Caspofungin zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KASPOFUNGIN ZENTIVA (CASPOFUNGIN ZENTIVA)

Composition:

active substance: caspofungin;

1 vial contains caspofungin 50 mg or 70 mg (as caspofungin acetate 55.52 mg or 77.69 mg);

excipients: sucrose, mannitol (E 421), glacial acetic acid, and sodium hydroxide for pH adjustment.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: white or almost white lyophilized powder.

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 (an 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 caspofungin's action on Aspergillus causes 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 transport mutations and those with acquired intrinsic resistance to fluconazole, amphotericin B, and 5-fluorocytosine.

Resistance to caspofungin in various clinical isolates of Candida and Aspergillus is rare.

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 governs 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, making it impossible to accurately determine the volume of distribution of caspofungin at this time.

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 protein binding. Low levels (≤7 pmol/mg protein or ≤1.3% of the administered dose) of covalent binding of radioactivity in plasma were observed later (≥5 days after administration of a single dose of [3H]-labeled caspofungin acetate), possibly due to the formation of two reactive intermediates during the chemical degradation of caspofungin. Additional metabolism includes hydrolysis into 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-mediated 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 9–11 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 radiolabeled pharmacokinetic study, blood plasma, urine, and feces were collected over 27 days after a single dose. 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 administration. Plasma concentrations of the radiolabel and caspofungin were similar during the first 24–48 hours after dosing, after which the drug concentration declined more rapidly. The radiolabel was quantitatively detected up to 22.3 weeks, whereas caspofungin concentrations fell below the quantifiable limit within 6–8 days after dosing. Elimination is slow, with a terminal half-life of the radiolabeled 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 nonlinear pharmacokinetics, with increased accumulation at higher doses and dose-dependent time to steady state with repeated dosing.

Special Patient Populations

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

Dose adjustment may be necessary 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. Plasma concentrations of the drug decrease with increasing body weight. It was estimated 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, AUC values increase 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 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 subjects. 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 impact on caspofungin concentrations was observed with mild or severe renal impairment. Dose adjustment is not necessary in patients with renal impairment. Caspofungin is not removed by dialysis; therefore, no supplemental dose is required after hemodialysis.

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

Elderly Patients. A moderate increase in AUC (by 28%) and C24h (by 32%) was observed in elderly men compared to younger men. A similarly moderate age-dependent effect was observed in patients receiving empirical treatment and 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.

Pediatrics. 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 administered to adolescents).

In children (2–11 years) receiving caspofungin at 50 mg/m²/day (maximum dose 70 mg/day), AUC0–24 values after multiple dosing were comparable to those observed in adults receiving 50 mg/day. On the first day of treatment, AUC0–24 was slightly higher in children than in adults (37% increase when comparing 50 mg/m²/day and 50 mg/day regimens). However, it should be noted that AUC values in these children on day 1 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 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), peak (C1h) and trough (C24h) caspofungin concentrations after multiple dosing were comparable to those observed in adults receiving 50 mg/day. On the first day of treatment, C1h values in these infants 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 caspofungin in neonates and infants under 3 months of age have not been well established.

Clinical characteristics.

Indications.

• For the treatment of invasive candidiasis in adults and children.
• For the treatment of invasive aspergillosis in adults and children who are refractory to or intolerant of 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 administered 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 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.

In two clinical studies involving healthy volunteers, cyclosporine A (one dose of 4 mg/kg or two doses of 3 mg/kg 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 liver transaminase activity [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] (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, 40 patients received 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 reduced trough concentrations of tacrolimus by 26% in healthy volunteers. In patients receiving both agents, standard monitoring of blood concentrations and appropriate dose adjustment of tacrolimus are mandatory.

In clinical studies involving healthy volunteers, the pharmacokinetics of caspofungin were not significantly altered when administered 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 concomitant use of caspofungin with amphotericin B, itraconazole, nelfinavir, or mycophenolate mofetil.

Rifampicin caused a 60% increase in AUC and a 170% increase in 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 after repeated dosing. After 2 weeks of rifampicin administration, there was minimal effect on AUC, but trough concentrations were 30% lower than in adult patients receiving caspofungin alone. The mechanism of interaction may involve 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 reduced AUC of caspofungin. 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 above-mentioned interaction studies with other drugs conducted in adult patients, caspofungin was administered at doses of 50 or 70 mg daily. Interactions of caspofungin at higher doses with other drugs have not been studied.

