Caspofungin asino

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Caspofungin Acino (Caspofungin Acino)

Composition:

Active substance: caspofungin;

One vial contains 50 mg of caspofungin in the form of caspofungin acetate (60.6 mg);

Excipients: sucrose, mannitol (E 421), glacial acetic acid, sodium hydroxide.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: porous mass or powder, white to almost white in color.

Pharmacotherapeutic group

Antifungal agents for systemic use. Other antifungal agents for systemic use. Caspofungin.

ATC code J02A X04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Caspofungin acetate is a semisynthetic lipopeptide compound (echinocandin) derived from the fermentation product of Glarea lozoyensis. Caspofungin acetate inhibits the synthesis of β-(1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeasts. β-(1,3)-D-glucan is not present in mammalian cells.

Fungicidal activity of caspofungin has been demonstrated against Candida yeasts. In vitro and in vivo studies show that exposure of Aspergillus to caspofungin results in lysis and death of the tips and branching points of hyphae, where cell growth and division occur.

Pharmacodynamic Effects

Caspofungin demonstrates in vitro activity against Aspergillus strains (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, and Aspergillus candidus). Caspofungin is also active in vitro against Candida strains (Candida albicans, Candida dubliniensis, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lipolytica, Candida lusitaniae, Candida parapsilosis, Candida rugosa, and Candida tropicalis), including isolates with multiple transporter mutations and isolates with acquired intrinsic resistance to fluconazole, amphotericin B, and 5-fluorocytosine.

Standardized susceptibility testing methods using EUCAST have been developed for yeasts. EUCAST has not yet established breakpoints for caspofungin due to significant interlaboratory variability in MIC ranges for caspofungin. Instead of interpretive breakpoints, Candida isolates susceptible to anidulafungin and micafungin should be considered susceptible to caspofungin. Similarly, C. parapsilosis isolates intermediate to anidulafungin and micafungin can be considered intermediate to caspofungin.

Mechanism of Resistance

Candida isolates with reduced susceptibility to caspofungin have been identified in a small number of patients during treatment (MIC for caspofungin > 2 mg/L [4- to 30-fold increase in MIC] were observed using standardized MIC testing methods approved by CLSI). The identified mechanism of resistance involves mutations in the FKS1 and/or FKS2 genes (for C. glabrata). These cases were associated with poor clinical outcomes.

Development of in vitro resistance to caspofungin has been observed in Aspergillus species. Limited clinical experience has shown resistance to caspofungin in patients with invasive aspergillosis. The mechanism of resistance has not been established. Cases of resistance to caspofungin among various clinical isolates of Aspergillus are rare. Resistance of Candida to caspofungin has been observed, but the frequency may vary depending on the species or region.

Clinical Efficacy and Safety

Invasive Candidiasis in Adult Patients

A total of 239 patients were enrolled in the initial study comparing caspofungin and amphotericin B for the treatment of invasive candidiasis.

Twenty-four patients had neutropenia. The most common diagnoses were bloodstream infections (candidemia) (77%, n=186) and candidal peritonitis (8%, n=19); patients with candidal endocarditis, osteomyelitis, or meningitis were excluded from this study. Caspofungin was administered at a dose of 50 mg daily (following a loading dose of 70 mg on the first day), whereas amphotericin B was administered at a dose of 0.6–0.7 mg/kg/day to patients without neutropenia or 0.7–1.0 mg/kg/day to patients with neutropenia. The mean duration of intravenous therapy was 11.9 days, ranging from 1 to 28 days. A favorable response required both resolution of symptoms and microbiological clearance of Candida infection. A total of 224 patients were included in the primary efficacy analysis (MITT analysis) at the end of intravenous study therapy; favorable response rates for invasive candidiasis were comparable between caspofungin (73% [80/109]) and amphotericin B (62% [71/115]) [% difference 12.7 (95.6% confidence interval –0.7, 26.0)]. Among patients with candidemia, favorable response rates at the end of intravenous study therapy were comparable between caspofungin (72% [66/92]) and amphotericin B (63% [59/94]) in the primary efficacy analysis (MITT analysis) [% difference 10.0 (95.0% confidence interval –4.5, 24.5)]. Limited data are available regarding treatment of patients with non-bloodstream infection sites. The favorable response rate in neutropenic patients was 7/14 (50%) in the caspofungin group and 4/10 (40%) in the amphotericin B group. These limited data are supported by results from the empirical therapy study.

In a second study, patients with invasive candidiasis received daily doses of caspofungin at 50 mg/day (following a loading dose of 70 mg on the first day) or caspofungin at 150 mg/day (see section "Adverse Reactions"). In this study, the caspofungin dose was infused over 2 hours (instead of the usual 1-hour infusion). The study excluded patients suspected of having endocarditis, meningitis, or osteomyelitis caused by Candida. As this was a primary therapy study, patients who were refractory to prior antifungal agents were also excluded. The number of neutropenic patients enrolled in this study was also limited (8.0%). Efficacy was a secondary endpoint in this study. Patients who met inclusion criteria and received one or more doses of study therapy with caspofungin were included in the efficacy analysis. The favorable overall response at the end of caspofungin therapy was similar in the two treatment groups: 72% (73/102) and 78% (74/95) for the 50 mg and 150 mg caspofungin treatment groups, respectively (difference 6.3% [95% confidence interval –5.9, 18.4]).

