Iloverum (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pharmsintez OJSC (Russia)

Manufactured By

Pharmasintez, JSC (Russia)

ATC Code

J02AX06 (Anidulafungin)

Active Substance

Anidulafungin (Rec.INN registered by WHO)

Dosage Form

Iloverum

Lyophilizate for the preparation of solution for infusion 100 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of concentrate for the preparation of solution for infusion white or almost white.

Excipients: fructose, mannitol, polysorbate 80, tartaric acid, hydrochloric acid solution 1M or sodium hydroxide solution 1M.

100 mg – vials of transparent colorless glass (1) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Systemic antifungal agents; other systemic antifungal agents

Pharmacological Action

Antifungal agent, a semisynthetic echinocandin, a lipopeptide synthesized by fermentation of Aspergillus nidulans products. Anidulafungin selectively inhibits 1,3-β-D-glucan synthase – an important fungal cell enzyme that is absent in mammalian cells. This leads to disruption of the formation of 1,3-β-D-glucan, the main component of the fungal cell wall. Anidulafungin has fungicidal activity against various species of fungi of the genus Candida and activity in areas of active growth of Aspergillus fumigatus hyphae cells.

Anidulafungin is active in vitro against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis.

In in vivo studies with parenteral administration, Anidulafungin showed efficacy against Candida spp. fungi, as shown in models of immunocompetent and immunocompromised mice and rabbits. Anidulafungin increased survival in animals and also reduced the organ burden of Candida fungi when determined 24-96 hours after the last administration.

Pharmacokinetics

The pharmacokinetics of anidulafungin has been described in healthy volunteers, in special subgroups and in patients treated with anidulafungin. At the same time, low interindividual variability in the systemic exposure of the drug was observed (the coefficient of variation was about 25%). C_ss is rapidly achieved after using a loading dose (double maintenance dose).

T_1/2 is 0.5-1 h, V_d is 30-50 l, which is close to the total volume of fluid in the body. Anidulafungin is largely (>99%) bound to human plasma proteins.

At physiological levels of temperature and pH, Anidulafungin undergoes slow chemical degradation to an open-ring peptide compound that has no antifungal activity. Under in vitro conditions, the T_1/2 of anidulafungin under physiological conditions is approximately 24 h. Under in vivo conditions, the open-ring compound is eventually converted into peptide degradation products and is eliminated from the body mainly through biliary excretion.

The clearance of anidulafungin is about 1 l/h. In the main phase, the T_1/2 of anidulafungin is about 24 h, which corresponds to most of the AUC profile, and the terminal T_1/2 is 40-50 h.

In a clinical study using a single dose of radioactively labeled (¹⁴C) Anidulafungin (about 88 mg) was administered to healthy individuals. Approximately 30% of the administered radioactive dose was excreted in the feces after more than 9 days, of which less than 10% was unchanged. Less than 1% of the administered dose of the radioactive drug was excreted in the urine, indicating insignificant renal clearance. After 6 days of administration, the concentration of anidulafungin decreased to values below the lower limit of quantification. After 8 weeks after administration of the drug, insignificant amounts of radioactive compounds were detected in the blood, urine and feces.

Anidulafungin has linear pharmacokinetics over a wide dose range (15-130 mg) when the drug is used once/day.

The pharmacokinetics of anidulafungin in patients with fungal infections is similar to that in healthy individuals, based on the results of population pharmacokinetic analyses. When using the drug at a daily dose of 200/100 mg and at an infusion rate of 1.1 mg/min, C_ss and C_min can be approximately 7 and 3 mg/l, respectively, with an average steady-state AUC of about 110 mg×h/l.

Changes in pharmacokinetics that occurred in connection with body weight had minor clinical manifestations.

Plasma concentrations of anidulafungin in healthy men and women were similar. In studies of the use of anidulafungin in multiple doses, it was shown that the clearance of anidulafungin was higher in male patients.

Population pharmacokinetic analysis showed that the mean clearance value differed in the group of elderly patients (≥65 years; mean clearance was 1.07 l/h) from the group of younger patients (<65 years; mean value was 1.22 l/h). However, the range of clearance values in these groups was similar.

In patients with hepatic insufficiency class C according to the Child-Pugh classification, a slight decrease in AUC was observed; this decrease was within the range of anidulafungin AUC levels in healthy individuals.

Renal clearance of anidulafungin is <1%.

Indications

Invasive candidiasis in adults without neutropenia.

ICD codes

Dosage Regimen

Before starting therapy, samples should be taken to determine the type of fungus. Therapy can be started before receiving the results of the study of these samples and after receiving the results, adjusted accordingly.

Administered intravenously by drip. Should not be used as a bolus injection.

Treatment begins with a single loading dose on the 1st day – 200 mg followed by administration of a dose of 100 mg daily.

The duration of treatment depends on the patient’s clinical response to therapy. Antifungal therapy is carried out for at least 14 days after receiving laboratory results confirming the absence of the pathogen.

Adverse Reactions

From the blood coagulation system often – coagulopathy.

From the digestive system: often – hypokalemia; rarely – hyperglycemia.

From the nervous system often – convulsions, headache.

From the cardiovascular system often – hot flashes; rarely – arterial hypertension, facial redness; frequency unknown – arterial hypotension.

From the respiratory system frequency unknown – bronchospasm, dyspnea.

From the digestive system often – diarrhea, vomiting, nausea; rarely – pain in the upper abdomen.

From the hepatobiliary system often – increased ALT, ALP, AST, bilirubin in the blood, GGT; rarely – cholestasis.

From the skin often – rash, itching.

Allergic reactions rarely – urticaria.

From the urinary system often – increased serum creatinine.

Contraindications

Hypersensitivity to anidulafungin and other drugs of the echinocandin class.

Use in Pregnancy and Lactation

Anidulafungin should not be used during pregnancy.

It is not known whether Anidulafungin is excreted in human breast milk. If it is necessary to use anidulafungin during lactation, breastfeeding should be discontinued.

In experimental studies in animals, it has been shown that Anidulafungin is excreted in breast milk.

Special Precautions

The clinical efficacy of anidulafungin has been studied mainly in patients with infections caused by Candida albicans, without neutropenia. The clinical efficacy of the drug in persons with endocarditis, osteomyelitis or meningitis caused by Candida fungi and in patients with an established infection caused by Candida krusei has not been studied.

Patients who experience an increase in liver enzyme activity during treatment with anidulafungin require monitoring for timely detection of signs of worsening liver function and for assessing the risk/benefit ratio of continuing therapy with anidulafungin.

An increase in reactions associated with infusion administration has been noted with simultaneous use with anesthetics. Caution is required when using anidulafungin and anesthetic agents together.

Use in pediatrics

Anidulafungin should not be used in children.

Drug Interactions

Anidulafungin is not an inducer or inhibitor of cytochrome P450 isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A). It should be noted that in vitro studies do not exclude possible interaction under in vivo conditions.

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.