Caspofungin is an intravenous echinocandin antifungal agent that is used for the treatment of invasive aspergillosis that is refractory to or intolerant of other therapies, esophageal candidiasis, candidemia, and for empiric treatment of presumed fungal infections in febrile neutropenia. Common adverse events reported with caspofungin include fever and infusion-related toxicity. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus. Caspofungin has been shown to be active both in vitro and in clinical infections against most strains of Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, and Candida tropicalis. Caspofungin was FDA-approved in January 2001.
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
-Add 10.8 mL of 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the 50-mg vial or 70-mg vial for a resultant concentration of 5 mg/mL or 7 mg/mL, respectively.
-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 or less (77 degrees F or less) for 1 hour prior to dilution.
Dilution
-Add appropriate dose to 250 mL of 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, 0.225% Sodium Chloride Injection, or Lactated Ringer's Injection. For fluid restricted patients, may dilute dose 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 or less (77 degrees F or less), or for up to 48 hours under refrigeration at 2 to 8 degrees C.
Intermittent IV Infusion
-Administer as a slow 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.
Adverse reactions with caspofungin use in invasive aspergillosis have been assessed by reports from one open-label, historical control study (n=69). The majority of these patients had underlying hematologic malignancies. Additional data regarding caspofungin-associated adverse reactions is derived from 34 trials involving 2036 patients (1865 adult and 171 pediatric).
During caspofungin clinical trials, edema and peripheral edema occurred in 3% to 4% and 6% to 11% of patients, respectively.
Elevated hepatic enzymes have been noted in both pediatric and adult patients receiving caspofungin, at similar incidences ranging from 4% to 21%. Overall in studies, elevated alanine aminotransferase (ALT) has been noted in approximately 13% of patients and elevated aspartate aminotransaminase (AST) has occurred in roughly 12% of patients. Alkaline phosphate elevations have been noted in approximately 12% of patients. Total bilirubin increases (hyperbilirubinemia) have been reported in 6% to 13% of patients with elevated conjugated bilirubin noted in 5% to 8% of adults. In some patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, isolated cases (less than 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 to benefit of continuing caspofungin. Hepatic necrosis and elevated gamma-glutamyltransferase concentrations have been reported in post-marketing surveillance. Healthy subjects 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 manufacturer 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 (overall incidence, 8.6%; adults, 4% to 16%; pediatrics, 6% to 23%), facial swelling, angioedema, pruritus (overall incidence, less than 5%; pediatrics, 6% to 7%), bronchospasm, and sensation of warmth. Other general or skin and subcutaneous tissue adverse events during clinical trials include mucosal inflammation (overall incidence, less than 5%; pediatrics, 4% to 10%), erythema (overall incidence, 5%; pediatrics, 4% to 9%), petechiae (less than 5%), skin lesions (less than 5%), and urticaria (less than 5%). An adult trial noted decubitus ulcers (skin ulcer) in 3% to 5% of patients. 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 patients receiving caspofungin during clinical trials, adverse events including fever (overall incidence, 20%; adults, 6% to 27%; pediatrics, 29% to 30%), flushing (overall incidence, less than 5%), headache (overall incidence, 10%; adults, 11% to 15%; pediatrics, 5% to 9%), and chills (overall incidence, 10%; adults, 9% to 23%; pediatrics, 10% to 13%) have occurred. While not specifically stated by the manufacturer, these reactions may be infusion-related. Based on the performed clinical trials, the incidence of infusion-related reactions with caspofungin (20% to 35%) appears to be much less than with amphotericin B (35% to 52%). 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 clinical trials included cough (overall incidence, 6.3%; adults, 11%; pediatrics, 6% to 9%), dyspnea (adults, 9% or less), pleural effusion (adults, 9%), rales (adults, 7%), and respiratory failure or distress (adults, 6% to 11%; pediatrics, 8%). Other, less common, adverse events included tachypnea (1%), epistaxis (less than 5%), and hypoxia (less than 5%). Pulmonary edema, adult respiratory distress syndrome, radiographic infiltrates, and respiratory failure (20%) were observed in caspofungin recipients during one open-label aspergillosis trial; it should be noted that such events may have been related to the patients underlying conditions or aspergillosis.