Invasive Aspergillosis in Adult Patients

Sixty-nine adult patients (aged 18–80 years) with invasive aspergillosis were enrolled in an open-label, uncontrolled study to evaluate the safety, tolerability, and efficacy of caspofungin. Patients were required to have either refractoriness (disease progression or lack of improvement with other antifungal agents for at least 7 days) (84% of enrolled patients) or intolerance (16% of enrolled patients) to other standard antifungal treatments. Most patients had underlying conditions (hematologic malignancies [n = 24], allogeneic bone marrow or stem cell transplantation [n = 18], organ transplantation [n = 8], solid tumor [n = 3], or other conditions [n = 10]). Strict definitions modeled after the Mycoses Study Group criteria were used for diagnosis of invasive aspergillosis and response to therapy (favorable response required clinically significant improvement in radiographic findings as well as signs and symptoms). The mean duration of therapy was 33.7 days, ranging from 1 to 162 days. An independent expert panel determined that 41% (26/63) of patients who received at least one dose of caspofungin had a favorable response. Among those patients who received more than 7 days of caspofungin therapy, 50% (26/52) had a favorable response. The favorable response rate among patients who were either refractory to or intolerant of prior therapies was 36% (19/53) and 70% (7/10), respectively. Despite the fact that prior antifungal therapy doses in 5 patients classified as refractory were lower than doses commonly used for invasive aspergillosis, the favorable response rate during caspofungin therapy in these patients was similar to that observed in other refractory patients (2/5 vs. 17/48, respectively). The response rate among patients with pulmonary disease and extrapulmonary disease was 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 out of 8 patients who also had definite, probable, or possible CNS involvement had a favorable response.

Empirical Therapy for Suspected Fungal Infections (Candida or Aspergillus) in Adults and Children with Febrile Neutropenia

A total of 1111 patients with persistent fever and neutropenia were enrolled in a clinical study and received either caspofungin at a dose of 50 mg/day (following a loading dose of 70 mg on the first day) or liposomal amphotericin B at a dose of 3.0 mg/kg/day. Eligible patients had undergone chemotherapy for malignancies or had undergone hematopoietic stem cell transplantation and had neutropenia (< 500 cells/mm³ for 96 hours) and fever (> 38.0°C) unresponsive to ≥ 96 hours of parenteral antibacterial therapy.

Patients were to be treated until 72 hours after resolution of neutropenia, with a maximum duration of 28 days. However, patients in whom a confirmed fungal infection was identified could be treated longer. If the study drug was well tolerated but fever persisted and the clinical condition worsened after 5 days of therapy, the dose of the study drug could be increased to 70 mg/day caspofungin (13.3% of patients receiving treatment) or to 5.0 mg/kg/day liposomal amphotericin B (14.3% of patients receiving treatment). A total of 1095 patients were included in the primary modified intent-to-treat (MITT) analysis for overall favorable response; caspofungin (33.9%) was as effective as liposomal amphotericin B (33.7%) [% difference 0.2 (95.2% confidence interval –5.6, 6.0)]. Overall favorable response required meeting each of five criteria: (1) successful treatment of any baseline fungal infection (caspofungin 51.9% [14/27], liposomal amphotericin B 25.9% [7/27]), (2) absence of progression of fungal infections during study drug administration or within 7 days after completion of therapy (caspofungin 94.8% [527/556], liposomal amphotericin B 95.5% [515/539]), (3) duration of absence of fungal infection for 7 days after completion of study therapy (caspofungin 92.6% [515/556], liposomal amphotericin B 89.2% [481/539]), (4) absence of discontinuation of study drug due to drug-related toxicity or lack of efficacy (caspofungin 89.7% [499/556], liposomal amphotericin B 85.5% [461/539]), and (5) reduction in body temperature during neutropenia (caspofungin 41.2% [229/556], liposomal amphotericin B 41.4% [223/539]).

The response rate to caspofungin and liposomal amphotericin B for baseline infections caused by Aspergillus species was 41.7% (5/12) and 8.3% (1/12), respectively, and for Candida species was 66.7% (8/12) and 41.7% (5/12), respectively. Patients in the caspofungin group experienced breakthrough infections caused by unusual yeast and mold species: Trichosporon spp. (1), Fusarium spp. (1), Mucor spp. (1), and Rhizopus spp. (1).

Pediatric Patient Cohort

The safety and efficacy of caspofungin were evaluated in pediatric patients aged 3 months to 17 years in two prospective, multicenter clinical studies. Study design, diagnostic criteria, and efficacy assessment criteria were similar to those in corresponding adult studies (see section "Pharmacodynamics").

In the first randomized, double-blind study involving 82 patients aged 2 to 17 years, caspofungin (50 mg/m² intravenously once daily after a loading dose of 70 mg/m² on the first day [not exceeding 70 mg/day]) was compared to liposomal amphotericin B (3 mg/kg intravenously daily) in a 2:1 treatment regimen (56 - caspofungin, 26 - liposomal amphotericin B) as empirical therapy in pediatric patients with persistent fever and neutropenia. The overall success rates in the MITT analysis, adjusted for risk categories, were 46.6% (26/56) for caspofungin and 32.2% (8/25) for liposomal amphotericin B.

In the second prospective, open-label, non-comparative study, the safety and efficacy of caspofungin were evaluated in 49 pediatric patients (aged 6 months to 17 years) with invasive candidiasis, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). Patients received caspofungin at a dose of 50 mg/m² intravenously once daily after a loading dose of 70 mg/m² on the first day (not exceeding 70 mg/day). Of these patients, 48 were included in the MITT analysis, of which 37 had invasive candidiasis, 10 had invasive aspergillosis, and 1 had esophageal candidiasis. In the MITT analysis, the favorable response rates at the end of caspofungin therapy were 81% (30/37) for invasive candidiasis, 50% (5/10) for invasive aspergillosis, and 100% (1/1) for esophageal candidiasis.

