isavuconazonium sulfate

Action and Spectrum

Actions and spectrum: 

isavuconazonium sulfate is an antifungal medication that belongs to the triazole class. It is used to treat invasive aspergillosis and invasive mucormycosis, which are serious fungal infections. It acts by inhibiting synthesis of ergosterol, leading to cell death and fungal growth inhibition.

The spectrum of isavuconazonium sulfate includes some specific fungal pathogens, particularly those causing invasive fungal infections in immunocompromised patients. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Vomiting (24.9%) 

Hypokalemia (19.1%) 

Dyspnea (17.1%) 

Headache (16.7%) 

Constipation (14%) 

Insomnia (10.5%) 

Renal failure (10.1%) 

Nausea (27.6%) 

Diarrhea (23.7%) 

Elevated liver tests (17.1%) 

Abdominal pain (16.7%) 

Peripheral edema (15.2%) 

Fatigue (10.5%) 

Back pain (10.1%)  

1-10% 

Decreased appetite (8.6%) 

Rash (8.6%) 

Hypotension (8.2%) 

Acute respiratory failure (7.4%) 

Dyspepsia (6.2%) 

Chest pain (8.9%) 

Delirium (8.6%) 

Pruritus (8.2%) 

Anxiety (8.2%) 

reaction at Injection site (6.2%) 

Hypomagnesemia (5.4%) 

Cardiac disorders: atrial flutter, reduced QT interval, palpitations, supraventricular tachycardia, cardiac arrest, Atrial fibrillation, bradycardia, supraventricular extrasystoles, ventricular extrasystoles (<5%) 

Psychiatric disorders: hallucination, Confusion, depression (<5%) 

Respiratory, mediastinal, and thoracic disorders: tachypnea, Bronchospasm (<5%) 

Nervous system disorders: dysgeusia, hypoesthesia, peripheral neuropathy, somnolence, syncope, Convulsion, encephalopathy, migraine, paraesthesia, stupor (<5%) 

Urinary and Renal disorders: proteinuria, Hematuria (<5%) 

Black Box Warning

Black Box Warning: 

There were no black box warnings specifically associated with isavuconazonium sulfate 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: isavuconazonium sulfate is contraindicated in patients with a history of hypersensitivity to isavuconazonium sulfate or any of its components. 
• Concomitant Use with CYP3A4 Inducers: The coadministration of isavuconazonium sulfate with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s wort) is contraindicated due to the potential for decreased isavuconazole plasma concentrations. 
• Concomitant Use with Certain Drugs: isavuconazonium sulfate is contraindicated with the use of the following drugs, as coadministration may lead to significant interactions: Sirolimus, Ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine), Long-acting barbiturates (e.g., phenobarbital) 
• Concomitant Use with Pimozide: isavuconazonium sulfate is contraindicated with the use of pimozide due to the potential for serious cardiac events. 
• Concomitant Use with Quinidine: isavuconazonium sulfate is contraindicated with the use of quinidine due to the potential for serious cardiac events. 

Caution: 

• Cardiovascular Effects: isavuconazonium sulfate may prolong the QT interval, leading to potential cardiac arrhythmias. Caution is advised in patients with pre-existing QT prolongation, history of torsades de pointes, or those taking medications that prolong QT interval. 
• Electrolyte Abnormalities: isavuconazonium sulfate can cause electrolyte disturbances, including hypokalemia and hypomagnesemia. Patients with a history of electrolyte abnormalities should be closely monitored. 
• Allergic Reactions: Hypersensitivity reactions, including serious skin reactions, have been reported with isavuconazonium sulfate. Patients should be monitored for allergic reactions, and treatment should be discontinued if such reactions occur. 
• Drug Interactions: isavuconazonium sulfate can interact with various medications, including strong CYP3A4 inhibitors and inducers, leading to altered plasma concentrations. Careful monitoring and dosage adjustments may be necessary when coadministering with other drugs. 
• Immunosuppressed Patients: isavuconazonium sulfate is not recommended for the treatment of fungal infections with severe immunosuppression, including those with hematopoietic stem cell or solid organ transplantation. 
• Hypersensitivity to Other Azole Antifungals: Caution should be exercised in patients with a history of hypersensitivity to other azole antifungals, as cross-reactivity may occur.

Comorbidities: 

• Liver Dysfunction: Patients with liver dysfunction or pre-existing liver diseases may have an increased risk of adverse effects with isavuconazonium sulfate. Close monitoring of liver function is essential in these patients. 
• Renal Impairment: Individuals with renal impairment may experience altered drug clearance, leading to changes in isavuconazonium sulfate’s pharmacokinetics. Dosage adjustments may be required in patients with renal dysfunction. 
• Electrolyte Abnormalities: Patients with pre-existing electrolyte imbalances, such as hypokalemia or hypomagnesemia, may be more susceptible to adverse effects of isavuconazonium sulfate. Regular monitoring of electrolyte levels is advised. 
• Immunosuppression: isavuconazonium sulfate is used to treat invasive fungal infections in immunocompromised patients. However, individuals with severe immunosuppression may have reduced treatment efficacy, and alternative antifungal therapies may be considered. 
• Allergic Conditions: Patients with a history of severe allergic reactions or hypersensitivity to other azole antifungals may be at an increased risk of developing hypersensitivity reactions with isavuconazonium sulfate. 
• Pregnancy: isavuconazonium sulfate is not recommended during pregnancy due to potential risks to the fetus. Pregnant patients with invasive fungal infections should be carefully managed by healthcare providers to balance the risks and benefits of treatment. 
• Breastfeeding: Breastfeeding is not recommended during treatment with isavuconazonium sulfate, as it is unclear if the drug is excreted in human milk. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: Not assigned. 

