Chemical formula: C₂₂H₁₇F₂N₅OS Molecular mass: 437.47 g/mol
Isavuconazole interacts in the following cases:
Isavuconazole is a mild inhibitor of UGT. Co-administration of isavuconazole with medicinal products which are substrates of UGT may result in mildly increased plasma concentrations of these medicinal products.
Isavuconazole is a mild inhibitor of the organic cation transporter 2 (OCT2). Co-administration of isavuconazole with medicinal products which are substrates of OCT2 may result in increased plasma concentrations of these medicinal products.
Isavuconazole is an inhibitor in vitro of BCRP, and plasma concentrations of substrates of BCRP may therefore be increased. Caution is advised when isavuconazole is given concomitantly with substrates of BCRP.
Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone and pioglitazone, may result in mild to moderate decreases of isavuconazole plasma levels; co-administration with mild CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk.
Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of isavuconazole with medicinal products which are substrates of CYP3A4/5 may result in increased plasma concentrations of these medicinal products.
Isavuconazole is a mild CYP2B6 inducer; co-administration of isavuconazole may result in decreased plasma concentrations of CYP2B6 substrates.
Isavuconazole is a mild inhibitor of P-glycoprotein (P-gp); co-administration with isavuconazole may result in increased plasma concentrations of P-gp substrates.
Co-administration of isavuconazole with the strong CYP3A4/5 inhibitor ketoconazole is contraindicated, since this medicinal product can significantly increase plasma concentrations of isavuconazole.
For the strong CYP3A4 inhibitor lopinavir/ritonavir, a two-fold increase in isavuconazole exposure was observed. For other strong CYP3A4 inhibitors, such as clarithromycin, indinavir and saquinavir, a less pronounced effect can be expected, based on their relative potency. No dose adjustment of isavuconazole is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactions may increase.
Caution is warranted when prescribing isavuconazole to patients taking other medicinal products known to decrease the QT interval, such as rufinamide.
Population group: only children (1 year - 12 years old)
No dose recommendation can be made for paediatric patients with hepatic impairment, as no relevant data are available.
Population group: only children (1 year - 12 years old)
No dose recommendation can be made for paediatric patients with hepatic impairment, as no relevant data are available.
Population group: only adults (18 - 65 years old)
Isavuconazole has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks.
There are no data from the use of isavuconazole in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Isavuconazole must not be used during pregnancy except in patients with severe or potentially life-threatening fungal infections, in whom isavuconazole may be used if the anticipated benefits outweigh the possible risks to the foetus.
Available pharmacodynamic/toxicological data in animals have shown excretion of isavuconazole/metabolites in milk. A risk to newborns and infants cannot be excluded. Breast-feeding should be discontinued during treatment with isavuconazole.
Isavuconazole is not recommended for women of childbearing potential who are not using contraception.
There are no data on the effect of isavuconazole on human fertility. Studies in animals did not show impairment of fertility in male or female rats.
Isavuconazole has a moderate potential to influence the ability to drive and use machines. Patients should avoid driving or operating machinery if symptoms of confusional state, somnolence, syncope, and/or dizziness are experienced.
The frequency of adverse reactions shown below is based on data from 403 patients with invasive fungal infections treated with isavuconazole in phase 3 studies.
The most common treatment-related adverse reactions were elevated liver chemistry tests (7.9%), nausea (7.4%), vomiting (5.5%), dyspnoea (3.2%), abdominal pain (2.7%), diarrhoea (2.7%), injection site reaction (2.2%), headache (2.0%), hypokalaemia (1.7%) and rash (1.7%).
The adverse reactions which most often led to permanent discontinuation of isavuconazole treatment were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnoea (0.5%), epilepsy (0.5%), respiratory failure (0.5%) and vomiting (0.5%).
The following list presents adverse reactions with isavuconazole in the treatment of invasive fungal infections, by System Organ Class and frequency.
The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Summary of adverse reactions by MedDRA System Organ Class and frequency:
Uncommon: Neutropenia; Thrombocytopenia^; Pancytopenia; Leukopenia^; Anaemia^
Uncommon: Hypersensitivity^
Common: Hypokalaemia; Decreased appetite
Uncommon: Hypomagnesaemia; Hypoglycaemia; Hypoalbuminaemia; Malnutrition^
Common: Delirium^#
Uncommon: Depression; Insomnia^
Common: Headache; Somnolence
Uncommon: Convulsion^; Syncope; Dizziness; Paraesthesia^; Encephalopathy; Presyncope; Neuropathy peripheral; Dysgeusia;
Uncommon: Vertigo
Uncommon: Atrial fibrillation; Tachycardia; Bradycardia^; Palpitations Atrial flutter; Electrocardiogram QT shortened; Supraventricular tachycardia; Ventricular extrasystoles; Supraventricular extrasystoles
Common: Thrombophlebitis^
Uncommon: Circulatory collapse; Hypotension
Common: Dyspnoea;^ Acute respiratory failure^
Uncommon: Bronchospasm; Tachypnoea; Haemoptysis; Epistaxis
Common: Vomiting; Diarrhoea; Nausea; Abdominal pain^
Uncommon: Dyspepsia; Constipation; Abdominal distension
Common: Elevated liver chemistry tests^#
Uncommon: Hepatomegaly; Hepatitis
Common: Rash^; Pruritus
Uncommon: Petechiae; Alopecia; Drug eruption; Dermatitis^
Uncommon: Back pain
Common: Renal failure
Common: Chest pain^; Fatigue; Injection site reaction^
Uncommon: Oedema peripheral;^ Malaise; Asthenia
^ Indicates that grouping of appropriate preferred terms into a single medical concept occurred.
# See section Description of selected adverse reactions below
Delirium includes reactions of confusional state.
Elevated liver chemistry tests includes events of alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, hepatic function abnormal, hyperbilirubinemia, liver function test abnormal, and transaminases increased.
In a double-blind, randomized, active-controlled clinical study of 516 patients with invasive fungal disease caused by Aspergillus species or other filamentous fungi, elevated liver transaminases (alanine aminotransferase or aspartate aminotransferase) >3 × Upper Limit of Normal (ULN) were reported at the end of study treatment in 4.4% of patients who received isavuconazole. Marked elevations of liver transaminases >10 × ULN developed in 1.2% of patients on isavuconazole.
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