
Infants 3 months and older, Children, and Adolescents : 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treat for at least 2 weeks followed by fluconazole for 6 to 12 months for osteomyelitis or 4 weeks for infectious arthritis. Recommended as an alternative to fluconazole as initial therapy. Surgical debridement may be helpful in some cases of osteomyelitis and is recommended for all cases of septic arthritis. For infection involving a prosthetic device, device removal in addition to antifungal therapy is recommended.
-for the treatment of Aspergillus osteomyelitis or infectious arthritis in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Neonates* and Infants 1 to 2 months*: No data are available. A dosage of 25 mg/m2/dose IV once daily appears to provide comparable exposure to that seen in adults receiving 50 mg IV daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Successful treatment of invasive candidiasis has been reported in neonates and young infants; however, available data are limited to small case series and studies. Although specific neonatal recommendations are not available, clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 8 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. Longer courses (greater than 6 months) are frequently necessary.
Infants 3 months and older, Children, and Adolescents : 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest caspofungin as salvage therapy. Treat for at least 8 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. Longer courses (greater than 6 months) are frequently necessary.

For candidiasis prophylaxis* or aspergillosis prophylaxis* in high-risk patients:
Intravenous dosage:
Infants 3 months and older, Children, and Adolescents: 50 mg/m2/dose IV (Max: 50 mg/dose) once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a retrospective study of pediatric patients (n = 120; 4 months to less than 18 years) undergoing hematopoietic stem cell transplantation (HSCT), caspofungin was initiated on day 1 after HSCT and continued for a median of 24 days (range, 14 to 49 days). An echinocandin, such as caspofungin, is recommended as an alternative therapy to fluconazole for candidiasis prophylaxis in high risk patients in intensive care units with a high rate (more than 5%) of invasive candidiasis. Clinical practice guidelines suggest caspofungin as an alternative to posaconazole for aspergillosis prophylaxis in high-risk patients (i.e., patients with graft-versus-host disease and neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome). Also recommended in patients with substantial risk of invasive candidiasis, such as allogeneic HSCT recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia, and in patients with previous invasive aspergillosis, anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HSCT.

For empirical therapy for presumed fungal infection in patients with febrile neutropenia:
Intravenous dosage:
Infants 3 months and older, Children, and Adolescents: 70 mg/m2/dose IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If the 50 mg/m2 daily dose is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment for at least 14 days and for at least 7 days after neutropenia and symptoms resolve is recommended for patients found to have a fungal infection. Recommended in patients with persistent or recurrent fever after 4 to 7 days of antibiotics and anticipated neutropenia duration more than 7 days. Aspergillosis clinical practice guidelines suggest caspofungin as a first line empiric therapy.

For the treatment of Pneumocystis pneumonia (PCP)* in patients with hematological malignancies, cancer, or autoimmune/inflammatory diseases or solid organ transplant recipients:
Intravenous dosage:
Infants 1 to 2 months: 25 mg/m2/dose IV once daily in combination with sulfamethoxazole; trimethoprim for 14 to 21 days as salvage therapy.
Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, then 50 mg/m2/dose (Max: 50 mg/dose) IV once daily in combination with sulfamethoxazole; trimethoprim for 14 to 21 days as salvage therapy.

For the treatment of asymptomatic candiduria in neutropenic patients:
Intravenous dosage:
Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, then 50 mg/m2/dose (Max: 70 mg/dose) IV once daily for 14 days. May increase the dose to 70 mg/m2/dose (Max: 70 mg/dose) if there is an inadequate clinical response. Candiduria may be the only microbiological documentation of disseminated candidiasis in neutropenic persons; therefore, candiduria should be treated as disseminated candidiasis in these persons. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 25 mg/m2/day IV are used off-label.
-Infants
< 3 months: Safety and efficacy have not been established; however, doses up to 25 mg/m2/day IV are used off-label.
>= 3 months: 70 mg/m2/day IV.
-Children
70 mg/m2/day IV (Max: 70 mg/day).
-Adolescents
70 mg/m2/day IV (Max: 70 mg/day).