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

Special precautions for use

Anaphylaxis has been reported during caspofungin administration. 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; these reactions may require discontinuation of therapy and/or administration of appropriate treatment.

Available data suggest that caspofungin is not effective against yeast species other than Candida and mold species 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 ALT and AST levels were observed, exceeding the upper limit of normal (ULN) by 3 times or less. These elevations resolved after discontinuation of the drugs. In a retrospective post-marketing study, 40 patients received caspofungin and cyclosporine for 1–290 days (median 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 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 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 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. In some adult and pediatric patients with severe underlying conditions who were receiving multiple concomitant medications, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported. However, a causal relationship with caspofungin administration has not been established. Patients who develop abnormalities in liver function tests during caspofungin therapy should be monitored closely to allow early detection of signs of worsening liver function and to assess the risk-benefit ratio if prolonged therapy with caspofungin is considered.

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.

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

Caspofungin should be used 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. Cospofungin should not be administered during pregnancy unless clearly necessary. There are no adequate data on the use of caspofungin in pregnant women.

In pregnant rats administered a toxic dose of 5 mg/kg, caspofungin caused reduced fetal body weight and increased incidence of incomplete ossification of vertebrae, sternum, and skull, accompanied by histamine release-related adverse reactions in pregnant females. An increased incidence 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 caspofungin should not breastfeed.

Ability to influence the 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 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's 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 drug at a dose of 50 mg/m² per day (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 drug 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 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 at least 14 days, and therapy 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 negative culture results, 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 an individual basis, depending on the 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 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) by approximately 30% has been observed. However, dose adjustment is not required. Experience with the use of the drug in patients aged 65 years and older is limited.

Patients with Renal Impairment

No dose adjustment of the drug 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 drug is required. For adult patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), the drug is recommended at a dose of 35 mg per day, taking into account pharmacokinetic data. On the first day, a loading dose of 70 mg should be administered. There is no clinical experience with the use of the drug 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 Warnings and Precautions for Use").

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 should be increased to 70 mg (after administration of a loading dose of 70 mg).

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

Route of Administration

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

Reconstitution of Caspofungin Zentiva

Step 1. Reconstitution of the product in vials.

To reconstitute the product, remove the refrigerated vial from the refrigerator and allow it to reach room temperature. Then, aseptically add 10.5 mL of Water for Injections. 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 can be stored for up to 24 hours at 25 °C or 5±3 °C.

Step 2. Adding the reconstituted Caspofungin Zentiva to an 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.

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

Table 1

Preparation of infusion solution for administration to adults

Dose*	Volume of reconstituted Caspofungin Zentiva to be transferred into an infusion bag or bottle containing diluent	Standard preparation (reconstituted Caspofungin Zentiva added to 250 ml) Final concentration	Reduced infusion volume (reconstituted Caspofungin Zentiva added to 100 ml) 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	10 ml	0.28 mg/ml	Not recommended
70 mg (from two 50 mg vials)**	14 ml	0.28 mg/ml	Not recommended
35 mg in moderate hepatic impairment (from one 70 mg vial)	5 ml	0.14 mg/ml	0.34 mg/ml

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

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

Preparation of infusion solution for pediatric use

Body surface area determination.

Before preparing the infusion solution, determine the patient's body surface area using the following formula: height (cm) × body weight (kg) Body surface area (m2) = 3600

Preparation of infusion solution for administration at doses of 70 mg/m² and 50 mg/m² in children aged 3 months (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) value:

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 Zentiva 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 or below, or at 5±3 °C. Inspect the reconstituted solution to ensure there are no visible particulates 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 Zentiva 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 48 hours when stored in a refrigerator at 2–8 °C or at room temperature (25 °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 administered to children (see section "Dosage and administration").

The efficacy and safety of caspofungin in children under 12 months of age have not been fully established.

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

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

Adults

In clinical studies, 1865 adults received caspofungin as single and multiple doses: 564 patients with febrile neutropenia (empirical therapy study), 382 patients with invasive candidiasis, 228 patients with invasive aspergillosis, 297 patients with Candida-related localized infection, and an additional 394 individuals enrolled in Phase I studies. In the empirical therapy study, patients were receiving 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 multiple concomitant medications. In the non-comparative Aspergillus study, patients often 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 frequently 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) who received caspofungin were generally mild in severity and rarely required drug discontinuation.

