Caspofungin (Lyophilisate) Instructions for Use

ATC Code

J02AX04 (Caspofungin)

Active Substance

Caspofungin (Rec.INN WHO registered)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal drugs for systemic use, other antifungal drugs for systemic use

Pharmacological Action

Antifungal agent for systemic use. It is a semisynthetic lipopeptide compound (echinocandin) synthesized from a fermentation product of Glarea lozoyensis. Caspofungin inhibits the synthesis of β-(1,3)-D-glucan, an essential component of the cell wall of many hyphomycetes and yeasts.

In vitro, Caspofungin is active against various pathogenic fungi of the genus Aspergillus (including Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus and Aspergillus candidus) and Candida (including Candida albicans, Candida dubliniensis, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lipolytica, Candida lusitaniae, Candida parapsilosis, Candida rugosa and Candida tropicalis).

In vivo activity of caspofungin was detected upon parenteral administration to immunocompetent and immunocompromised animals infected with Aspergillus and Candida. The use of caspofungin in these cases contributes to an increase in the lifespan of infected animals (Aspergillus and Candida) and the eradication of pathogenic fungi (Candida) in the affected organs. Caspofungin is also active in immunocompromised animals infected with Candida glabrata, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, achieving eradication of pathogenic fungi (Candida) in the affected organs. Caspofungin exhibits high activity in the prevention and treatment of pulmonary aspergillosis, as detected in studies on models of lethal pulmonary infections in vivo.

Caspofungin is active against strains of Candida fungi resistant to fluconazole, amphotericin B or flucytosine, which have a different mechanism of action. In some patients during treatment with caspofungin, varieties of Candida fungi with reduced susceptibility to caspofungin are isolated.

Pharmacokinetics

After a single intravenous infusion over 1 hour, the plasma concentration of caspofungin decreases in a multiphasic manner. Immediately after the infusion, a short alpha phase occurs, followed by a beta phase with a T_1/2 of 9 to 11 hours, which is the main characteristic of the profile and has a distinct log-linear dependence between 6 and 48 hours after the infusion. During this period, the plasma concentration of the drug decreases significantly. There is also an additional gamma phase with a T_1/2 of 40 to 50 hours. The predominant mechanism affecting plasma clearance is distribution rather than excretion or biotransformation. Caspofungin is highly bound to proteins (approximately 97%) with minimal penetration into erythrocytes. About 92% of the ³H label is detected in tissues 36-48 hours after administration of a single 70 mg dose of labeled ³H caspofungin acetate. During the first 30 hours after administration, the excretion and biotransformation of caspofungin are insignificant.

Caspofungin is slowly metabolized by hydrolysis and N-acetylation and undergoes spontaneous chemical degradation to an open-ring peptide compound. At later times (5 or more days after administration of a single dose of labeled ³H caspofungin acetate), a low level (less than 7 pmol/mg protein or 1.3% or less of the administered dose) of covalent binding of the radioactive label is noted in plasma, which may be due to the formation of two reactive intermediates of caspofungin chemical degradation. 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 their rapid renal clearance.

Approximately 75% of the dose is excreted from the body (pharmacokinetic study with radiolabeled caspofungin): 41% in urine and 34% in feces. Plasma concentrations of the label and caspofungin do not differ during the first 24-48 hours after dose administration, after which the concentration of caspofungin decreases faster, with its concentration falling below the quantitation level observed 6-8 days after dose administration, and the radioactive label after 22.3 weeks. A small amount of caspofungin is excreted unchanged in the urine (approximately 1.4% of the dose). Renal clearance of the unchanged substance is low and is approximately 0.15 ml/min.

The plasma concentration of caspofungin in healthy men and women on the 1st day after administration of a single 70 mg dose is the same. After 13 daily administrations of 50 mg, the plasma concentration of caspofungin in some women is approximately 20% higher than in men.

The plasma content of caspofungin in healthy elderly men and women (65 years and older), compared with healthy young men, is slightly increased by 28% (AUC). In elderly patients with invasive candidiasis or during empirical therapy, the same moderate changes in plasma drug concentration were observed as in the group of healthy elderly patients relative to healthy young patients. No dose adjustment is required for elderly (65 years and older) patients.

The plasma concentration of caspofungin in patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) after administration of a single 70 mg dose increases by approximately 55% (AUC) compared with healthy volunteers. Administration to these patients for 14 days (70 mg on day 1 followed by daily administration of 50 mg) is accompanied by a moderate increase in its plasma concentration and amounts to 19-25% (AUC) on day 7 and 14, compared with healthy volunteers.

