Cresemba^® (Capsules, Lyophilisate) Instructions for Use

ATC Code

J02AC05 (Isavuconazole)

Active Substance

Isavuconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Systemic antifungal drug

Pharmacotherapeutic Group

Antifungal drugs for systemic use, triazole derivatives

Pharmacological Action

Antifungal agent from the triazole group. The fungicidal action of isavuconazole is based on the blockade of ergosterol synthesis, the main component of the fungal cell membrane, by inhibiting the cytochrome P450-dependent enzyme lanosterol-14-alpha-demethylase, which provides the conversion of lanosterol to ergosterol.

This leads to the accumulation of methylated sterol precursors and a decrease in ergosterol content in the cell membrane, resulting in disruption of the structure and function of the fungal cell membrane.

It is effective against fungi of the genus Aspergillus: A. fumigatus, A. flavus, A. niger, A. terreus.

Pharmacokinetics

The absolute bioavailability of isavuconazole after a single oral dose is 98%. Based on pharmacokinetic data, the intravenous and oral dosage forms of isavuconazole are considered interchangeable.

Isavuconazole is actively distributed in the body, with a mean steady-state V_d of approximately 450 L. More than 99% of isavuconazole is bound to plasma proteins, predominantly albumin.

In vitro studies have shown that CYP3A4, CYP3A5, and then UGT isoenzymes are involved in the metabolism of isavuconazole, forming numerous inactive metabolites.

After oral administration of radiolabeled isavuconazonium sulfate (the prodrug of isavuconazole) to healthy volunteers, an average of 46.1% of the radiolabeled dose was found in feces, and another 45.5% of the dose was found in urine.

Renal excretion of unchanged isavuconazole was less than 1% of the administered dose.

Indications

Invasive aspergillosis; mucormycosis in patients for whom amphotericin B is not an option.

ICD codes

Dosage Regimen

Initiate treatment with a loading dose for both oral and intravenous administration routes.

Administer the loading dose as 200 mg of isavuconazole (equivalent to two 100 mg capsules or one 200 mg vial for reconstitution) every 8 hours for the first 48 hours (six doses total).

Follow the loading dose with a maintenance dose of 200 mg once daily, starting 12 to 24 hours after the last loading dose.

Administer capsules orally at least one hour before or after food. Swallow capsules whole; do not chew, crush, or dissolve.

For the intravenous formulation, reconstitute the lyophilisate and further dilute prior to infusion. Infuse over a minimum of 60 minutes.

Switch between intravenous and oral formulations as clinically appropriate; no dose adjustment is required when switching due to equivalent bioavailability.

The total duration of therapy should be based on clinical response. For invasive aspergillosis, continue treatment for a minimum of 6 to 12 weeks.

In patients with moderate hepatic impairment (Child-Pugh class B), closely monitor for signs of toxicity; no specific dose adjustment is recommended.

No dose adjustment is required for patients with renal impairment, including those with end-stage renal disease.

Do not administer to patients with hypersensitivity to isavuconazole or any excipients.

Adverse Reactions

Blood and lymphatic system disorders uncommon – neutropenia, thrombocytopenia, pancytopenia, leukopenia, anemia.

Immune system disorders uncommon – hypersensitivity.

Metabolism and nutrition disorders : common – hypokalemia, decreased appetite; uncommon – hypomagnesemia; hypoglycemia; hypoalbuminemia; malnutrition.

Psychiatric disorders common – delirium; uncommon – depression; insomnia.

Nervous system disorders common – headache; drowsiness; uncommon – seizures; syncope; dizziness; paresthesia; encephalopathy; presyncope; peripheral neuropathy; dysgeusia.

Ear and labyrinth disorders uncommon – vertigo.

Cardiac disorders: common – thrombophlebitis; uncommon – atrial fibrillation; tachycardia, bradycardia, palpitations, atrial flutter, decreased QT interval on ECG, supraventricular tachycardia; ventricular extrasystole, supraventricular extrasystole, vascular collapse, arterial hypotension.

Respiratory, thoracic and mediastinal disorders : common – dyspnea, acute respiratory failure; uncommon – bronchospasm; tachypnea, hemoptysis, epistaxis.

Gastrointestinal disorders common – vomiting, diarrhea, nausea, abdominal pain; uncommon – dyspepsia, constipation, abdominal distension.

Hepatobiliary disorders common – increased liver function biochemical parameters; uncommon – hepatomegaly, hepatitis.

Skin and subcutaneous tissue disorders common – rash, pruritus; uncommon – petechiae, alopecia, drug eruption, dermatitis.

Musculoskeletal and connective tissue disorders uncommon – back pain.