In a double-blind, randomized (2:1), comparative study, the safety, tolerability, and efficacy of caspofungin (2 mg/kg/day intravenously, infused over 2 hours) were compared to amphotericin B deoxycholate (1 mg/kg/day) in neonates and infants up to 3 months of age with (culture-confirmed) invasive candidiasis. Due to low patient enrollment, the study was terminated prematurely, and only 51 patients were randomized. The proportion of patients free of fungal infection 2 weeks after therapy in the caspofungin group (71.0%) was similar to that observed in the amphotericin B deoxycholate group (68.8%). Based on this study, no dosage recommendations can be made for neonates and infants.

Pharmacokinetics

Distribution

Caspofungin is highly protein-bound in blood. The unbound fraction of caspofungin in plasma ranges from 3.5% in healthy volunteers to 7.6% in patients with invasive candidiasis. Distribution plays a major role in the pharmacokinetics of caspofungin in plasma and is the rate-controlling phase for the alpha- and beta-disposition phases. Maximum tissue distribution occurs 1.5–2 days after drug administration, when 92% of the administered dose is distributed into tissues. It is likely that only a small fraction of caspofungin that penetrates into tissues later re-enters plasma as the parent compound. Therefore, elimination occurs without distribution equilibrium, and accurate determination of the volume of distribution of caspofungin at this time is not possible.

Biotransformation

Caspofungin undergoes spontaneous degradation to an open-ring compound. Further metabolism occurs via protein hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound. Two intermediate products formed during the degradation of caspofungin to the open-ring compound form covalent adducts with plasma proteins, resulting in low levels and irreversible protein binding.

In vitro studies show that caspofungin is not an inhibitor of cytochrome P450 enzymes 1A2, 2A6, 2C9, 2C19, 2D6, or 3A4. In clinical studies, caspofungin did not induce or inhibit CYP3A4 metabolism of other drugs. Caspofungin is not a substrate of P-glycoprotein and is a weak substrate of cytochrome P450 enzymes.

Elimination

Caspofungin is slowly eliminated from plasma; clearance is 10–12 mL/min. After a single intravenous infusion (over 1 hour), plasma concentrations of caspofungin decline in a polyphasic manner. A short alpha-phase occurs immediately after infusion, followed by a beta-phase with a half-life of 9 to 11 hours. An additional gamma-phase with a half-life of 45 hours is also observed. Distribution, compared to elimination or biotransformation, is the primary mechanism influencing plasma clearance.

In a pharmacokinetic study using a single radiolabeled dose, plasma, urine, and feces were collected over 27 days. Approximately 75% of the administered radioactive dose was recovered within 27 days: 41% in urine and 34% in feces. Minimal elimination or biotransformation of caspofungin was observed within the first 30 hours after drug administration.

Elimination is slow, with a terminal half-life of the radioactive dose ranging from 12 to 15 days. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4% of the dose).

Caspofungin exhibits moderate non-linear pharmacokinetics with increasing accumulation at higher doses and dose-dependency in achieving steady-state with repeated dosing.

Special Patient Populations

Increased caspofungin exposure has been observed in adult patients with mild hepatic impairment and renal impairment, in women, and in elderly patients. Generally, the increase was moderate and not significant enough to require dose adjustment.

Dose adjustment may be necessary for adult patients with moderate hepatic impairment or for patients with higher body weight (see below).

Body Weight. Pharmacokinetic analysis in adult patients with candidiasis showed that caspofungin pharmacokinetics are dependent on body weight. Drug concentrations in plasma decrease with increasing body weight. It is estimated that the average exposure in adult patients weighing 80 kg is 23% lower than in patients weighing 60 kg (see section "Dosage and Administration").

Hepatic Impairment. In adult patients with mild and moderate hepatic impairment, the area under the concentration-time curve (AUC) increases by approximately 20% and 75%, respectively. There is no clinical experience with the use of the drug in adult patients with severe hepatic impairment or in children with any hepatic impairment. In a multiple-dose study, it was shown that reducing the daily dose to 35 mg in adult patients with moderate hepatic impairment results in an AUC similar to that in adults with normal hepatic function receiving the standard dosing regimen (see section "Dosage and Administration").

Renal Impairment. In a clinical study using a single 70 mg dose, the pharmacokinetics of caspofungin were similar in adult volunteers with mild renal impairment (creatinine clearance 50–80 mL/min) and in control group participants. With moderate (creatinine clearance 31–49 mL/min), severe (creatinine clearance 5–30 mL/min), and end-stage renal impairment (creatinine clearance < 10 mL/min with dialysis), plasma concentrations of caspofungin moderately increased after a single dose (AUC increased by 30–49%). However, in patients with invasive candidiasis, esophageal candidiasis, or invasive aspergillosis receiving multiple doses of caspofungin at 50 mg/day, no significant effect on caspofungin concentrations was observed with mild and severe renal impairment. Dose adjustment is not necessary in patients with renal impairment. Caspofungin is not removed by dialysis, so there is no need for supplemental dosing after hemodialysis.

Gender. Plasma concentrations of caspofungin in women were on average 17–38% higher than in men.

Elderly. A moderate increase in AUC (by 28%) and C24h (by 32%) was observed in elderly men compared to younger men. A similar moderately pronounced age-dependent effect was observed in patients receiving empirical therapy and those with invasive candidiasis.

Race. Pharmacokinetic data in patients indicate no clinically significant differences in pharmacokinetic parameters among Caucasian, African American, Hispanic, and mixed-race populations.

