Caspofungin-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CASPOFUNGIN-VISTA (CASPOFUNGIN-VISTA)

Composition:

Active substance: caspofungin;

1 vial contains caspofungin acetate 55.52 mg or 77.69 mg, equivalent to caspofungin 50 mg or 70 mg;

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

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: lyophilized powder of white or almost white color.

Pharmacotherapeutic group. Antifungal agents for systemic use. Other antifungal agents for systemic use. Caspofungin. ATC code J02AX04.

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. Caspofungin has demonstrated fungicidal activity against Candida yeasts. In vitro and in vivo studies show that caspofungin's action against Aspergillus results in lysis and death of the hyphal tips and branching points, 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 transport mutations and those with acquired intrinsic resistance to fluconazole, amphotericin B, and 5-flucytosine.

The frequency of resistance development to caspofungin among various clinical isolates of Candida and Aspergillus is low.

Pharmacokinetics.

Distribution.

The medicinal product Caspofungin-Vista binds extensively to plasma proteins. 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 step for the alpha- and beta-disposition phases. Maximum tissue distribution occurs 1.5–2 days after 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 the volume of distribution of caspofungin cannot be accurately determined.

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-level, irreversible binding to plasma proteins. Later (≥ 5 days after administration of a single dose of radiolabeled [3H] caspofungin acetate), a low level (≤ 7 pmol/mg protein or ≤ 1.3% of the administered dose) of covalent binding of radioactivity in plasma is observed, likely due to the formation of two reactive intermediates during the chemical degradation of caspofungin. Additional metabolism includes hydrolysis to constituent amino acids and their derivatives, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, indicating rapid renal clearance. 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 medicinal products. Caspofungin is not a substrate of P-glycoprotein and is a weak substrate of cytochrome P450 enzymes.

Elimination.

Caspofungin is slowly eliminated from plasma, with a clearance rate of 10–12 mL/min. After a single intravenous infusion (1 hour duration), caspofungin plasma concentrations decline polyphasically. 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, rather than 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 occurs within the first 30 hours after administration. Radiolabel and caspofungin plasma concentrations were similar during the first 24–48 hours after dosing, after which the drug concentration declined more rapidly. Radioactive label was quantitatively detected up to 22.3 weeks, whereas caspofungin concentrations fell below the quantification limit within 6–8 days after dosing. 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). Renal clearance of the parent drug is low (approximately 0.15 mL/min). Caspofungin exhibits moderate non-linear pharmacokinetics, with increased accumulation at higher doses and dose dependency in the time to reach steady-state with repeated dosing.

Special patient groups

Increased caspofungin exposure has been observed in adult patients with mild hepatic impairment, renal impairment, and in elderly patients. The increase is generally moderate and not significant enough to require dose adjustment. Dose adjustment may be required for adult patients with moderate hepatic impairment or for patients with higher body weight.

Body weight. Pharmacokinetic analysis in adult patients with candidiasis showed that caspofungin pharmacokinetics are body weight-dependent. Drug concentration in plasma decreases with increasing body weight. It was calculated that average exposure in adult patients weighing 80 kg is 23% lower than in patients weighing 60 kg.

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 medicinal product in adults with severe hepatic impairment or in children with any degree of hepatic impairment. In a multiple-dose study, reducing the daily dose to 35 mg in adult patients with moderate hepatic impairment resulted in AUC values similar to those in adults with normal liver function receiving the standard dosing regimen.

Renal impairment. In a clinical study using a single 70 mg dose, caspofungin pharmacokinetics were similar in adult volunteers with mild renal impairment (creatinine clearance 50–80 mL/min) and control group participants. With moderate renal impairment (creatinine clearance 31–49 mL/min), progressive impairment (creatinine clearance 5–30 mL/min), and end-stage renal disease (creatinine clearance < 10 mL/min with dialysis), plasma caspofungin concentrations 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 50 mg daily, no significant impact on caspofungin concentrations was observed with mild to progressive renal impairment. Dose adjustment is not necessary in patients with renal impairment. Caspofungin is not removed during dialysis; therefore, no supplemental dose is required after hemodialysis.

Gender. Caspofungin plasma concentrations 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 moderate age-dependent effect was observed in patients receiving empirical treatment or those with invasive candidiasis.

Race. Pharmacokinetic data in patients indicate no clinically significant differences in pharmacokinetic parameters among Caucasians, African Americans, Hispanics, and mixed-race individuals.