Indications

Empirical therapy in patients with febrile neutropenia with suspected fungal infection, invasive candidiasis (including candidemia) in patients with and without neutropenia, invasive aspergillosis (in patients refractory to or intolerant of other therapy), esophageal candidiasis, oropharyngeal candidiasis.

ICD codes

Dosage Regimen

Administer caspofungin by intravenous infusion over approximately 1 hour once daily.

For empirical therapy in febrile neutropenia, invasive candidiasis, and invasive aspergillosis, the loading dose is 70 mg on the first day, followed by a maintenance dose of 50 mg daily.

For esophageal or oropharyngeal candidiasis, the recommended dose is 50 mg daily without a loading dose.

In patients receiving concomitant therapy with potent drug clearance inducers (e.g., rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, carbamazepine), increase the daily maintenance dose to 70 mg after the standard 70 mg loading dose.

For patients with moderate hepatic impairment (Child-Pugh score 7 to 9), reduce the maintenance dose to 35 mg daily following the standard 70 mg loading dose.

There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score greater than 9); use is not recommended.

No dosage adjustment is required for renal impairment or for elderly patients.

Reconstitute the lyophilisate with 0.9% Sodium Chloride Injection or Sterile Water for Injection.

After reconstitution, further dilute the resulting solution in 250 mL of 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, 0.225% Sodium Chloride Injection, or Lactated Ringer’s Injection for infusion.

Do not mix or co-infuse caspofungin with other medications, as compatibility data are limited.

Store the unopened vial refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light.

Adverse Reactions

From the digestive system nausea, diarrhea, vomiting, increased activity of liver enzymes (AST, ALT, ALP), increased concentration of direct and total bilirubin; impaired liver function.

From the urinary system increased serum creatinine levels.

From the hematopoietic system anemia (decreased hemoglobin and hematocrit), leukopenia, neutropenia, thrombocytopenia, eosinophilia.

From the cardiovascular system tachycardia, phlebitis, thrombophlebitis, venous post-infusion complications, facial redness, edema.

From the respiratory system shortness of breath.

From the blood coagulation system increased partial thromboplastin time and prothrombin time.

From the urinary system microhematuria, leukocyturia, proteinuria.

Dermatological reactions rash, itching, increased sweating.

Allergic reactions in some cases – rash, facial swelling, itching, feeling of heat, bronchospasm, anaphylaxis.

From metabolism hypercalcemia, hypoalbuminemia, hypoproteinemia, hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia.

From the body as a whole hyperthermia, headache, abdominal pain, feeling of chills.

Contraindications

Hypersensitivity to caspofungin.

Use in Pregnancy and Lactation

There is no clinical experience with the use of the drug during pregnancy and lactation (breastfeeding). In animals, Caspofungin crosses the placental barrier. Caspofungin should not be used during pregnancy except in cases of vital necessity.

Since there are no data on the excretion of caspofungin in breast milk, if it is necessary to use it during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in patients with moderate hepatic impairment (7 to 9 points on the Child-Pugh scale). There is no clinical experience with the use of the drug in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Pediatric Use

Not recommended for use in children and adolescents under 18 years of age.

Special Precautions

Use with caution in patients receiving cyclosporine, as well as in patients with moderate hepatic impairment (7 to 9 points on the Child-Pugh scale). There is no clinical experience with the use of the drug in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Use in pediatrics

Not recommended for use in children and adolescents under 18 years of age.

Drug Interactions

Caspofungin reduces the 12-hour blood concentration of tacrolimus by 26% (with simultaneous use, standard monitoring of tacrolimus blood concentration is recommended and, if necessary, adjustment of its dosage regimen).

With simultaneous use with cyclosporine, a transient increase in AST and ALT activity (no more than 3 times compared to the upper limit of normal), as well as an increase in the AUC of caspofungin by approximately 35% without changing the concentration of cyclosporine, is possible (if simultaneous use is necessary, the potential benefit of therapy and the possible risk should be weighed).

Rifampin can both accelerate and slow down the distribution of caspofungin.

Concomitant use of caspofungin with drug clearance inducers (efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine) may lead to a clinically significant decrease in the concentration of caspofungin. Available data indicate that the reduction in caspofungin concentration induced by these drugs occurs more due to accelerated elimination than metabolism. Therefore, when caspofungin is used concomitantly with efavirenz, nelfinavir, nevirapine, rifampin, dexamethasone, phenytoin or carbamazepine, consideration should be given to increasing the daily dose of caspofungin to 70 mg after the usual loading dose of 70 mg.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.