Children. In children aged 12–17 years receiving caspofungin at 50 mg/m²/day (maximum dose 70 mg/day), plasma AUC0-24 values were generally comparable to those observed in adults receiving caspofungin at 50 mg/day. All children aged 12–17 years received drug doses exceeding 50 mg/day, and 6 out of 8 patients received the maximum dose of 70 mg/day. Plasma caspofungin concentrations in children aged 12–17 years were lower compared to adults receiving the drug at 70 mg/day (the dose most commonly prescribed to children aged 12–17 years).

In children (2–11 years) receiving caspofungin at 50 mg/m²/day (maximum dose 70 mg/day), plasma AUC0-24 values after multiple dosing were comparable to those observed in adults receiving caspofungin at 50 mg/day.

In younger children (12–23 months) receiving caspofungin at 50 mg/m²/day (maximum dose 70 mg/day), plasma AUC0-24 values after multiple dosing were comparable to those observed in adults receiving caspofungin at 50 mg/day and in older children (2–11 years) receiving caspofungin at 50 mg/m²/day.

Overall, available data on pharmacokinetics, efficacy, and safety of caspofungin in patients aged 3 to 10 months are limited. Pharmacokinetic data from one 10-month-old child receiving a daily dose of 50 mg/m² indicate that AUC0-24 is within the same range as in older children and adults receiving doses of 50 mg/m² and 50 mg, respectively, whereas in one 6-month-old child receiving a dose of 50 mg/m², AUC0-24 was slightly higher.

In neonates and infants (< 3 months of age) receiving caspofungin at 25 mg/m²/day (mean daily dose 2.1 mg/kg), maximum (C1h) and minimum (C24h) plasma concentrations of caspofungin after multiple dosing were comparable to concentrations observed in adults receiving caspofungin at 50 mg/day. In these children, C1h on the first day of caspofungin administration was similar to that in adults, while C24h was moderately higher (by 36%). However, variability was observed in both C1h (geometric mean on day 4: 11.73 µg/mL, range: 2.63–22.05 µg/mL) and C24h (geometric mean on day 4: 3.55 µg/mL, range: 0.13–7.17 µg/mL). AUC0-24 was not determined in this study due to infrequent sampling. It should be noted that the efficacy and safety of caspofungin have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.

Clinical Characteristics

Indications

• Treatment of invasive candidiasis in adults and children.
• Treatment of invasive aspergillosis in adults and children who are refractory or intolerant to amphotericin B, lipid formulations of amphotericin B, and/or itraconazole. Refractoriness is defined as progression of infection or inadequate clinical improvement after at least 7 days of effective antifungal therapy at therapeutic doses.
• Empirical therapy for suspected fungal infections (Candida or Aspergillus) in adults and children with febrile neutropenia.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").

Interaction with other medicinal products and other forms of interaction

In vitro studies indicate that caspofungin is not an inhibitor of any of the cytochrome P450 (CYP) enzyme system. In clinical studies, caspofungin did not induce CYP3A4 metabolism of other substances. Caspofungin is not a substrate for P-glycoprotein enzymes and is a poor substrate for cytochrome P450 enzymes. However, pharmacological and clinical studies have demonstrated interactions between caspofungin and other medicinal products (see below).

In two clinical studies involving healthy volunteers, cyclosporine A (single dose of 4 mg/kg or two doses of 3 mg/kg given 12 hours apart) increased the area under the concentration-time curve (AUC) of caspofungin by approximately 35%, possibly due to reduced hepatic uptake of caspofungin. Caspofungin did not increase cyclosporine plasma levels. Transient elevations in hepatic transaminase activity (ALT and AST) (up to 3 times or less than the upper limit of normal) were observed with concomitant administration of caspofungin and cyclosporine, which resolved after discontinuation of the drugs.

In a retrospective post-marketing study of 40 patients receiving caspofungin and cyclosporine for 1–290 days (mean duration 17.5 days), no serious hepatic adverse reactions were observed (see section "Special warnings and precautions for use"). Liver enzyme activity should be monitored when caspofungin and cyclosporine are used concomitantly.

Caspofungin decreased the trough concentration of tacrolimus by 26% in healthy volunteers. Patients receiving both of these medicinal products must undergo standard monitoring of blood concentrations and appropriate dose adjustments of tacrolimus.

In clinical studies involving healthy volunteers, the pharmacokinetics of caspofungin were not significantly altered by co-administration with itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin did not affect the pharmacokinetics of amphotericin B, itraconazole, rifampicin, or mycophenolate mofetil. Although safety data are limited, there are no specific warnings regarding the concomitant use of caspofungin with amphotericin B, itraconazole, nelfinavir, or mycophenolate mofetil.

Rifampicin caused a 60% increase in AUC and a 170% increase in the trough concentration of caspofungin on the first day of co-administration when both drugs were given to healthy adult volunteers. Trough levels of caspofungin gradually decreased with repeated dosing. After 2 weeks of rifampicin administration, the effect on AUC was limited, but trough concentrations were 30% lower than in adult patients receiving caspofungin alone. The mechanism of interaction is possibly related to initial inhibition followed by induction of protein transport. A similar effect may occur with other drugs that induce enzyme metabolism.

Limited pharmacokinetic data suggest that concomitant administration of caspofungin with inducers such as efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine may lead to a reduction in caspofungin AUC. When enzyme-inducing agents are co-administered, consideration should be given to increasing the daily dose of Caspofungin Acino to 70 mg after administration of a 70 mg loading dose in adult patients (see section "Method of administration and dosage").