Clinically relevant hypokalemia has been noted in 6% of adults and 5% to 8% of pediatric patients who received caspofungin; however, some degree of decreased blood potassium has been reported in 11.8% of patients overall (adults, 6% to 23%; pediatrics, 9% to 18%). Blood potassium increases were observed in up to 3% of pediatric patients, but the cases were not noted as hyperkalemia. Other clinically significant metabolic events occurring in less than 5% of caspofungin recipients during clinical trials, regardless of causality, included hyperglycemia, hypomagnesemia, and hypercalcemia.
During clinical trials, caspofungin was associated with the development of hematologic adverse events. Anemia was reported in 11% of adult and 2% of pediatric patients who receive caspofungin. Although not defined as anemia, decreased hemoglobin and hematocrit concentrations were noted in 18% to 21% and 13% to 18% of adult patients, respectively. Neutropenia occurred in less than 5% of patients in clinical trials; however, some reduction in white blood cells was noted in 12% of adult patients in one study. Coagulopathy and thrombocytopenia were also observed in less than 5% of caspofungin-treated patients. Reductions in serum albumin occurred in 7% of adult patients, but were not reported as hypoalbuminemia.
An injection site reaction (specifically infused vein complications) has occurred in less than 5% of patients receiving caspofungin during clinical trials. The overall incidence of phlebitis and/or thrombophlebitis was less than 5%; however, one adult trial reported phlebitis in 18% of patients. Erythema (overall incidence, 5%; pediatrics, 4% to 9%) and induration (3.1%) have also been infrequently reported. Infusion site pain, swelling and pruritus were noted in less than 5% of patients overall.
Diarrhea has been reported in 14% of patients (adults, 6% to 27%; pediatrics, 7% to 17%) receiving caspofungin overall. Other gastrointestinal adverse reactions include abdominal pain (overall incidence, 6%; adults, 9%; pediatrics, 4% to 7%), nausea (overall incidence, 9%; adults, 5% to 15; pediatrics, 4%), vomiting (overall incidence, 8%; adults, 6% to 17%; pediatrics, 8% to 11%), and anorexia (less than 5% overall). Abdominal distention, upper abdominal pain, constipation, and dyspepsia have occurred in less than 5% of patients. Decreased appetite has been noted in less than 5% of patients. Pancreatitis has been reported in postmarketing surveillance. Due to the voluntary nature of postmarket reports, neither frequency nor a definitive causal relationship with caspofungin can be established.
Infectious complications (infection) associated with caspofungin include pneumonia (overall incidence, 6%; adults, 4% to 11%), central line infections (1% to 9% of pediatrics), septic shock (up to 11% to 14% of adults), and sepsis (up to 7% of adults). Bacteremia, febrile neutropenia, and urinary tract infections have been noted in less than 5% of patients overall.
Arrhythmia or arrhythmia exacerbation, atrial fibrillation, bradycardia, cardiac arrest, and myocardial infarction have been reported in less than 5% of patients receiving caspofungin. Sinus tachycardia has also been noted in less than 5% of patients overall, but rates up to 8% were reported in one adult study and 4% to 11% in pediatric trials. Hypertension has occurred in less than 5% of patients in overall clinical trials; however, some trials have reported higher rates (adults, 5% to 6%; pediatrics 9% to 10%). Hypotension has been reported in 3% to 20% of adults and 9% to 12% of pediatric patients in clinical trials.
Renal failure (unspecified) and hematuria have been reported in less than 5% of patients receiving caspofungin. Some degree of increased serum creatinine has occurred in 3% to 11% of adult patients. Also, increased blood urea has been noted in 4% to 9% of adult patients. One adult trial reported positive urine red blood cells in 10% of patients. Fluid retention or overload has occurred in less than 5% of patients. Postmarketing reports have noted clinically significant renal dysfunction.
During clinical trials, back pain (4%), arthralgia, extremity pain, asthenia, and fatigue were reported in less than 5% of patients who receive caspofungin.
Neurologic and psychiatric adverse events reported by less than 5% of caspofungin recipients during clinical trials included convulsions (seizures), dizziness, somnolence or drowsiness, tremor, anxiety, confusional state (confusion), depression, and insomnia.