Contraindications

Hypersensitivity to isavuconazole; concomitant use of ketoconazole; concomitant use of high-dose ritonavir; concomitant use of strong inducers of CYP3A4/5, such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin, St. John’s wort extract, or moderate inducers of CYP3A4/5, such as efavirenz, nafcillin and etravirine; patients with hereditary short QT syndrome.

With caution

Patients with hypersensitivity to other antifungal drugs from the azole group; in patients taking other drugs that may shorten the QT interval, for example, rufinamide; women of childbearing potential; severe hepatic impairment (Child-Pugh class C); during the use of other drugs for which concomitant use with isavuconazole requires caution (including clarithromycin, lopinavir/ritonavir, indinavir, saquinavir; drug substrates of BCRP, substrates of CYP2B6, especially drugs with a narrow therapeutic index, such as cyclophosphamide); during the use of other drugs for which concomitant use with isavuconazole should be avoided, including prednisone, aprepitant, pioglitazone.

Use in Pregnancy and Lactation

Not recommended for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment.

Use in Renal Impairment

In renal impairment, including end-stage renal disease, dose adjustment is not required.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Dose adjustment is not required, but clinical experience is limited.

Special Precautions

Isavuconazole should be used with caution in patients with hypersensitivity to other antifungal agents from the azole group.

If infusion reactions occur, the necessity to discontinue the infusion should be considered.

If severe skin adverse reactions, such as Stevens-Johnson syndrome, occur, isavuconazole treatment should be discontinued.

Elevation of hepatic transaminases rarely requires discontinuation of treatment. Liver enzymes should be monitored as clinically indicated.

Patients with hepatic impairment should be carefully monitored for possible toxicity of isavuconazole.

Patients receiving Isavuconazole concomitantly with other medicinal products should be monitored.

Effect on ability to drive and operate machinery

Isavuconazole has a moderate influence on the ability to drive and use machines. Patients should avoid driving vehicles and operating machinery if they experience symptoms such as confusion, drowsiness, syncope, and/or dizziness.

Drug Interactions

Isavuconazole is a substrate of CYP3A4 and CYP3A5 isoenzymes. Concomitant use with drugs that are inhibitors of CYP3A4 and/or CYP3A5 may lead to an increase in plasma concentrations of isavuconazole.

Concomitant use with drugs that are inducers of CYP3A4 and/or CYP3A5 isoenzymes may lead to a decrease in plasma concentrations of isavuconazole.

Concomitant use of isavuconazole and ketoconazole, a strong inhibitor of CYP3A4/5, is contraindicated, as this drug may significantly increase plasma concentrations of isavuconazole.

When used concomitantly with the lopinavir/ritonavir combination, a potent inhibitor of CYP3A4, a twofold increase in isavuconazole exposure was observed. For other potent inhibitors of the CYP3A4 isoenzyme, such as clarithromycin, indinavir and saquinavir, a less pronounced effect can be expected based on their relative activity.

No dose adjustment of isavuconazole is required when co-administered with potent inhibitors of CYP3A4/5, but caution is recommended as an increased frequency of adverse reactions may be observed.

Concomitant use of isavuconazole and potent inducers of CYP3A4/5, such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin, St. John’s wort extract, or moderate inducers of CYP3A4/5, such as efavirenz, nafcillin and etravirine is contraindicated, as these drugs can significantly reduce plasma concentrations of isavuconazole.

Concomitant use with weak inducers of CYP3A4/5, such as aprepitant, prednisone and pioglitazone, may lead to a mild or moderate decrease in plasma concentrations of isavuconazole; concomitant use with weak inducers of CYP3A4/5 should be avoided, except when the potential benefit of such use is deemed to outweigh the risk.

Concomitant use of high-dose ritonavir (>200 mg twice daily) is contraindicated, as high-dose ritonavir may induce CYP3A4/5 and decrease plasma concentrations of isavuconazole.

Isavuconazole is a moderate inhibitor of CYP3A4/5; concomitant use of Isavuconazole with drugs that are substrates of CYP3A4/5 may increase the plasma concentrations of these drugs.

Isavuconazole is a weak inducer of CYP2B6; concomitant use with isavuconazole may lead to a decrease in plasma concentrations of CYP2B6 substrates.

Isavuconazole is a weak inhibitor of P-glycoprotein; concomitant use with isavuconazole may lead to an increase in plasma concentrations of P-glycoprotein substrates.

Isavuconazole is an inhibitor of BCRP in vitro, so plasma concentrations of BCRP substrates may increase. Caution should be exercised when isavuconazole is used concomitantly with BCRP substrates.

Isavuconazole is a weak inhibitor of organic cation transporter 2 (OCT2). Concomitant use of isavuconazole with drugs that are substrates of OCT2 may lead to an increase in plasma concentrations of these drugs.

Isavuconazole is a weak inhibitor of UGT; concomitant use of isavuconazole with drugs that are substrates of UGT may lead to a slight increase in plasma concentrations of these drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.