Caspofungin

1092.33

1091.65000

1806241-263-5

J - Antiinfectives for systemic use

400.00000

0.76120

1.36±0.1 g/cm3(Predicted)

1408.1±65.0 °C(Predicted)

805.4ºC

1.623

Slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2)

Store lyophilized cake/powder between 2 and 8 °C (36 and 46 °F). Store reconstituted concentrate and infusion solution at or below 25 °C (77 °F).

0mmHg at 25°C

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Hoang A; Caspofungin Acetate: An Antifungal Agent; Am J Health Syst Pharm 58 (13): 1206-14 (2001)|Keating G, Figgitt D; Caspofungin: A Review of its Use in Oesophageal Candidiasis, Invasive Candidiasis and Invasive Aspergillosis; Drugs 63 (20): 2235-63 (2003)|Groll AH, Walsh TJ; Caspofungin: Pharmacology, Safety and Therapeutic Potential in Superficial and Invasive Fungal Infections;.Expert Opin Investig Drugs 10 (8): 1545-58 (2001)|Wiederhold NP, Lewis RE; The Echinocandin Antifungals: An Overview of the Pharmacology, Spectrum and Clinical Efficacy; Expert Opin Investig Drugs 12 (8): 1313-33 (2003)|Kulemann V et al; Pharmacology 75 (4): 165-78 (2005). Due to their broad antimycotic spectrum and the relatively low rate of side effects, the two antifungals caspofungin and voriconazole are considered as attractive therapeutic alternatives to amphotericin B. However, treatment of severe mycotic infections in patients taking co-medication is associated with the risk of severe adverse drug interactions. The risk of such interactions is increased if voriconazole and, much less pronounced caspofungin, are co-administered with drugs which have an inducing or inhibiting effect on the CYP 450 system, primarily on the isoenzymes CYP2C19, CYP2C9 and CYP3A4. This review provides a comprehensive overview on the potential drug interactions of caspofungin and voriconazole in multimorbid patients.

... In this study the efficacies of caspofungin and meropenem - separately and together - in mice with disseminated candidiasis were studied. Immunocompetent mice were infected intravenously with 2x10(6) CFU of Candida albicans. At 24 hr postinfection, intraperitoneal therapy was initiated and was continued for 7 days. Therapy groups included those given caspofungin (0.5, 1.25, 5 mg/kg/day), meropenem (20 mg/kg/day), and a combination of the two drugs. ... Kidney CFU counts showed that mice that had received both drugs had lower residual burdens. Caspofungin was effective at doses of 0.5, 1.25, 5 mg/kg compared to infected untreated controls. In vitro, MICs of caspofungin and meropenem were <0.075 ug/mL and >64 ug/mL, respectively. Synergism was observed with the combination. Histopathology showed that the degree of inflammation was 25% less and tubular necrosis was more restricted in combined therapy than monotherapy. The results indicate that concurrent caspofungin and meropenem therapy may be beneficial.|Concomitant use /with tacrolimus/ may result in decreased tacrolimus blood concentrations; monitoring of tacrolimus concentrations is recommended, and dosage adjustments may be required.|Potential pharmacokinetic interaction (reduction in caspofungin plasma concentrations.). Coadministration of caspofungin with inducers or mixed inducer/inhibitors of drug clearance such as efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine may result in clinically important reductions in plasma caspofungin concentrations. ...|The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-hr period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 hr after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24hr) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24hr) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.|For more Interactions (Complete) data for CASPOFUNGIN (9 total), please visit the HSDB record page.

Caution should be exercised in dosing adults with severe hepatic impairment (Child-Pugh score exceeding 9) because of a lack of clinical experience in this patient population.|Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with cancidas. In some patients with serious underlying conditions who were receiving multiple concomitant medications along with cancidas, clinical hepatic abnormalities have also occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported in patients; a causal relationship to cancidas has not been established. Patients who develop abnormal liver function tests during cancidas therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing cancidas therapy.

/EXPL/ Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans. Caution should be exercised if caspofungin is used in nursing women.

Caspofungin is indicated for the empirical therapy for presumed fungal infections in febrile, neutropenic patients. /Included in US product labeling/|Caspofungin is indicated for the treatment of candidemia and the following Candidiasis infections: esophageal, intra-abdominal and abscesses, peritonitis, and plural space infections. /Included in US product labeling/|Caspofungin is indicated in the tretment of invasive aspergillosis in patients who are refractory t or intolerant of other therapies, including amphotericin B (lipid and non-lipid formulations) and/or itraconazole. /Included in US product labeling/|/Expl Ther/ ... Azole-resistant isolates of Candida albicans remain susceptible to caspofungin ... /Caspofungin acetate/ is active in experimental animal infection with C. albicans, Aspergillus fumigatus, Pneumocystis carinii, and Histoplasma capsulatum. Clinical trials are in progress with iv formulations of caspofungin ... in patients with deep candidiasis, and with neutropenia and fever not responding to antibacterial therapy. /Caspofungin acetate/|For more Therapeutic Uses (Complete) data for CASPOFUNGIN (8 total), please visit the HSDB record page.

Adverse effects occurring in 2% or more of patients with invasive aspergillosis receiving caspofungin acetate in an open-label, noncomparative clinical study include fever, infused vein complications, nausea, vomiting, or flushing. Fever, phlebitis/thrombophlebitis, infused vein complication, headache, nausea, pain (unspecified), rash, anemia, abdominal pain, diarrhea, vomiting, facial edema, flu-like illness, myalgia, paresthesia, induration, chills, and pruritus reported in clinical studies for uses other than aspergillosis.|The following postmarketing adverse events have been reported: Hepatobiliary: rare cases of clinically significant hepatic dysfunction Cardiovascular: swelling and peripheral edema Metabolic: hypercalcemia|Possible histamine-mediated symptoms have been reported including reports of rash, facial swelling, pruritus, sensation of warmth, or bronchospasm. Anaphylaxis has been reported during administration of CANCIDAS.|Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans. Caution should be exercised if caspofungin is used in nursing women.|For more Drug Warnings (Complete) data for CASPOFUNGIN (6 total), please visit the HSDB record page.

