Isavuconazole

Isavuconazole is an Antifungal agent belonging to the pharmacological class of Triazole.

Isavuconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, invasive, Candidiasis, Mucormycosis, invasive, Prophylaxis against invasive fungal infections.

Isavuconazole's absorption characteristics were examined after oral administration of different doses. When isavuconazole is taken with or without food, there is no significant impact on its bioavailability, which remains at a high level of 98% following oral administration. The mean steady-state volume of distribution (Vss) was approximately 450 L after intravenous administration, and the drug is highly protein bound (greater than 99%), predominantly to albumin. Isavuconazole's metabolism occurs through rapid conversion of its prodrug form to isavuconazole itself, with minor metabolites identified but none contributing significantly to its effects. The primary enzymes involved in isavuconazole's metabolism are CYP3A4, CYP3A5, and uridine diphosphate-glucuronosyltransferases (UGT), as determined by in vivo and in vitro studies. The drug's elimination primarily occurs through feces (46.1% of radiolabeled isavuconazole) and urine (about 45.5% of radiolabeled isavuconazole), with less than 1% of unchanged isavuconazole excreted in the urine.

The common side effects involved in using Isavuconazole areNausea, Vomiting, Diarrhea, Headache, Rash, Increased liver enzymes (seen in blood tests), Abnormal taste sensation (dysgeusia), Fatigue, Fever, Abdominal pain, Decreased appetite, Anemia.

Isavuconazole is available in the form of Intravenous injection, Oral Capsules.

Isavuconazole is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Isavuconazole, belonging to the pharmacological class of Triazoles, acts as an Antifungal agent.

Isavuconazole exhibits a fungicidal effect by hindering the synthesis of ergosterol, a crucial element of the fungal cell membrane. This inhibition is achieved by blocking the action of the cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase, which is responsible for converting lanosterol to ergosterol. Consequently, there is an accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane, leading to the weakening of its structure and functionality.

Isavuconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, invasive, Candidiasis, Mucormycosis, invasive, Prophylaxis against invasive fungal infections.

After taking 200 mg of isavuconazole orally, the average highest amount of the drug in the bloodstream (Cmax) at a consistent level was 7499 ng/mL. When taking 600 mg orally, the Cmax was 20028 ng/mL. It usually takes 2 to 3 hours for the Cmax to be reached after taking one or more doses of isavuconazole. When taking 400 mg orally, the average amount of the drug in the bloodstream over time (AUC) was 189462.8 hng/mL, while intravenous administration resulted in a mean AUC of 193906.8 hng/mL. Eating a high-fat meal while taking oral isavuconazole decreased the Cmax by 9% but increased AUC by 9%.

Isavuconazole is found to be available in the form of Intravenous injection, Oral Capsules.

Isavuconazole can be used in the following treatment:

• Aspergillosis, invasive
• Candidiasis
• Mucormycosis, invasive
• Prophylaxis against invasive fungal infections

Isavuconazole can help to relieve symptoms and also for the treatment and maintenance of Aspergillosis, invasive, Candidiasis, Mucormycosis, invasive, Prophylaxis against invasive fungal infections.

Isavuconazole is approved for use in the following clinical indications:

• Aspergillosis, invasive
• Candidiasis
• Mucormycosis, invasive
• Prophylaxis against invasive fungal infections

Aspergillosis, invasive:

• Intravenous (IV) or Oral administration
• Initial dose: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses
• Maintenance dose: 372 mg (isavuconazole 200 mg) once daily
• Start maintenance dose 12 to 24 hours after the last loading dose.
• Duration of therapy: Minimum of 6 to 12 weeks, but duration depends on degree/duration of immunosuppression, disease site, and evidence of disease improvement.

Candidiasis:

• Esophageal, fluconazole-refractory disease (alternative agent) (off-label use)
• Oral administration
• Initial dose: 744 mg (isavuconazole 400 mg) as a single dose
• Maintenance dose: 186 mg (isavuconazole 100 mg) once daily for 14 to 28 days, or 744 mg (isavuconazole 400 mg) once weekly for 4 weeks.