Patients with Hepatic Impairment Dosing
There are no data for dosage adjustment in pediatric patients with any degree of hepatic impairment. In adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9, class B), a 30% dose reduction (i.e., 50 mg/day to 35 mg/day) is recommended for the maintenance dose. For pediatric patients, this would be equivalent to a maintenance dose of 35 mg/m2/day. No adjustment in the loading dose is needed. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score more than 9, class C).

Patients with Renal Impairment Dosing
No dosage adjustment is needed in patients with renal impairment.

Intermittent and Continuous Hemodialysis
Caspofungin is not dialyzable. Supplemental dosing is not required following hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Caspofungin inhibits the synthesis of a major fungal cell wall component, beta (1,3)-D-glucan. Beta (1,3)-D-glucan is not present in mammalian cells and therefore is an attractive target for antifungal activity. Morphologically, fungi hyphae and yeast shapes are altered. Caspofungin is fungicidal against Candida sp., and has activity against Aspergillus sp. with hyphae undergoing active cell growth.

The following organisms are generally considered susceptible to caspofungin in vitro: Aspergillus sp., including Aspergillus flavus, Aspergillus fumigatus, and Aspergillus terreus, and Candida sp., including Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, and Candida tropicalis. Activity against Trichosporon beigelii, Fusarium sp., and Rhizopus arrhizus is limited. It has no activity against Cryptococcus neoformans, but in vitro has shown synergistic activity against C. neoformans when combined with amphotericin B or fluconazole. In murine models, caspofungin has been shown to have less activity against histoplasmosis than amphotericin B. The Clinical and Laboratory Standards Institute (CLSI) defines MICs for C. albicans, C. krusei, and C. tropicalis as susceptible at 0.25 mcg/mL or less, intermediate at 0.5 mcg/mL, and resistant at 1 mcg/mL or more. For C. glabrata, the MICs for susceptible, intermediate, and resistant are 0.12 mcg/mL or less, 0.25 mcg/mL, and 0.5 mcg/mL or more, respectively. C. parapsilosis and C. guilliermondii have the highest MIC break-points, susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more. For Aspergillus sp., a minimum effective concentration (MEC) is used to determine susceptibility to echinocandins. The MEC is defined as the lowest concentration that results in morphologic changes and is used in place of MIC values because treatment with echinocandins does not completely inhibit growth in Aspergillus sp., making accurate MIC breakpoints difficult to determine. As with Candida sp., different species of Aspergillus have varying susceptibilities to echinocandins. For example, A. niger is considerably more susceptible to caspofungin (MEC of 0.1 to 0.5 mcg/mL) than A. fumigatus (MEC of 0.2 to 6 mcg/mL).

Resistance to caspofungin resulting in clinical failures has been observed with Candida and Aspergillus sp. In some cases, specific mutations in the Fks subunits (encoded by the fks1 and/or fks2 genes) of the glucan synthase enzyme were identified. These mutations are associated with higher MICs and breakthrough infection. In addition, some Candida sp. that exhibit reduced susceptibility to caspofungin have been found with increased chitin content of the fungal cell wall; the significance of this phenomenon in vivo is not well known. Because of its unique mechanism of action, cross-resistance with amphotericin B and the azoles is not expected.

Pharmacokinetics: Caspofungin is administered by intravenous infusion. Distribution, the primary mechanism influencing plasma clearance of caspofungin, follows a three-compartment model. A short alpha-phase is followed by a beta-phase (half-life of 9 to 11 hours), which is then followed by the final phase (half-life of 40 to 50 hours). After a single 70 mg dose in adults, approximately 92% of a dose is distributed to tissues by 36 to 48 hours after the dose. Caspofungin is widely distributed to most major organ sites; however, very little data are available on CNS penetration. There is concern regarding the ability of caspofungin to adequately treat CNS infections. In 1 study, poor penetration of caspofungin into the cerebrospinal fluid was noted; however, data was only available from 1 patient. Caspofungin is 97% bound to albumin, and distribution into red blood cells is minimal.