Mutants of Candida with reduced susceptibility to caspofungin have been identified in some patients during treatment. Similar observations were made in a study in mice infected with C. albicans and treated with orally administered doses of caspofungin. MIC values for caspofungin should not be used to predict clinical outcome, since a correlation between MIC values and clinical outcome has not been established. The incidence of drug resistance by various clinical isolates of Candida and Aspergillus species is unknown.

Elimination: Fecal: 35% as drug or metabolites. Renal: 41% as drug (approximately 1.4% unchanged) or metabolites. In dialysis: Not removed by hemodialysis.|Following administration of a single 70 mg irradiated dose, approximately 92% of the administered radioactivity was distributed into tissues within 36 to 48 hours. Distribution into red blood cells in minimal.|Caspofungin crosses the placenta in rats and rabbits and was detected in the plasma of fetuses of pregnant animals who were dosed with caspofungin.|Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans.|For more Absorption, Distribution and Excretion (Complete) data for CASPOFUNGIN (13 total), please visit the HSDB record page.

Slowly metabolized by hydrolysis and N-acetylation; also undergoes spontaneous chemical degradation and further hydrolysis to constitutive amino acids and their degredates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine.|Caspofungin is slowly metabolized in the liver via hydrolysis and N-acetylation; 35 and 41% of the parent drug and metabolites were excreted in feces and urine, respectively, following a single IV radiolabeled dose.|The metabolism, excretion, and pharmacokinetics of caspofungin were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. ... Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 (N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine). Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. ...|Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (> or = 5 days postdose), there is a low level (< or = 7 picomoles/mg protein, or < or = 1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of (3)H caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. /Caspofungin acetate/|... Following a 1 hr IV infusion of 70 mg of (3)HCaspofungin acetate to healthy subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respectively, over 27 days. Plasma and urine samples collected around 24 hr postdose contained predominantly unchanged caspofungin acetate, together with trace amounts of a peptide hydrolysis product, M0, a linear peptide. However, at later sampling times, M0 proved to be the major circulating component, whereas corresponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excretion over the first 16 days postdose represented 13, 71, 1, and 9%, respectively, of the urinary radioactivity. The major metabolite, M2, was highly polar and extremely unstable under acidic conditions when it was converted to a less polar product identified as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine gamma-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding gamma-hydroxy acid, N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine. Metabolite M1, which was extremely polar, eluting from HPLC column just after the void volume, was identified by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/or N-acetylation. /Caspofungin acetate/

Initial: 9 TO 11 hours (beta phase). Additional: 40 to 50 hours (gamma phase).|After administration of a single intravenous dose to mice, rats, rabbits, and monkeys, caspofungin had a ... long terminal elimination half-life (11.7 hr to 59.7 hr) in all preclinical species.

Caspofungin inhibits the synthesis of beta(1,3)-d-glucan, an integral component of the fungal cell wall that is not present in mammalian cells.|Caspofungin acetate ... /belongs to a class of drugs/ referred to as echinocandins, which inhibit the formation of beta(1,3)-D-glucans in the fungal cell wall. Resistance is conferred by mutations in the FKS1 gene, which codes for a large subunit of (1,3)beta-glucan synthase. /Caspofungin acetate/|Caspofungin acetate, the active ingredient of cancidas, inhibits the synthesis of alpha(1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus. /Caspofungin acetate/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/ALTERNATIVE and IN VITRO TESTS/ ... the aim of this study was to assess toxic effects of caspofungin (CAS) on human renal proximal and distal tubular epithelial cells (PTC and DTC) in vitro, and to compare them to those of amphotericin B (AmB). Cells were isolated from human kidney tissue, and exposed to clinically relevant concentrations of CAS and AmB for 24 hr. ... DTC were more vulnerable towards the antifungal agents than PTC. In contrast to AmB, cell-damaging effects of CAS were less severe. DAPI staining revealed slight and dose-dependent antiproliferative effects of CAS at concentrations reflecting relevant plasma levels. At these concentrations, cell viability, determined by MTT assay, was not decreased in PTC and DTC. LDH release was marginally increased in a dose-dependent manner; apoptosis was not detected. Nevertheless, at CAS concentrations reflecting potential tissue concentrations, cell damaging effects were considerably more pronounced. ...|/CASE REPORTS/ ... A 68-year-old man developed reversible severe thrombocytopenia, possibly due to caspofungin, after being successfully treated for Candida albicans endocarditis. Given the limited clinical experience with caspofungin, continued vigilance for unusual and serious adverse events associated with the drug is imperative.

Parenteral: For injection, for IV infusion: 50 mg Cancidas ( with sucrose 39 mg and mannitol 26 mg), (Merck); 70 mg Cancidas (with sucrose 54 mg and mannitol 36 mg), (Merck).|Trade name: CANCIDASE, MK-0991 /Caspofungin acetate/

Caspofungin acetate ... is a water-soluble, semisynthetic lipopeptide derivative of pneumocandin B0. /Caspofungin acetate/

Analyte: caspofungin; matrix: plasma; procedure: high-performance liquid chromatography with fluorescence detection at 220 nm|Analyte: caspofungin; matrix: human plasma, urine; procedure: high-performance liquid chromatography with fluoresence detection