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.
Isavuconazole can be considered a moderate inhibitor of CYP3A4/5, and systemic exposure to medicinal products metabolised by CYP3A4 may be increased when co-administered with isavuconazole. Concomitant use of isavuconazole with CYP3A4 substrates such as the immunosuppressants tacrolimus, sirolimus or ciclosporin may increase the systemic exposure to these medicinal products. Appropriate therapeutic drug monitoring and dose adjustment may be necessary during co-administration.
Isavuconazole is an inducer of CYP2B6. Systemic exposure to medicinal products metabolised by CYP2B6 may be decreased when co-administered with isavuconazole. Therefore, caution is advised when CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such as cyclophosphamide, are co-administered with isavuconazole. The use of the CYP2B6 substrate efavirenz with isavuconazole is contraindicated because efavirenz is a moderate inducer of CYP3A4/5.
Isavuconazole may increase the exposure of medicinal products that are P-gp substrates. Dose adjustment of medicinal products that are P-gp substrates, especially medicinal products with a narrow therapeutic index such as digoxin, colchicine and dabigatran etexilate, may be needed when concomitantly administered with isavuconazole.
Isavuconazole has not been studied in 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. These patients should be carefully monitored for potential drug toxicity.
Isavuconazole is a substrate of CYP3A4 and CYP3A5. Co-administration of medicinal products which are inhibitors of CYP3A4 and/or CYP3A5 may increase the plasma concentrations of isavuconazole.
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.
No dose adjustment is warranted for moderate to mild CYP3A4/5 inhibitors.
Caution is warranted when prescribing isavuconazole to patients taking other medicinal products known to decrease the QT interval, such as rufinamide.
Elevated liver transaminases have been reported in clinical studies. The elevations in liver transaminases rarely required discontinuation of isavuconazole. Monitoring of hepatic enzymes should be considered, as clinically indicated. Hepatitis has been reported with azole antifungal agents including isavuconazole.
Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported during treatment with azole antifungal agents. If a patient develops a severe cutaneous adverse reaction, isavuconazole should be discontinued.
Caution should be used in prescribing isavuconazole to patients with hypersensitivity to other azole antifungal agents. Hypersensitivity to isavuconazole may result in adverse reactions that include: hypotension, respiratory failure, dyspnoea, drug eruption, pruritus, and rash.
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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