Mucormycosis, invasive:

• Intravenous (IV) or Oral administration
• Initial dose: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses
• Maintenance dose: 372 mg (isavuconazole 200 mg) once daily
• Start maintenance dose 12 to 24 hours after the last loading dose.

Prophylaxis against invasive fungal infections (alternative agent) (off-label use):

• Hematology malignancy or hematopoietic cell transplant:
• IV or Oral administration
• Initial dose: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses
• Maintenance dose: 372 mg (isavuconazole 200 mg) once daily
• Duration of therapy varies based on degree and duration of immunosuppression.

Isavuconazole is available in the following dosage forms and strengths:

Intravenous (IV) Injection:

• Isavuconazonium Sulfate Lyophilized Powder for Reconstitution: The strength of the IV formulation is 372 mg of isavuconazonium sulfate, which is equivalent to 200 mg of isavuconazole (prodrug form).

Oral Capsules:

• Isavuconazole Capsules: The strength of the oral capsules is 100 mg of isavuconazole per capsule.

Intravenous injection, Oral Capsules.

Dosage Adjustments in Pediatric Patients:

• Aspergillosis, invasive:
• Adolescents ≥18 years
• Intravenous (IV) or Oral administration
• Initial (loading doses): 372 mg isavuconazonium sulfate every 8 hours for 6 doses
• Maintenance: 372 mg isavuconazonium sulfate every 24 hours (begin 12 to 24 hours after last loading dose)
• Minimum duration of treatment: 6 to 12 weeks (individualized based on factors such as immunosuppression, disease site, and improvement)
• Candidiasis, esophageal (alternative agent):
• HIV-infected Adolescents
• Oral administration
• Regimens:
• 744 mg isavuconazonium sulfate as a single dose, followed by 186 mg isavuconazonium sulfate every 24 hours
• Or 372 mg isavuconazonium sulfate as a single dose, followed by 93 mg isavuconazonium sulfate every 24 hours
• Or 744 mg isavuconazonium sulfate once weekly
• Treatment duration: 14 to 21 days
• Mucormycosis, invasive (salvage treatment):
• Adolescents ≥13 years weighing ≥40 kg (limited data available in ages <18 years)
• IV or Oral administration
• Initial (loading doses): 372 mg isavuconazonium sulfate every 8 hours for 6 doses
• Maintenance: 372 mg isavuconazonium sulfate every 24 hours (begin 12 to 24 hours after last loading dose)
• Treatment duration: Highly individualized (weeks to months or longer) based on factors such as immunosuppression, disease site, clinical resolution, and improvement on imaging studies.

When taking Isavuconazole, there are certain dietary restrictions that should be followed to ensure the medication's effectiveness and safety:

• There are no specific food warnings related to the use of isavuconazole. However, it is generally recommended to take isavuconazole with a full meal or a substantial snack to enhance its absorption. Avoiding grapefruit and grapefruit juice during isavuconazole treatment is advisable, as they may interact with the drug and affect its metabolism.

The dietary restriction should be individualized as per patient requirements.

Isavuconazole may be contraindicated under the following conditions:

• Hypersensitivity to the active substance or to any of the excipients
• Co-administration with drug such as ketoconazole, high-dose ritonavir (>200 mg every 12 hours), strong CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin, and St. John's wort or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin, and etravirine .
• Patients who havce short QT syndrome.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

Hypersensitivity Reactions

Hypersensitivity to isavuconazole may lead to adverse reactions, including anaphylactic reactions, hypotension, respiratory failure, dyspnea, drug eruption, pruritus, and rash If an anaphylactic reaction occurs, immediate discontinuation of isavuconazole is necessary, followed by appropriate medical treatment. Caution should be exercised when prescribing isavuconazole to patients with hypersensitivity to other azole antifungal agents.

Infusion-Related Reactions

During intravenous administration of isavuconazole, infusion-related reactions such as hypotension, dyspnea, dizziness, paresthesia, nausea, and headache have been reported. If any of these reactions occur, the infusion should be promptly stopped.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, have been reported during treatment with azole antifungal agents. In the event of a severe cutaneous adverse reaction, Isavuconazole treatment should be discontinued.