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.
For adult patients with moderate hepatic disease (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) and in pediatric patients with any degree of hepatic impairment.
Data regarding use of caspofungin during human pregnancy are insufficient to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on animal studies, caspofungin may cause fetal harm. Caspofungin crosses the placenta in animal models and is detected in the plasma of animal fetuses. In pregnant rats and rabbits, caspofungin exposure at doses equivalent to 0.8- to 2-times the human clinical dose (based on body surface area comparison) during organogenesis was associated with embryotoxic effects such as increased fetal resorptions, increased peri-implantation loss, and incomplete ossification of the talus/calcaneus, skull, or torso.
There are no data on the presence of caspofungin in human milk, the effects on the breast-fed child, or the effects on milk production. Caspofungin was detected in the milk of lactating, drug-treated rats. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for caspofungin and any potential adverse effects on the breast-fed child from caspofungin or the underlying maternal condition.
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:
Adults: 70 mg IV loading dose on day 1, then 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.
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.
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.
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.
-for the treatment of chronic disseminated (hepatosplenic) candidiasis*:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily for several weeks, followed by oral fluconazole for patients who are unlikely to have a fluconazole-resistant isolate. 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/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:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. 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.
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.
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.
For the treatment of fluconazole-refractory oropharyngeal candidiasis (thrush)*:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg 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.
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.
For the treatment of esophageal candidiasis, including fluconazole-refractory disease:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily for 14 to 21 days as an alternative. The FDA-approved dosage is 50 mg IV once daily for 7 to 14 days. 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.
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.
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:
Adults: 150 mg IV once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 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.
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.
-for the treatment of Aspergillus cardiovascular system infections in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. 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.
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.
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.
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:
Adults: 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 IV loading dose on day 1, then 50 mg IV once daily. 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: 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.
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.
-for the treatment of Aspergillus pneumonia and pleural space infections in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. 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.
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.
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.
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:
Adults: 70 mg IV loading dose on day 1, then 50 mg 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.
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. 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.
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.
-for the treatment of peritoneal dialysis-related peritonitis*:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg 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.
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:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. 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.
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.
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.
-for the treatment of Aspergillus osteomyelitis or infectious arthritis in patients who are refractory to or intolerant of other antifungal therapies:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. 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.
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.
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.
For candidiasis prophylaxis* and aspergillosis prophylaxis* in high-risk patients:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 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 hematopoietic stem cell transplant (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.
Infants 3 months and older, Children, 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:
Adults: 70 mg IV loading dose on day 1, followed by 50 mg IV once daily. If 50 mg/day is well tolerated but there is an inadequate clinical response, may increase maintenance dose to 70 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Duration of treatment is based on clinical response. Empirical therapy should be continued until neutropenia resolution. 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.
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. Duration of treatment is based on clinical response. Empirical therapy should be continued until neutropenia resolution. 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 disease or solid organ transplant recipients:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg 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.
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.
For the treatment of asymptomatic candiduria in neutropenic persons:
Intravenous dosage:
Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily for 14 days. 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.
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:
-Adults
70 mg/day IV; doses up to 150 mg/day IV have been recommended for cardiovascular infections.
-Geriatric
70 mg/day IV; doses up to 150 mg/day IV have been recommended for cardiovascular infections.
-Adolescents
70 mg/m2/day IV, not to exceed 70 mg IV.
-Children
70 mg/m2/day IV, not to exceed 70 mg IV.
-Infants
>= 3 months: 70 mg/m2/day IV, not to exceed 70 mg IV.
< 3 months: Safety and efficacy have not been established; however, doses up to 25 mg/m2/day IV are used off-label.
-Neonates
Safety and efficacy have not been established; however, doses up to 25 mg/m2/day IV are used off-label.