Lactation: Excreted into human milk: Unknown  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

isavuconazonium sulfate is an antifungal agent that belongs to the triazole class. It exhibits its activity by inhibiting the enzyme lanosterol 14-alpha demethylase, which is essential for the synthesis of ergosterol, a crucial component of fungal cell membranes. The inhibition of this enzyme disrupts the integrity of the fungal cell membrane, leading to cell death. 

isavuconazonium sulfate exhibits broad-spectrum activity against various fungi, including yeasts (e.g., Candida species) and molds (e.g., Aspergillus species). It is particularly effective against invasive fungal infections caused by these pathogens.  

Pharmacodynamics: 

• Antifungal Activity: isavuconazonium sulfate demonstrates potent antifungal activity against a broad spectrum of fungal pathogens like yeasts and molds. It primarily targets the cytochrome P450 enzyme lanosterol 14-alpha demethylase for the conversion of lanosterol to ergosterol in the fungal cell membrane. Inhibition of this enzyme disrupts the membrane integrity, leading to increased permeability and leakage of intracellular contents, ultimately causing fungal cell death. 
• Time- and Dose-Dependent Activity: The antifungal activity of isavuconazonium sulfate is time- and dose-dependent. It exhibits concentration-dependent killing, meaning that higher drug concentrations achieve more rapid and profound fungal eradication. 
• Spectrum of Fungi: isavuconazonium sulfate is effective against a wide range of fungi, including Candida species (e.g., Candida albicans, Candida glabrata) and Aspergillus species (e.g., Aspergillus fumigatus, Aspergillus terreus). It is also active against less common molds, such as mucormycetes (e.g., Rhizopus, Mucor) and certain dematiaceous fungi. 
• Synergy with Other Antifungals: isavuconazonium sulfate may exhibit synergistic effects when combined with other antifungal agents, particularly echinocandins or amphotericin B, against certain fungal infections. Combination therapy may enhance overall efficacy and reduce the risk of resistance. 
• Post-Antifungal Effect: isavuconazonium sulfate possesses a prolonged post-antifungal effect, meaning that even after the drug has been removed from the system, its antifungal activity continues to exert an effect on fungal growth. 

Pharmacokinetics: 

Absorption 

isavuconazonium sulfate is administered as a prodrug and is rapidly hydrolyzed to its active form, isavuconazole, in the systemic circulation. Following oral administration, isavuconazonium sulfate is well-absorbed, with peak plasma concentrations achieved within 2 to 4 hours. 

Distribution 

Isavuconazole has a moderate volume of distribution and can penetrate into various tissues, including lung, liver, kidney, and brain. 

Metabolism 

Isavuconazole undergoes extensive hepatic metabolism via cytochrome P450 enzymes, CYP3A4, to form inactive metabolites. 

Elimination and excretion 

Isavuconazole and its metabolites are excreted primarily in the feces, with a smaller portion excreted in the urine. 

Adminstartion

Administration: 

isavuconazonium sulfate is available as a prodrug for intravenous (IV) administration, and it is converted to its active form, isavuconazole, in the body. Here are the key points regarding the administration of isavuconazonium sulfate: 

• Route of Administration: isavuconazonium sulfate is administered only through the intravenous (IV) route. It is not available for oral administration. 
• Dosage: The dosage of isavuconazonium sulfate is based on the patient’s weight and the indication for treatment. The healthcare provider will determine the appropriate dosage and schedule based on the patient’s condition and response to therapy. 
• Infusion Time: The drug is usually administered as an IV infusion over a specific duration, typically over one to three hours. The infusion time may vary depending on the dose and the patient’s individual characteristics. 
• Inpatient Setting: isavuconazonium sulfate is primarily used in the hospital or clinical setting, as it requires careful monitoring and adjustment by healthcare professionals during administration. 
• Duration of Treatment: It depends on the type and severity of the fungal infection being treated. Treatment may continue for several days to weeks, as determined by the healthcare provider. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: isavuconazonium sulfate 

Pronounced: (eye-sa-vyoo-koh-nuh-zoh-nee-uhm sul-fate)  

Why do we use isavuconazonium sulfate? 

isavuconazonium sulfate is an antifungal medication used for the treatment of invasive mucormycosis and invasive aspergillosis, which are serious fungal infections that can affect individuals with weakened immune systems or other underlying health conditions. These infections can be life-threatening and difficult to treat with standard antifungal agents. 

isavuconazonium sulfate is indicated for use in patients who have failed other antifungal therapies. It belongs to the azole class of antifungal drugs and works by inhibiting the ergosterol synthesis, a key component of fungal cell membrane, leading to disruption of the cell membrane and eventual fungal cell death.