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

In children (2–11 years) receiving caspofungin at 50 mg/m²/day (maximum dose 70 mg/day), AUC₀–₂₄ values in plasma after multiple dosing were comparable to those observed in adults receiving 50 mg/day. After the first day of administration, AUC₀–₂₄ was slightly higher in children than in adults (37% increase when comparing 50 mg/m²/day and 50 mg/day regimens). However, AUC values in these children on the first day were lower than AUC values in adults at steady-state.

In younger children (12–23 months) receiving caspofungin at 50 mg/m²/day (maximum dose 70 mg/day), AUC₀–₂₄ values in plasma after multiple dosing were comparable to those observed in adults receiving 50 mg/day and in older children (2–11 years) receiving 50 mg/m²/day. 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) caspofungin concentrations after multiple dosing were comparable to those observed in adults receiving 50 mg/day. On the first day of treatment in these infants, C1h values were similar to those in adults, while C24h values were 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. The efficacy and safety of the medicinal product in neonates and infants under 3 months of age have not been sufficiently studied.

Clinical characteristics.

Indications.

• For the treatment of invasive candidiasis in adults and children.
• For the treatment of invasive aspergillosis in adults and children when refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, and/or itraconazole. Refractoriness is defined as progression of infection or insufficient clinical improvement after at least 7 days of effective antifungal therapy administered at therapeutic doses.
• For empirical therapy in 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 transporters and is a poor substrate for cytochrome P450 enzymes. In two clinical studies involving healthy volunteers, cyclosporine A (single dose 4 mg/kg or two doses of 3 mg/kg 12 hours apart) increased the AUC of caspofungin by approximately 35%, possibly due to reduced hepatic uptake of caspofungin. The drug did not increase cyclosporine plasma levels. Transient elevations in liver transaminase activity (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) (up to 3 times or less than the upper limit of normal [ULN]) were observed when caspofungin and cyclosporine were administered concomitantly, which resolved after discontinuation of the drugs.

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

Caspofungin reduced the trough concentration of tacrolimus by 26% in healthy volunteers. If patients are receiving both drugs, standard monitoring of blood concentrations and appropriate dose adjustment of tacrolimus are required. In clinical studies involving healthy volunteers, the pharmacokinetics of caspofungin were not significantly altered by concomitant administration of 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 an increase in AUC by 60% and an increase in the trough concentration of caspofungin by 170% on the first day of co-administration when both drugs were administered to healthy adult volunteers. Trough levels of caspofungin gradually decreased with repeated dosing. After 2 weeks of rifampicin administration, there was limited effect on AUC, 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 medicinal products that induce enzyme metabolism.

Some pharmacokinetic study data suggest that concomitant use 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 to 70 mg after a loading dose of 70 mg in adult patients (see section "Dosage and administration").

In all the aforementioned drug interaction studies conducted in adult patients, caspofungin was administered at doses of 50 or 70 mg daily. Interactions of caspofungin at higher doses with other medicinal products have not been studied. In children, results of pharmacokinetic data regression analysis suggest that concomitant use of dexamethasone and caspofungin may lead to a clinically significant reduction in caspofungin trough concentrations. These data may indicate that when enzyme inducers are used in children, a similar reduction in trough concentrations may occur as in adults. When caspofungin is co-administered with enzyme inducers such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine in children (aged 12 months to 17 years), consideration should be given to increasing the dose of the drug to 70 mg/m² daily (daily dose not to exceed 70 mg).

Special precautions for use

Anaphylaxis has been reported during administration of caspofungin. If anaphylaxis occurs, caspofungin should be discontinued immediately and appropriate treatment 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 initiation of appropriate therapy.

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

Concomitant use of caspofungin and cyclosporine has been evaluated in healthy adult volunteers and adult patients. Transient increases in ALT and AST levels, exceeding the upper limit of normal (ULN) by up to 3 times, were observed in some healthy adult volunteers who received two doses of 3 mg/kg cyclosporine and caspofungin. These elevations resolved after discontinuation of the drugs. In a retrospective study of 40 patients who received caspofungin and cyclosporine in the post-marketing setting 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 anticipated benefit outweighs the potential risk. However, liver enzyme activity should be monitored when caspofungin and cyclosporine are used concomitantly.

In adult patients with mild to moderate hepatic impairment, AUC increased by approximately 20% and 75%, respectively. A reduced daily dose of 35 mg is recommended for adult patients with moderate hepatic impairment. There is no clinical experience with the use of caspofungin in patients with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment. Higher caspofungin exposure is expected in these patients compared to those with moderate hepatic impairment; therefore, the drug should be used with caution in such patients.