Patients with Hepatic Impairment Dosing
Dosage adjustment information is only available for adults. No adjustment needed in mild impairment. A reduced maintenance dose of 35 mg/day IV (30% dose reduction) is recommended for patients with moderate hepatic impairment (Child-Pugh score 7 to 9, class B). 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 those 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
Carbamazepine: (Major) Data suggest that coadministration of inducers or mixed inducers/inhibitors of hepatic drug clearance along with caspofungin may result in reduced caspofungin blood concentrations. The reductions may be clinically significant. According to the manufacturer, drugs that may lead to reductions in caspofungin concentrations include carbamazepine. For adult patients receiving carbamazepine, an increase in the caspofungin dose to 70 mg/day should be considered. For pediatric patients receiving carbamazepine, a daily dosage of 70 mg/m2, not to exceed 70 mg, should be considered.
Cyclosporine: (Major) In two clinical studies, cyclosporine increased the systemic exposure (AUC) of caspofungin by approximately 35%. Cyclosporine concentrations are not altered by coadministration with caspofungin. Seven of 20 healthy subjects who received caspofungin (35 mg or 70 mg) in combination with cyclosporine (3 mg/kg or 4 mg/kg) developed transient elevations in alanine transaminase (ALT) up to 3 times the upper limit of normal. Elevations in aspartate transaminase (AST) paralleled ALT elevations but were of lesser magnitude. As determined retrospectively, 14 of 40 patients who received caspofungin and cyclosporine (1 to 290 days, median 17.5 days) had an ALT concentration elevation greater than 5 times the upper limit of normal or greater than 3 times the baseline value during concurrent therapy or the following 14 days. Five of the 14 cases and one case of elevated bilirubin were considered possibly related to concomitant therapy; no clinical evidence of hepatotoxicity or serious hepatic events occurred. The manufacturer recommends against the concomitant use of caspofungin with cyclosporine unless the potential benefit outweighs the risk. Monitor patients who develop abnormal liver enzyme concentrations; a risk versus benefit decision for therapy continuation is recommended.
Dexamethasone: (Major) Consider a caspofungin dosage increase if concomitant use with dexamethasone is necessary. Increase the caspofungin dose to 70 mg/day in adults and 70 mg/m2/day (up to 70 mg/day) in pediatric patients. Concomitant use may decrease caspofungin exposure which may reduce its efficacy. Caspofungin is a CYP3A substrate and dexamethasone is a CYP3A inducer.
Dichlorphenamide: (Moderate) Use dichlorphenamide and caspofungin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
Efavirenz: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving efavirenz. Administering inducers of hepatic cytochrome P450, such as efavirenz, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving efavirenz. Administering inducers of hepatic cytochrome P450, such as efavirenz, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving efavirenz. Administering inducers of hepatic cytochrome P450, such as efavirenz, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Encorafenib: (Major) Consider a caspofungin dosage increase if concomitant use with encorafenib is necessary. Increase the caspofungin dose to 70 mg/day in adults and 70 mg/m2/day (up to 70 mg/day) in pediatric patients. Concomitant use may decrease caspofungin exposure which may reduce its efficacy. Caspofungin is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced caspofungin trough concentrations by 30%.
Ethotoin: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving ethotoin. Administering inducers of hepatic cytochrome P450, such as ethotoin, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Fosphenytoin: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving fosphenytoin. Administering inducers of hepatic cytochrome P450, such as fosphenytoin, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Dose caspofungin as 70 mg IV once daily for adult patients and 70 mg/m2 (Max: 70 mg/day) IV once daily for pediatric patients when coadministered with rifampin. Coadministration of caspofungin with CYP450 enzyme inducers, such as rifampin, may reduce the plasma concentrations of caspofungin. Rifampin has been shown to decrease caspofungin trough concentrations by 30%.
Isoniazid, INH; Rifampin: (Major) Dose caspofungin as 70 mg IV once daily for adult patients and 70 mg/m2 (Max: 70 mg/day) IV once daily for pediatric patients when coadministered with rifampin. Coadministration of caspofungin with CYP450 enzyme inducers, such as rifampin, may reduce the plasma concentrations of caspofungin. Rifampin has been shown to decrease caspofungin trough concentrations by 30%.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving rifabutin. Coadministration of CYP450 enzyme inducers, such as rifabutin, with caspofungin may reduce the plasma concentrations of caspofungin.
