Adult: 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole. Doses are expressed in terms of isavuconazole. Loading dose: 200 mg 8 hourly for the 1st 48 hours (total of 6 doses). Maintenance: 200 mg once daily, starting 12-24 hours following the last loading dose. Doses are given via infusion over at least 1 hour. Duration of treatment must be determined according to clinical response. Review the benefit-risk balance for long-term therapy beyond 6 months. Consider local treatment guidelines on the appropriate use of antifungals.
Intravenous Mucormycosis
Adult: In patients for whom amphotericin B is inappropriate: 372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole. Doses are expressed in terms of isavuconazole. Loading dose: 200 mg 8 hourly for the 1st 48 hours (total of 6 doses). Maintenance: 200 mg once daily, starting 12-24 hours following the last loading dose. Doses are given via infusion over at least 1 hour. Duration of treatment must be determined according to clinical response. Review the benefit-risk balance for long-term therapy beyond 6 months. Consider local treatment guidelines on the appropriate use of antifungals.
Oral Invasive aspergillosis
Adult: 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole. Doses are expressed in terms of isavuconazole. Loading dose: 200 mg 8 hourly for the 1st 48 hours (total of 6 doses). Maintenance: 200 mg once daily, starting 12-24 hours following the last loading dose. Duration of treatment must be determined according to clinical response. Review the benefit-risk balance for long-term therapy beyond 6 months. Consider local treatment guidelines on the appropriate use of antifungals.
Oral Mucormycosis
Adult: In patients for whom amphotericin B is inappropriate: 186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole. Doses are expressed in terms of isavuconazole. Loading dose: 200 mg 8 hourly for the 1st 48 hours (total of 6 doses). Maintenance: 200 mg once daily, starting 12-24 hours following the last loading dose. Duration of treatment must be determined according to clinical response. Review the benefit-risk balance for long-term therapy beyond 6 months. Consider local treatment guidelines on the appropriate use of antifungals.
Administration
cap: May be taken with or without food. Swallow whole, do not chew/crush/dissolve/open cap.
Reconstitution
IV infusion: Reconstitute vial labelled as 200 mg isavuconazole with 5 mL sterile water for inj. Further dilute the reconstituted solution by removing 5 mL from the vial and adding it to an infusion bag containing at least 250 mL of either 0.9% NaCl solution or 5% dextrose solution, to make a final concentration of approx 0.8 mg/mL isavuconazole. Mix gently or roll the bag to minimise particulate formation. Avoid unnecessary vibration or vigorous shaking of the solution.
Contraindications
Hypersensitivity to isavuconazole or isavuconazonium sulfate. Familial short QT syndrome. Lactation. Concomitant use with ketoconazole, high-dose ritonavir (>200 mg 12 hourly), strong CYP3A4/5 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort), or moderate CYP3A4/5 inducers (e.g. efavirenz, nafcillin).
Special Precautions
Patient with hypersensitivity to other azole antifungal agents; serious underlying medical conditions (e.g. haematologic malignancy). Patient taking other agents known to decrease QT interval (e.g. rufinamide). Severe hepatic impairment (Child-Pugh class C). Pregnancy.
Adverse Reactions
Significant: Serious hypersensitivity (e.g. anaphylaxis) and severe cutaneous reactions (e.g. Stevens-Johnson syndrome), shortened QTc interval (dose-related), hepatic effects (e.g. hepatitis, cholestasis), infusion-related reactions (e.g. chills, dizziness, hypotension, paraesthesia, hypoaesthesia). Cardiac disorders: Chest pain. Gastrointestinal disorders: Vomiting, diarrhoea, abdominal pain, nausea, constipation, dyspepsia. General disorders and administration site conditions: Fatigue, peripheral oedema; inj site reaction. Investigations: Increased AST, ALT, alkaline phosphatase, and total bilirubin. Metabolism and nutrition disorders: Hypokalaemia, decreased appetite, hypomagnesaemia. Musculoskeletal and connective tissue disorders: Back pain. Nervous system disorders: Somnolence, headache. Psychiatric disorders: Delirium including confusional state; insomnia. Renal and urinary disorders: Renal failure. Respiratory, thoracic and mediastinal disorders: Dyspnoea, acute respiratory failure, cough. Skin and subcutaneous tissue disorders: Rash, pruritus. Vascular disorders: Thrombophlebitis. Potentially Fatal: Hepatic failure (in patients with serious underlying medical conditions).