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 serious underlying conditions who were receiving multiple concomitant medications along with caspofungin. However, a causal relationship to caspofungin administration has not been established. To enable early detection of signs of hepatic dysfunction and to assess the risk-benefit ratio of continuing therapy with Caspofungin-Vista, patients who develop abnormalities in liver function tests during treatment should be closely monitored.

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in the post-marketing period. Caspofungin-Vista should be administered with caution to patients with a history of allergic skin reactions (see section "Adverse reactions").

Important information about excipients. The medicinal product contains sucrose. This medicinal product should not be used in patients with rare hereditary conditions such as fructose intolerance or sucrase-isomaltase deficiency.

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-Vista should not be administered during pregnancy unless clearly necessary. Adequate data on the use of caspofungin in pregnant women are not available. In pregnant rats administered a toxic dose of 5 mg/kg, caspofungin caused reduced fetal weight and increased incidence of incomplete ossification of vertebrae, sternum, and skull, accompanied by histamine release-related adverse reactions in pregnant females. An increased frequency of cervical ribs was also observed. Animal studies have shown that caspofungin crosses the placental barrier.

Breastfeeding. Caspofungin passes into the milk of lactating rats. It is unknown whether the drug passes into human breast milk. Therefore, women receiving this medicinal product should not breastfeed.

Ability to affect the speed of reactions when driving or operating machinery. Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted.

Administration and Dosage

The medicinal product Caspofungin-Vista 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 50 mg once daily.

For patients with body weight exceeding 80 kg, after administration of the initial loading dose of 70 mg, caspofungin is recommended at a dose of 70 mg per day.

There is no need for dose adjustment based on patient sex or race.

Children. Dosing for children aged 12 months to 17 years depends on the patient's 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 medicinal product 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 in clinical studies involving neonates and infants under 12 months of age have not been sufficiently studied. The medicinal product should be prescribed with caution in this patient group. Some 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 per day and for treatment of children aged 3 to 11 months at a dose of 50 mg/m² per day.

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 a minimum of 14 days; after resolution of neutropenia and clinical symptoms, treatment should be continued for at least 7 days.

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 the safety of using the medicinal product for periods longer than 4 weeks is limited. However, available data indicate that caspofungin is well tolerated during longer treatment courses (up to 162 days in adult patients and up to 87 days in children).

Special patient groups.

Elderly patients. Experience with the use of the medicinal product in patients aged 65 years and older is limited. In such patients, an increase in AUC of approximately 30% has been observed. However, no dose adjustment is required.

Patients with renal impairment. No dose adjustment of the medicinal product is necessary.

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 per day, 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) and in children with any degree of hepatic impairment (see section "Special precautions").

Concomitant use with enzyme inducers

When caspofungin is co-administered with certain enzyme inducers (efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine) in adults, the daily dose of Caspofungin-Vista should be increased to 70 mg (after administration of a loading dose of 70 mg).

When co-administering Caspofungin-Vista with the above-mentioned enzyme inducers in children aged 12 months to 17 years, consideration should be given to increasing the daily dose of the medicinal product to 70 mg/m² (not exceeding an actual daily dose of 70 mg).

Administration method

After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour.

Preparation of Caspofungin-Vista for administration.

Step 1. Reconstitution of Caspofungin-Vista

To reconstitute the medicinal product, remove the cooled vial from the refrigerator and allow it to reach room temperature, then aseptically add 10.5 mL of water for injection.

The concentration of the reconstituted solution will be 7.2 mg/mL (in 70 mg vials) or 5.2 mg/mL (in 50 mg vials).

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

Step 2. Adding reconstituted Caspofungin-Vista to infusion solution

Diluents for preparing the final infusion solution: 0.9% sodium chloride injection solution or lactated Ringer's solution. The standard infusion solution for patient administration is prepared under aseptic conditions by adding the appropriate amount of reconstituted concentrate (see 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.

Do not use the solution if it is cloudy or contains precipitate.

The infusion solution must be used within 24 hours if stored at a temperature not exceeding 25 °C, or within 48 hours if stored in a refrigerator at 2–8 °C.