Phenytoin: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving phenytoin. Administering inducers of hepatic cytochrome P450, such as phenytoin, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Rifabutin: (Moderate) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving rifabutin. Coadministration of CYP450 enzyme inducers, such as rifabutin, with caspofungin may reduce the plasma concentrations of caspofungin.
Rifampin: (Major) Dose caspofungin as 70 mg IV once daily for adult patients and 70 mg/m2 (Max: 70 mg/day) IV once daily for pediatric patients when coadministered with rifampin. Coadministration of caspofungin with CYP450 enzyme inducers, such as rifampin, may reduce the plasma concentrations of caspofungin. Rifampin has been shown to decrease caspofungin trough concentrations by 30%.
Rifapentine: (Moderate) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving rifapentine. Coadministration of CYP450 enzyme inducers, such as rifapentine, with caspofungin may reduce the plasma concentrations of caspofungin.
Tacrolimus: (Moderate) Tacrolimus concentrations are reduced approximately 25% in those patients receiving concurrent caspofungin. The mechanism of this interaction has not been identified; monitor tacrolimus blood concentrations. Increased dosage of tacrolimus may be required. The pharmacokinetic parameters of caspofungin are not altered by tacrolimus.
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.
Caspofungin is administered by slow intravenous infusion. Distribution, the primary mechanism influencing plasma clearance, follows a three-compartment model. A short alpha-phase is followed by a beta-phase (half-life of 9 to 11 hours); once-daily dosing is adequate. The final phase (half-life of 40 to 50 hours) results in significant tissue distribution. Animal studies reveal distribution primarily into the liver and kidneys. Caspofungin is 97% bound to serum proteins. Approximately 92% of a 70 mg radiolabeled dose is distributed to tissues within 36 to 48 hours after the dose. There is little excretion or biotransformation during the first 30 hours post-infusion. The clinical significance of the extensive tissue accumulation is unknown but may contribute to the activity of the drug against localized tissue infections. Metabolism occurs by hydrolysis and N-acetylation. Hydrolysis results in two tyrosine amino acid by-products that are rapidly cleared by the kidneys. Chemical degradation leads to the formation of the metabolite L-747969 and very low levels of reactive intermediates. The pathway of chemical degradation is uncertain. Caspofungin does not interact substantially with the cytochrome P450 enzyme system but does undergo significant hepatic metabolism. Single-dose IV administration 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.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Oral Route
Caspofungin has limited oral bioavailability.
Intravenous Route
Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour intravenous (IV) infusions. A short alpha-phase occurs immediately post-infusion, followed by a beta-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose, during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, gamma-phase, (half-life of 40 to 50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance.
-Special Populations
Hepatic Impairment
Plasma concentrations (AUC) of caspofungin after a single 70 mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were approximately 55% higher compared to healthy controls; however, a 14-day, multi-dose study in adults showed lower increases in AUC (19 to 25%) compared to healthy controls. No dosage adjustment is necessary in patients with mild hepatic impairment. Single-dose studies showed increased caspofungin AUCs (76%) in adults with moderate hepatic impairment (Child-Pugh score 7 to 9) compared to healthy controls; therefore, the manufacturer recommends a reduced daily maintenance dosage of 35 mg (after the 70 mg loading dose). There is no experience in severe hepatic impairment (Child-Pugh score 9 or greater, class C) or in pediatric patients with any degree of hepatic impairment.
Renal Impairment
In adults, one single-dose clinical study noted that there was no effect of mild to severe renal impairment on caspofungin trough concentrations, and no dosage adjustments are recommended. Pharmacokinetic data are unavailable in pediatric patients with renal impairment. The drug is not removed by hemodialysis.
Pediatrics
Infants 3 months or 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.
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 younger 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.
Geriatric
While plasma concentrations of caspofungin were 28% higher in the elderly versus younger adults, no specific dosage alterations are required based on age alone.
Gender Differences
Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70-mg IV dose. After 13 daily 50-mg IV doses, caspofungin plasma concentrations in women were elevated slightly (roughly 22% increase in AUC) relative to men. No dosage adjustment is necessary based on gender.
Ethnic Differences
Analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics. No dosage adjustment is necessary on the basis of ethnicity.