In all the above-mentioned interaction studies with other medicinal products conducted in adult patients, caspofungin was administered at doses of 50 or 70 mg per day. Interactions of caspofungin at higher doses with other medicinal products have not been studied.

In children, regression analysis of pharmacokinetic data indicates that concomitant administration of dexamethasone and caspofungin may lead to a clinically significant reduction in caspofungin trough concentrations. These data suggest that when enzyme inducers are used in children, reductions in trough concentrations similar to those observed in adults may occur. When Caspofungin Acino is co-administered to children (aged 12 months to 17 years) with enzyme inducers such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, consideration should be given to increasing the dose of Caspofungin Acino to 70 mg/m² per day (not exceeding a daily dose of 70 mg).

Special precautions for use

Anaphylaxis has been reported during administration of caspofungin. If anaphylaxis occurs, caspofungin infusion should be discontinued immediately and appropriate therapy initiated. Adverse reactions possibly mediated by histamine, such as rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm, have been reported; such reactions may require discontinuation of treatment and/or administration of appropriate therapy.

Limited data indicate that caspofungin is ineffective against yeast species other than Candida and against molds other than Aspergillus. The efficacy of caspofungin against these fungal pathogens has not been established.

The concomitant use of caspofungin and cyclosporine has been evaluated in healthy adult volunteers and adult patients. In some healthy adult volunteers who received two doses of 3 mg/kg cyclosporine and caspofungin, transient elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to levels exceeding the upper limit of normal (ULN) by 3 times or less were observed. These elevations resolved after discontinuation of the drugs. In a retrospective study of 40 patients who received caspofungin and cyclosporine in the post-marketing period for 1–290 days (mean duration 17.5 days), no serious hepatic adverse reactions were observed. These data suggest that caspofungin may be administered to patients receiving cyclosporine if the potential benefit outweighs the potential risk. Liver enzyme activity should be monitored when caspofungin and cyclosporine are used concomitantly.

In adult patients with mild to moderate hepatic impairment, the AUC increased by approximately 20% and 75%, respectively. A reduced daily dose of 35 mg is recommended when administering caspofungin to adult patients with moderate hepatic impairment. There is no clinical experience with the use of caspofungin in patients with severe hepatic impairment or in children with any degree of hepatic impairment. Exposure to caspofungin is expected to be higher in these patients than in those with moderate hepatic impairment; therefore, Caspofungin Asino should be used with caution in such patients (see sections “Pharmacokinetics” and “Dosage and administration”).

Abnormalities in liver function test parameters have been observed in healthy volunteers as well as in adult and pediatric patients receiving caspofungin. Isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported in some adult and pediatric patients with severe underlying conditions who received multiple concomitant medications along with caspofungin. However, a causal relationship with caspofungin administration has not been established. Patients who develop abnormalities in liver function tests during treatment with Caspofungin Asino should be monitored closely to detect early signs of worsening liver function and to assess the risk-benefit ratio of continuing therapy.

The medicinal product contains sucrose. Patients with rare hereditary conditions such as fructose intolerance or sucrase-isomaltase deficiency should not use this medicinal product.

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during the post-marketing period.

Caspofungin should be administered with caution in patients with a history of skin allergic reactions (see section “Adverse reactions”).

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially “sodium-free”.

Use during pregnancy or breastfeeding

Pregnancy

Clinical data on the use of this medicinal product during pregnancy are lacking or limited. Caspofungin should not be administered during pregnancy unless clearly necessary. There are no adequate data on the use of caspofungin in pregnant women. Animal studies have shown fetal toxicity.

In pregnant rats administered a toxic dose of 5 mg/kg caspofungin, the drug caused reduced fetal body weight and increased incidence of incomplete ossification of vertebrae, sternum, and skull, accompanied by adverse reactions in pregnant females such as histamine release. Increased incidence of developmental abnormalities of cervical ribs was also observed in fetuses. Animal studies have demonstrated that caspofungin crosses the placental barrier.

Breastfeeding

It is unknown whether the medicinal product passes into human breast milk.

Available pharmacodynamic/toxicological data in animals indicate excretion of caspofungin into the milk of lactating rats.

Therefore, women receiving Caspofungin Asino must not breastfeed.

Fertility

In studies conducted in male and female rats administered a toxic dose of 5 mg/kg, caspofungin had no effect on fertility. Clinical data on the effect of caspofungin on fertility are lacking.

Effect on ability to drive and use machines

Studies on the effect of the medicinal product on the ability to drive and operate machinery have not been conducted.

Method of Administration and Dosage

Caspofungin is prescribed by a physician experienced in the management of invasive fungal infections.

Dosage

Adult Patients

On the first day, a single loading dose of 70 mg should be administered, followed by daily administration of 50 mg.

For patients with body weight over 80 kg, after administration of the initial loading dose of 70 mg, it is recommended to use caspofungin at a dose of 70 mg daily (see section "Pharmacokinetics").

There is no need for dose adjustment based on patient's sex or race (see section "Pharmacokinetics").

Children (from 12 months to 17 years)

For children aged 12 months to 17 years, dosing is based on body surface area. For all indications: on the first day, a single loading dose of 70 mg/m² (not exceeding an actual dose of 70 mg) should be administered, followed by daily administration of the drug at 50 mg/m² (not exceeding an actual daily dose of 70 mg). If the daily dose of 50 mg/m² is well tolerated but an adequate clinical response is not observed, the daily dose may be increased to 70 mg/m² (not exceeding an actual daily dose of 70 mg).