The medicinal product solution diluted in sterile lactated Ringer's solution or 0.9% sodium chloride injection solution at concentrations of 9 mg/mL (0.9%), 4.5 mg/mL (0.45%), and 2.25 mg/mL (0.225%) is chemically and physically stable for 24 hours at a temperature not exceeding 25 °C and for 48 hours at a temperature of 2–8 °C.

From a microbiological standpoint, the medicinal product should be used immediately after preparation. If not used immediately, storage duration and conditions should be controlled: store no longer than 24 hours at a temperature not exceeding 25 °C or no longer than 48 hours at 2–8 °C.

Table 1

Preparation of infusion solution for administration to adults

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

** If a 70 mg vial is not available, the 70 mg dose can be prepared using two 50 mg vials.

Preparation of infusion solution for pediatric use

Body surface area calculation

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 and 70 mg vials).

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

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 cooled vial of Caspofungin-Vista medicinal product 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. This reconstituted solution may be stored for up to 24 hours at ≤ 25 °C. Inspect the reconstituted solution to ensure absence of 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) and 7.2 mg/mL (in 70 mg vials).
4. From the vial containing the 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-Vista medicinal product 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. This infusion solution should be used within 24 hours when stored at ≤ 25 °C or within 48 hours if stored refrigerated at 2–8 °C.

*Withdrawing 10 mL of reconstituted solution from the vial ensures delivery of the full labeled dose of caspofungin (50 mg or 70 mg).

Children. The medicinal product is used in pediatric patients. The efficacy and safety of Caspofungin-Vista in children under 12 months of age have not been sufficiently studied.

Overdose. Accidental administration of 400 mg of caspofungin in one day has been reported, which did not result in clinically significant adverse reactions. Caspofungin is not removed by dialysis.

Adverse Reactions

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

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

Adults.

In clinical studies, 1865 adults received caspofungin as single and multiple doses: 564 patients with febrile neutropenia (empirical therapy studies), 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 received chemotherapy for malignancy or had undergone hematopoietic stem cell transplantation (including 39 allogeneic transplants). In studies involving patients with confirmed Candida-related infection, most patients with invasive candidiasis had serious underlying conditions (e.g., hematological or other forms of malignancy, recent surgery, HIV) requiring concomitant use of multiple medications. In the non-comparative Aspergillus study, patients frequently had serious medical conditions (bone marrow or peripheral stem cell transplantation, hematological malignancies, solid tumors, or organ transplantation), necessitating combination therapy. Phlebitis was the most frequently reported adverse reaction related to the route of administration of caspofungin 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) who received caspofungin were generally mild and rarely led to discontinuation of the drug.

Adverse reactions are presented in Table 2.

Table 2

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

The use of caspofungin at a dose of 150 mg once daily (for up to 51 days) was evaluated in 100 adult patients.

In this study, the use of caspofungin at a dose of 50 mg once daily (after administration of 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 caspofungin at the higher dose was generally similar to that at the 50 mg once-daily dose.

The number of patients with serious adverse reactions related to caspofungin administration, or reactions leading to discontinuation of caspofungin, was similar between the two treatment groups.

Children.

Data from 5 completed clinical studies involving 171 children indicate that the overall incidence of clinical adverse reactions (26.3%; 95% confidence interval (CI) — 19.9; 33.6) is not higher than that in adult patients receiving caspofungin (43.1%; 95% CI — 40.0; 46.2). However, children likely have a different adverse reaction profile compared to adult patients.

The most common clinical adverse reactions associated with caspofungin observed in children were fever (11.7%), rash (4.7%), and headache (2.9%).

Adverse reactions are presented in Table 3.

Table 3

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 and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of effectiveness of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Caspofungin-Vista resuspended in vials. Resuspended caspofungin may be stored at a temperature not exceeding 25 °C for up to 24 hours prior to preparation of the infusion solution.

Caspofungin-Vista solution for infusion. The ready-to-administer solution in an infusion bag or bottle may be stored at a temperature not exceeding 25 °C for 24 hours or at a temperature between 2 and 8 °C for 48 hours.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature between 2 °C and 8 °C. Keep out of the reach of children.

Incompatibilities. Do not use solvents containing glucose, as the medicinal product Caspofungin-Vista is unstable in such solutions.

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

Packaging. 50 mg or 70 mg per vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. ELPEN PHARMACEUTICAL CO. INC.

Manufacturer's address and location of operations. Marafonos Avenue 95, Pikermi, 190 09, Greece.

Manufacturer. FARMATEN S.A.

Manufacturer's address and location of operations. Derivenakion 6, Pallini Attica, 15351, Greece.