Patient Counseling Information
This drug may cause dizziness, somnolence, confusion, or syncope; if affected, do not drive or operate machinery.
Monitoring Parameters
Confirm pregnancy status prior to use in women of reproductive potential. Monitor LFTs (e.g. alkaline phosphatase, AST, ALT, total bilirubin) at baseline and periodically during treatment. Assess for signs or symptoms of hypersensitivity reactions during treatment initiation; infusion-related reactions during IV administration; hepatitis, cholestasis or hepatic failure (particularly in patients with other comorbidities).
Overdosage
Symptoms: Dizziness, headache, somnolence, paraesthesia, anxiety, disturbance in attention, restlessness, dry mouth, dysgeusia, oral hypoaesthesia, vomiting, diarrhoea, hot flush, arthralgia, photophobia, palpitations, and tachycardia. Management: Supportive treatment.
Drug Interactions
Significantly increased exposure with lopinavir/ritonavir. May cause mild to moderate decreases of isavuconazole plasma concentrations with mild CYP3A4/5 inducers (e.g. aprepitant, prednisone, pioglitazone). May reduce QT interval with rufinamide. May increase the exposure and plasma levels of CYP3A4/5 substrates (e.g. tacrolimus, sirolimus, ciclosporin), P-glycoprotein substrates (e.g. digoxin, colchicine, dabigatran etexilate, vinca alkaloids), breast cancer resistance protein (BCRP) substrates (e.g. daunorubicin, doxorubicin, irinotecan, lapatinib), and organic cation transporter 2 (OCT2) substrates (e.g. metformin). May mildly elevate plasma concentrations of UGT substrates (e.g. mycophenolate mofetil). May decrease the exposure and plasma levels of CYP2B6 substrates (e.g. cyclophosphamide, bupropion). Potentially Fatal: Significantly increased isavuconazole plasma concentrations with ketoconazole (a strong CYP3A4/5 inhibitor). High-dose ritonavir (>200 mg 12 hourly) may induce CYP3A4/5 or inhibit CYP3A4 isoenzyme resulting in decreased or increased isavuconazole plasma concentrations, respectively. Strong CYP3A4/5 inducers (e.g. rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin) or moderate CYP3A4/5 inducers (e.g. efavirenz, nafcillin, etravirine) may significantly decrease plasma concentrations of isavuconazole.
Food Interaction
Avoid use with St. John’s wort as it may significantly decrease the plasma concentrations of isavuconazole.
Action
Description: Isavuconazole is the active moiety of the prodrug isavuconazonium sulfate. It blocks the synthesis of ergosterol (the key component of the fungal cell membrane) by inhibiting the CYP450-dependent enzyme lanosterol 14-α-demethylase, thus leading to the accumulation of methylated sterol precursors and depletion of ergosterol within the fungal cell membrane. This action weakens the function and structure of the fungal cell membrane. Pharmacokinetics: Absorption: Bioavailability: 98% (oral). Time to peak plasma concentrations: Approx 2-3 hours (oral). Distribution: Extensively distributed in the body. Plasma protein binding: >99%, mainly to albumin. Metabolism: Isavuconazonium sulfate is rapidly metabolised via hydrolysis in the blood by esterases into isavuconazole (active form) and inactive cleavage product. CYP3A4, CYP3A5 and consequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole. Excretion: Via faeces (33% as unchanged isavuconazole); urine (<1% as unchanged isavuconazole). Elimination half-life: 130 hours (IV).
Chemical Structure
Isavuconazole Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 6918485, Isavuconazole. https://pubchem.ncbi.nlm.nih.gov/compound/Isavuconazole. Accessed Apr. 28, 2021.
Storage
Cap: Store between 15-30°C. Protect from moisture. IV: Store intact vials between 2-8°C. Reconstituted solution: Use solution immediately, or store below 25°C for a max of 1 hour before preparation of admixed solution in 0.9% NaCl or 5% dextrose. Diluted solution for infusion: Store between 2-8°C for 24 hours or between 20-25°C for up to 6 hours prior to use. Do not freeze.
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