The efficacy and safety of caspofungin have not been sufficiently studied in clinical trials involving neonates and infants under 12 months of age. The medicinal product should be prescribed with caution in this patient group. Limited data suggest the possibility of using caspofungin for treatment of neonates and infants up to 3 months of age at a dose of 25 mg/m² daily, and for treatment of children aged 3 to 11 months at a dose of 50 mg/m² daily (see section "Pharmacokinetics").

Duration of Treatment

The duration of empirical therapy depends on the patient's clinical response. Treatment should be continued for up to 72 hours after resolution of neutropenia (absolute neutrophil count ≥ 500). Patients with documented fungal infection should be treated for at least 14 days, and treatment should continue for at least 7 days after resolution of neutropenia and clinical symptoms.

The duration of treatment for invasive candidiasis is determined by the patient's clinical and microbiological response. After resolution of symptoms of invasive candidiasis and obtaining a negative culture result, consideration may be given to switching to oral antifungal therapy. In general, antifungal therapy should be continued for at least 14 days after the last positive culture result.

The duration of treatment for invasive aspergillosis is determined on a case-by-case basis and should be based on assessment of the severity of the underlying disease, recovery from immunosuppression, and clinical response. In general, therapy should be continued for at least 7 days after resolution of symptoms.

Information on safety of use beyond 4 weeks is limited. However, available data indicate that caspofungin is well tolerated with longer treatment courses (up to 162 days in adult patients and up to 87 days in pediatric patients).

Special Patient Groups

Geriatric Patients

In patients aged 65 years and older, an increase in the area under the concentration-time curve (AUC) of approximately 30% has been observed. However, no adjustment of the maintenance dose is required. Experience with the use of the medicinal product in patients aged 65 years and older is limited (see section "Pharmacokinetics").

Patients with Renal Impairment

No dose adjustment of the medicinal product is necessary (see section "Pharmacokinetics").

Patients with Hepatic Impairment

For adult patients with mild hepatic impairment (5–6 points on the Child–Pugh scale), no dose adjustment of the medicinal product is required. For adult patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), it is recommended to administer the medicinal product at a dose of 35 mg daily, taking into account pharmacokinetic data. On the first day, an initial loading dose of 70 mg should be administered. There is no clinical experience with the use of the medicinal product in adult patients with severe hepatic impairment (more than 9 points on the Child–Pugh scale) or in children with any degree of hepatic impairment (see section "Special Warnings and Precautions for Use").

Concomitant Use with Enzyme Inducers

When administering Caspofungin Asinota to adults concomitantly with certain enzyme inducers (efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine), the daily dose of Caspofungin Asinota should be increased to 70 mg (after administration of a loading dose of 70 mg) (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

When administering Caspofungin Asino to children aged 12 months to 17 years concomitantly with the above-mentioned enzyme inducers, consideration should be given to increasing the daily dose of Caspofungin Asino to 70 mg/m² (not exceeding an actual daily dose of 70 mg) (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Method of Administration

After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour. Caspofungin Asino should be administered as a single daily infusion.

Reconstitution of Caspofungin Asino Medicinal Product

Step 1. Reconstitution of Standard Vials

To reconstitute the medicinal product, remove the vial from the refrigerator and allow it to reach room temperature. Then, under aseptic conditions, add 10.5 mL of water for injection. The concentration of the reconstituted solution will be 5.2 mg/mL (in 50 mg vials).

The white or almost white lyophilized powder will dissolve completely. Gently swirl to obtain a clear solution. Inspect the reconstituted solution to ensure absence of mechanical particles or discoloration. This reconstituted solution may be stored for up to 24 hours at ≤ 25 °C.

Step 2. Adding Reconstituted Caspofungin Asino to Infusion Solution

Diluents for preparing the final infusion solution: 0.9% sodium chloride injection or lactated Ringer's solution. The standard infusion solution for patient administration is prepared under aseptic conditions by adding the appropriate volume of reconstituted concentrate (as shown in Table 1) to a 250 mL bag or bottle of infusion diluent. For daily doses of 50 mg or 35 mg, if therapeutically necessary, the infusion volume may be reduced to 100 mL.

Visually inspect the infusion solution for presence of particles or discoloration. Do not use the solution if it is cloudy or contains a precipitate.

From a microbiological standpoint, the infusion solution should be used immediately after preparation. If not used immediately, storage duration and conditions should not exceed 24 hours at a temperature of 2 to 8 °C and must be controlled.

Table 1

Preparation of Infusion Solution for Use in Adults

Note: The medicinal product Caspofungin Asino is not available in 70 mg vials.

Dose*	Volume of reconstituted Caspofungin Asinu to be transferred into an infusion bag or bottle containing diluent	Standard medicinal product (reconstituted Caspofungin Asinu added to 250 ml diluent) Final concentration	Reduced infusion volume (reconstituted Caspofungin Asinu added to 100 ml diluent) Final concentration
50 mg	10 ml	0.20 mg/ml	−
50 mg reduced volume	10 ml	−	0.47 mg/ml
35 mg in moderate hepatic impairment (from one 50 mg vial)	7 ml	0.14 mg/ml	−
35 mg in moderate hepatic impairment (from one 50 mg vial) reduced volume	7 ml	−	0.34 mg/ml
70 mg (from two 50 mg vials)**	14 ml	0.28 mg/ml	Not recommended

* The contents of all vials should be reconstituted in 10.5 mL.

**The dose of 70 mg can be prepared from two 50 mg vials.

Preparation of infusion solution for use in children

Body surface area determination

Before preparing the infusion solution, the patient's body surface area should be determined using the following formula: height (cm) × body weight (kg) Body surface area (m2) = 3 600

Preparation of infusion solution for administration at doses of 70 mg/m² and 50 mg/m² in children aged 3 months and older (using 50 mg vials).

