Maxcand^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Manufactured By

Gland Pharma, Limited (India)

ATC Code

J02AX04 (Caspofungin)

Active Substance

Caspofungin (Rec.INN registered by WHO)

Dosage Forms

	Maxcand®	Lyophilisate for preparation of concentrate for solution for infusion 50 mg: vial 1 pc.
		Lyophilisate for preparation of concentrate for solution for infusion 70 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of concentrate for solution for infusion white in color, in the form of a lyophilisate or lyophilized mass; reconstituted solution is clear, colorless.

Excipients : mannitol – 26 mg, sucrose – 39 mg, glacial acetic acid – 2 mg, sodium hydroxide – q.s. for pH adjustment*, glacial acetic acid – q.s. for pH adjustment*.

* target pH range 5.8-6.2

Colorless glass vials (type I) (1) – cardboard packs.

Lyophilisate for preparation of concentrate for solution for infusion white in color, in the form of a lyophilisate or lyophilized mass; reconstituted solution is clear, colorless.

Excipients : mannitol – 36 mg, sucrose – 54 mg, glacial acetic acid – 2.7 mg, sodium hydroxide – q.s. for pH adjustment*, glacial acetic acid – q.s. for pH adjustment*.

* target pH range 5.8-6.2

Colorless glass vials (type I) (1) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

Antifungal agent for systemic use. It is a semi-synthetic 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 eradication of pathogenic fungi (Candida) in 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 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 protein-bound (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, 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 eliminated 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 day 1 after 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 to healthy young men, is slightly increased by 28% (AUC). In elderly patients with invasive candidiasis or undergoing 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 a single 70 mg dose increases by approximately 55% (AUC), compared to 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 to 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 as a single daily intravenous infusion over approximately 1 hour.

For empirical therapy and invasive candidiasis, use a 70 mg loading dose on day 1, followed by a 50 mg maintenance dose daily.

For invasive aspergillosis and esophageal/oropharyngeal candidiasis, use a 70 mg loading dose on day 1, followed by a 50 mg maintenance dose daily.

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

Reconstitute the 50 mg or 70 mg vial with 10.5 ml of 0.9% Sodium Chloride Injection, Sterile Water for Injection, or Bacteriostatic Water for Injection with methylparaben and propylparaben. Gently mix until clear.

Dilute the reconstituted solution in 250 ml of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringer’s Injection. Do not use diluents containing dextrose.

Do not mix or co-infuse with other medications. Complete infusion within 24 hours when stored at controlled room temperature, or within 48 hours if refrigerated.

When co-administered with potent drug clearance inducers (e.g., rifampin, efavirenz, carbamazepine, dexamethasone, phenytoin), increase the daily maintenance dose to 70 mg after the standard 70 mg loading dose.

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 level.

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 dyspnea.

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, 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 inducers of drug clearance (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 rather 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.