Table 2

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

System organ classes	Common (≥1/100 to <1/10)	Uncommon (≥1/1000 to <1/100)	Unknown (cannot be estimated from available data)
Blood and lymphatic system disorders	decreased hemoglobin levels, decreased hematocrit, decreased white blood cell count	anemia, thrombocytopenia, coagulopathy, leukopenia, increased eosinophils, decreased platelet count, increased platelet count, decreased lymphocyte count, increased white blood cell count, decreased neutrophil count
Metabolism and nutrition disorders	hypokalemia	fluid retention, hypomagnesemia, anorexia, electrolyte imbalance, hyperglycemia, hypocalcemia, metabolic acidosis
Psychiatric disorders		anxiety, disorientation, insomnia
Nervous system disorders	headache	dizziness, dysgeusia, paraesthesia, somnolence, tremor, hypoaesthesia
Eye disorders		jaundice of sclera, blurred vision, eyelid edema, increased lacrimation
Cardiac disorders		palpitations, tachycardia, arrhythmia, atrial fibrillation, congestive heart failure
Vascular disorders	phlebitis	thrombophlebitis, facial flushing, flushing, arterial hypertension, arterial hypotension
Respiratory, thoracic and mediastinal disorders	dyspnea	nasal congestion, pharyngolaryngeal pain, tachypnea, bronchospasm, cough, nocturnal paroxysmal dyspnea, hypoxia, wheezing, stridor
Gastrointestinal disorders	nausea, diarrhea, vomiting	abdominal pain, upper abdominal pain, dry mouth, dyspepsia, gastric discomfort, bloating, ascites, constipation, dysphagia, flatulence
Hepatobiliary disorders	increased liver function tests: ALT, 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, scarlatiniform 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, itching at infusion site	pain, catheter site pain, weakness, feeling cold, feeling of heat, erythema at infusion site, induration at infusion site, pain at infusion site, swelling at infusion site, phlebitis at injection site, peripheral edema, pain, discomfort in chest, chest pain, facial edema, sensation of temperature change, induration, bruising 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 blood urine test, 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 immunosuppressive drug levels, increased international normalized ratio, cylinders in urine, positive urine leukocyte test, increased urine pH

The safety of caspofungin 150 mg once daily (for up to 51 days) was evaluated in 100 adult patients. This study compared caspofungin 50 mg once daily (after a loading dose of 70 mg on day 1) with caspofungin 150 mg once daily in the treatment of invasive candidiasis. In this patient group, the safety profile of the higher caspofungin dose was generally similar to that of the 50 mg daily dose. The number of patients with serious drug-related adverse reactions or reactions requiring discontinuation of the drug was similar in the two treatment groups.

Pediatric

Data from 5 completed clinical studies involving 171 pediatric patients 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, pediatric patients may have a different adverse reaction profile compared to adults. The most common drug-related clinical adverse reactions in pediatric patients treated with caspofungin were: increased body temperature (11.7%), rash (4.7%), and headache (2.9%). Adverse reactions in pediatric patients are presented in Table 3.

Table 3

Body systems	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, hypotension
Hepatobiliary disorders		elevated liver enzymes (ALT, AST)
Skin and subcutaneous tissue disorders		rash, pruritus
General disorders and administration site conditions	fever	chills, catheter site pain
Investigations		decreased potassium level, hypomagnesemia, increased glucose level, decreased phosphorus level, increased phosphorus level

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Reconstituted Caspofungin Zentiva in vials.

Reconstituted Caspofungin Zentiva may be stored at 25°C or below for up to 24 hours prior to preparation of the infusion solution.

Infusion solution of Caspofungin Zentiva.

The ready-to-administer solution in an infusion bag or bottle may be stored at 25°C or below for up to 24 hours or at 2–8°C for up to 48 hours.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the duration and conditions of storage are the responsibility of the user. Generally, solutions should not be stored for longer than 24 hours at 2–8°C, except for reconstituted and diluted solutions prepared under controlled and validated sterile conditions.

Storage conditions. Store in the original packaging at 2–8°C. Keep out of the reach of children.

Incompatibilities.

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

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

Packaging. 50 mg or 70 mg powder in a vial. One vial in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

FARMATEN S.A.

ELPEN PHARMACEUTICAL CO., INC.

Manufacturers' locations and addresses of their business sites.

6, Dervenakion, Pallini Attikis, 15351, Greece.

Marathonos Ave. 95, Pikermi Attikis, 19009, Greece.