1. Calculate the actual loading dose / daily maintenance dose for the child using the body surface area:

For the 70 mg/m² dose:

body surface area (m²) × 70 mg/m² = loading dose.

For the 50 mg/m² dose:

body surface area (m²) × 50 mg/m² = daily maintenance dose.

The maximum loading dose on Day 1 must not exceed 70 mg regardless of the calculated dose.

The daily maintenance dose must not exceed 70 mg regardless of the calculated dose.

2. Remove the vial of Caspofungin Asinо medication from the refrigerator and allow it to reach room temperature.
3. Under aseptic conditions, add 10.5 mL of Water for Injections. The white or almost white lyophilized powder will dissolve completely. Gently mix until a clear solution is obtained. The reconstituted solution may be stored for up to 24 hours at ≤ 25 °C. Inspect the reconstituted solution to ensure there are no mechanical particles or discoloration. Do not use the solution if it is cloudy or contains a precipitate. The final concentration of the reconstituted solution will be 5.2 mg/mL (in 50 mg vials).
4. From the vial of reconstituted solution, withdraw the volume corresponding to the calculated loading dose / daily maintenance dose (see point 1 above). Under aseptic conditions, transfer this volume* into an infusion bag or bottle containing 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection solution, or Lactated Ringer’s Injection solution. Alternatively, this volume* of reconstituted Caspofungin Asinо medication may be added to a reduced volume of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection solution or Lactated Ringer’s Injection solution. Do not exceed the final solution concentration of 0.5 mg/mL. From a microbiological standpoint, the infusion solution should be used immediately after preparation. If not used immediately, the duration and conditions of storage, which must not exceed 24 hours at 2 to 8 °C, should be strictly controlled.

* Withdrawing 10 mL of reconstituted solution from the vial ensures the full labeled dose of caspofungin (50 mg).

Children

The medicinal product can be used in children (see section "Dosage and administration").

The efficacy and safety of Caspofungin Asinо in children under 12 months of age have not been sufficiently studied.

Overdose

Cases of accidental administration of caspofungin at a dose of 400 mg within 24 hours have been reported, which did not result in clinically significant adverse reactions.

Caspofungin is not dialyzable.

Adverse Reactions

Hypersensitivity reactions have been reported (anaphylaxis and histamine-mediated adverse reactions).

In patients with invasive aspergillosis, pulmonary edema, adult respiratory distress syndrome, and infiltrates on radiographic examination have also been reported.

Adults

In clinical studies, 1865 adults received single or multiple doses of caspofungin: 564 patients with febrile neutropenia (empirical therapy study), 382 patients with invasive candidiasis, 228 patients with invasive aspergillosis, 297 patients with localized Candida infection, and an additional 394 individuals enrolled in Phase I studies. In the empirical therapy study, patients were undergoing chemotherapy for malignancy or had undergone hematopoietic stem cell transplantation (including 39 allogeneic transplants). In studies involving patients with confirmed Candida infection, most patients with invasive candidiasis had serious underlying conditions (e.g., hematologic or other malignancies, recent surgery, HIV) requiring concomitant use of multiple medications. In the non-comparative Aspergillus study, patients frequently had serious medical conditions (such as bone marrow or peripheral stem cell transplantation, hematologic malignancies, solid tumors, or organ transplantation) requiring combination therapy.

Phlebitis was the most commonly reported adverse reaction related to the route of administration across all patient groups. Other local reactions included: erythema, pain/tenderness, pruritus, secretion, and burning sensation.

Clinical and laboratory abnormalities in all adult patients (total 1780) receiving caspofungin were generally mild and rarely led to drug discontinuation.