There is little excretion or biotransformation of caspofungin during the first 30 hours post-infusion. Metabolism of caspofungin occurs by hydrolysis and N-acetylation. Hydrolysis results in two tyrosine amino acid by-products that are rapidly cleared by the kidneys. Chemical degradation of caspofungin leads to the formation of the metabolite L-747969 and very low levels of reactive intermediates. Caspofungin does not interact substantially with the cytochrome P450 enzyme system but does undergo significant hepatic metabolism. Single-dose IV administration of caspofungin resulted in excretion of 35% and 41% of the dose in the feces and urine, respectively. Approximately 1.4% of caspofungin is excreted unchanged in the urine. Metabolites are removed primarily via biliary excretion.

Studies in vitro and in vivo of caspofungin in combination with amphotericin B suggest no antagonism of antifungal activity against Aspergillus fumigatus.

Affected cytochrome P450 isoenzymes and drug transporters: none
In vitro, drug interaction studies demonstrate that caspofungin is not an inhibitor of any enzyme in the cytochrome P450 enzyme system. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for CYP450 enzymes. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs.


-Route-Specific Pharmacokinetics
Oral Route
Caspofungin has poor oral bioavailability.

Intravenous Route
After multiple doses of 25 mg/m2/day IV (neonates and infants < 3 months), 50 mg/m2/day IV (pediatric patients > 3 months), or 50 mg/day IV (adults), mean serum concentrations have been reported as follows :
1 hour post-infusion
< 3 months: 11.1 mcg/mL (95% CI, 8.8 to 13.9)
3 to 23 months: 17.6 +/- 3.9 mcg/mL
2 to 11 years: 16.1 +/- 4.2 mcg/mL
12 to 17 years: 14 +/- 6.9 mcg/mL
Adults (empiric): 8 +/- 3.4 mcg/mL

24 hours post-infusion
< 3 months: 2.4 mcg/mL (95% CI, 1.8 to 3.4)
3 to 23 months: 1.7 +/- 0.7 mcg/mL
2 to 11 years: 1.7 +/- 0.8 mcg/mL
12 to 17 years: 2.4 +/- 1 mcg/mL
Adults (empiric): 1.6 +/- 0.7 mcg/mL


-Special Populations
Pediatrics
Neonates and Infants younger than 3 months
Pharmacokinetic data are limited; neonates and young infants clear caspofungin at a slower rate than older children. In a pharmacokinetic study in 18 neonates and infants younger than 3 months of age (majority had a gestational age less than 36 weeks) receiving single or multiple doses of caspofungin 25 mg/m2/day IV, plasma exposure was comparable to that seen in children and adolescents receiving 50 mg/m2/day. On day 4 of therapy, mean plasma concentrations 1 hour and 24 hours after administration were 11.1 mcg/mL (95% CI, 8.8 to 13.9) and 2.4 mcg/mL (95% CI, 1.8 to 3.4), respectively. In this study, a CSF sample was examined from 1 patient on day 1 of therapy. Caspofungin was not detected in the CSF (limit of quantification = 10 ng/mL); plasma concentrations on the same day were peak = 10.3 mcg/mL and trough = 1.8 mcg/mL. The timing of CSF collection relative to caspofungin administration was not reported.

Infants 3 months and older, Children, and Adolescents
Caspofungin clearance increases from infancy to childhood and then decreases from childhood to adolescence. Clearance of caspofungin is higher in children and adolescents compared with adults. Mean elimination half-lives of 8.8, 8.2 and 11.2 hours have been reported for infants/toddlers, children, and adolescents, respectively. This compares with an elimination half-life of approximately 13 hours in adults. Plasma exposure in infants, children, and adolescents receiving 50 mg/m2/day is comparable to that of adults receiving 50 mg/day.

Hepatic Impairment
Pharmacokinetic data are unavailable in pediatric patients with hepatic impairment. The following data have been reported in adults :
Mild hepatic impairment (Child-Pugh score 5 to 6): Plasma concentrations were increased by 19 to 25% compared to healthy controls during a 14-day study.
Moderate hepatic impairment (Child-Pugh score of 7 to 9): Plasma concentrations were increased by 76% compared to control subjects after a single 70 mg dose. A dose adjustment is recommended in patients with moderate hepatic impairment.
Severe hepatic impairment (Child-Pugh score > 9): No pharmacokinetic data are available.

Renal Impairment
Pharmacokinetic data are unavailable in pediatric patients with renal impairment. In adult patients, renal impairment does not result in a clinically significant change in caspofungin exposure. Caspofungin is not dialyzable.