Adverse reactions are presented in Table 2

Table 2

Adverse reactions identified during clinical studies and/or post-marketing use

System organ class	Common (from ≥ 1/100 to < 1/10)	Uncommon (from ≥ 1/1,000 to < 1/100)	Unknown (cannot be estimated based on available data)
Blood and lymphatic system disorders	decreased hemoglobin levels, decreased hematocrit, decreased number of leukocytes	anemia, thrombocytopenia, coagulopathy, leukopenia, increased number of eosinophils, decreased number of platelets, increased number of platelets, decreased number of lymphocytes, increased number of leukocytes, decreased number of neutrophils
Metabolism and nutrition disorders	hypokalemia	fluid retention, hypomagnesemia, anorexia, electrolyte imbalance, hyperglycemia, hypocalcemia, metabolic acidosis
Psychiatric disorders		anxiety, confusion, insomnia
Nervous system disorders	headache	dizziness, dysgeusia, paraesthesia, somnolence, tremor, hypesthesia
Eye disorders		scleral icterus, blurred vision, eyelid edema, increased lacrimation
Cardiac disorders		palpitations, tachycardia, arrhythmia, atrial fibrillation, congestive heart failure
Vascular disorders	phlebitis	thrombophlebitis, sensation of blood rushing to the face and upper body, hot flushes, arterial hypertension, arterial hypotension
Respiratory, thoracic and mediastinal disorders	dyspnea	nasal congestion, pharyngolaryngeal pain, tachypnea, bronchospasm, cough, paroxysmal nocturnal dyspnea, hypoxia, rales, wheezing
Gastrointestinal disorders	nausea, diarrhea, vomiting	abdominal pain, upper abdominal pain, dry mouth, dyspepsia, stomach discomfort, bloating, ascites, constipation, dysphagia, flatulence
Hepatobiliary disorders	increased liver function tests – alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, conjugated bilirubin, blood bilirubin	cholestasis, hepatomegaly, hyperbilirubinemia, jaundice, liver function abnormalities, hepatotoxicity, liver disease, increased gamma-glutamyl transferase levels
Skin and subcutaneous tissue disorders	rash, pruritus, erythema, hyperhidrosis	multiform erythema, macular rash, maculopapular rash, pruritic rash, urticaria, allergic dermatitis, generalized pruritus, erythematous rash, generalized rash, measles-like rash, skin lesions	toxic epidermal necrolysis and Stevens-Johnson syndrome (see section "Special precautions")
Musculoskeletal and connective tissue disorders	arthralgia	back pain, limb pain, bone pain, muscle weakness, myalgia
Renal and urinary disorders		renal failure, acute renal failure
General disorders and administration site conditions	increased body temperature, chills, infusion site pruritus	pain, catheter site pain, weakness, feeling of cold, feeling of warmth, erythema at infusion site, induration at infusion site, pain at infusion site, swelling at infusion site, phlebitis at injection site, peripheral edema, pain, chest discomfort, chest pain, facial edema, sensation of body temperature change, induration, hemorrhage at infusion site, irritation at infusion site, phlebitis at infusion site, rash at infusion site, urticaria at infusion site, erythema at injection site, swelling at injection site, pain at injection site, swelling at injection site, malaise, edema
Investigations	decreased blood potassium levels, decreased blood albumin levels	increased blood creatinine levels, positive urine test for erythrocytes, decreased total protein levels, proteinuria, prolonged prothrombin time, shortened prothrombin time, decreased blood sodium levels, increased blood sodium levels, decreased blood calcium levels, increased blood calcium levels, decreased blood chloride levels, increased blood glucose levels, decreased blood magnesium levels, decreased blood phosphate levels, increased blood phosphate levels, increased blood urea levels, prolonged activated partial thromboplastin time, decreased blood bicarbonate levels, increased blood chloride levels, increased blood potassium levels, increased blood pressure, decreased blood uric acid levels, hematuria, abnormal respiratory sounds, decreased carbon dioxide levels, increased blood levels of immunosuppressive drugs, increased international normalized ratio, urine cylinders, positive urine test for leukocytes, increased urine pH

The use of caspofungin at a dose of 150 mg once daily (for up to 51 days) was evaluated in 100 adult patients (see section "Pharmacodynamics"). In this study, caspofungin administered at a dose of 50 mg once daily (following a loading dose of 70 mg on day 1) was compared with 150 mg once daily in the treatment of invasive candidiasis. In this patient group, the safety of the higher caspofungin dose was generally similar to that observed with caspofungin at the 50 mg daily dose. The number of patients with serious adverse reactions related to caspofungin administration, or reactions leading to discontinuation of caspofungin, was similar in both treatment groups.

Children

Data from 5 completed clinical trials involving 171 pediatric patients indicate that the overall incidence of clinical adverse reactions (26.3%; 95% confidence interval – 19.9, 33.6) is not higher than that observed in adult patients receiving caspofungin (43.1%; 95% confidence interval – 40.0, 46.2). However, children likely have a different adverse reaction profile compared to adult patients. The most common drug-related clinical adverse reactions reported in pediatric patients treated with caspofungin were: increased body temperature (11.7%), rash (4.7%), and headache (2.9%).

Adverse reactions are presented in Table 3

Table 3

System organ class	Very common (≥ 1/10)	Common (from ≥ 1/100 to < 1/10)
Blood and lymphatic system disorders		increased eosinophil count
Nervous system disorders		headache
Cardiac disorders		tachycardia
Vascular disorders		flushing, arterial hypotension
Hepatobiliary disorders		elevation of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST))
Skin and subcutaneous tissue disorders		rash, pruritus
General disorders and administration site conditions	fever	chills, pain at catheter site
Investigations		decreased potassium levels, hypomagnesemia, increased glucose levels, decreased phosphate levels, increased phosphate levels

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

The storage time of the medicinal product after reconstitution of the concentrate for infusion solution and after dilution of the infusion solution should not be added together.

Reconstituted concentrate for infusion solution

Chemical and physical stability of the medicinal product after reconstitution has been confirmed for

24 hours at a temperature ≤ 25 °C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, the duration and conditions of storage after reconstitution depend on the user’s responsibility, but usually do not exceed 24 hours at a temperature of 2 to 8 °C, unless reconstitution was performed under controlled and validated aseptic conditions.

Do not freeze the reconstituted concentrate for infusion solution.

Diluted infusion solution

Chemical and physical stability of the medicinal product after dilution has been confirmed for

24 hours at a temperature ≤ 25 °C and for 48 hours at a temperature of 2 to 8 °C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, the duration and conditions of storage after dilution depend on the user’s responsibility, but usually do not exceed 24 hours at a temperature of 2 to 8 °C, unless dilution was performed under controlled and validated aseptic conditions.

Storage conditions

Store out of the reach of children at a temperature of 2 to 8 °C.

Incompatibilities

Solvents containing glucose should not be used, as Caspofungin Asino is unstable in such solutions.

Due to lack of compatibility studies, Caspofungin Asino should not be mixed with other medicinal products.

Packaging

50 mg in a vial. 1 vial in a cardboard pack.

Prescription status. By prescription only.

Manufacturer

BAG Health Care GmbH.

Manufacturer’s address and location of operations

Amtsgerichtsstrasse 1-5, Lich, 35423, Germany.

Marketing Authorization Holder

LLC "ASINO UKRAINE"

Address of the Marketing Authorization Holder

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse reactions or questions regarding safety and efficacy of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.