Cardiovascular Considerations

QT Shortening

Isavuconazole is found to be contraindicated in patients with familial short QT syndrome . In a QT study conducted with healthy human subjects, isavuconazole showed concentration-related QTc interval shortening. Caution is advised when prescribing isavuconazole to patients taking other medications known to decrease the QT interval, such as rufinamide.

Elevated Liver Transaminases or Hepatitis

Clinical studies have reported elevated liver transaminases . While these elevations rarely required discontinuation of isavuconazole, monitoring of the hepatic enzymes should be considered as clinically indicated. Hepatitis cases have been reported with azole antifungal agents, including isavuconazole.

Severe Hepatic Impairment

Isavuconazole has not found to be studied in patients with severe hepatic impairment (Child-Pugh Class C). Its use in such patients is not recommended unless the potential benefits outweigh the risks. Close monitoring for potential drug toxicity is essential in these patients.

It is advisable to avoid alcohol consumption during Isavuconazole treatment, as it may increase the risk of liver toxicity and other adverse effects.

Pharmacodynamic and toxicological data in animals indicate the excretion of isavuconazole and its metabolites in milk. There is a potential risk to newborns and infants, and therefore, breast-feeding should be stopped while undergoing treatment with Isavuconazole.

Pregnancy:

Pregnancy Category D

There is a lack of data regarding the use of Isavuconazole in pregnant women. Animal studies have demonstrated reproductive toxicity , but the potential risk for humans remains uncertain. In general, Isavuconazole should not be used during pregnancy, except in cases of severe or potentially life-threatening fungal infections where the benefits of using isavuconazole may outweigh the potential risks to the fetus.

For women of child-bearing potential, it is advised to avoid using Isavuconazole unless they are using contraception to prevent pregnancy.

There are certain food-related warnings and precautions to consider when using Isavuconazole:

• There are no specific food warnings related to the use of isavuconazole. However, it is generally recommended to take isavuconazole with a full meal or a substantial snack to enhance its absorption. Avoiding grapefruit and grapefruit juice during isavuconazole treatment is advisable, as they may interact with the drug and affect its metabolism.

The adverse reactions related to Isavuconazole can be categorized as follows:

Common:

• Nausea
• Vomiting
• Diarrhea
• Headache
• Rash
• Increased liver enzymes (seen in blood tests)
• Abnormal taste sensation (dysgeusia)
• Fatigue

Less common:

• Fever
• Abdominal pain
• Decreased appetite
• Anemia

The clinically relevant drug interactions of Isavuconazole are briefly summarized here:

Carbamazepine, phenobarbital, and phenytoin (strong CYP3A4/5 inducers):

• Isavuconazole concentrations may decrease due to the induction of CYP3A enzymes by these drugs. Therefore, the simultaneous use of isavuconazole with carbamazepine, phenytoin, and long-acting barbiturates like phenobarbital is contraindicated.

Rifampicin (strong CYP3A4/5 inducer):

• Concomitant administration of isavuconazole with rifampicin leads to a significant decrease in AUCtau by 90% and Cmax by 75% due to CYP3A4/5 induction. Therefore, the use of isavuconazole with rifampicin is contraindicated.

Rifabutin (strong CYP3A4/5 inducer):

• The effect of co-administering isavuconazole with rifabutin has not been studied. However, isavuconazole concentrations are expected to significantly decrease due to CYP3A4/5 induction. Consequently, the concurrent use of isavuconazole and rifabutin is contraindicated.

Nafcillin (moderate CYP3A4/5 inducer):

• The effect of co-administering isavuconazole with nafcillin has not been studied. However, isavuconazole concentrations are expected to significantly decrease due to CYP3A4/5 induction. Therefore, the concurrent use of isavuconazole and nafcillin is contraindicated.

Clarithromycin (strong CYP3A4/5 inhibitor):

• The effect of co-administering isavuconazole with clarithromycin has not been studied. However, isavuconazole concentrations may increase due to CYP3A4/5 inhibition. No isavuconazole dose adjustment is necessary, but caution is advised as adverse drug reactions might increase.

Ketoconazole (strong CYP3A4/5 inhibitor):

• Co-administration of isavuconazole with ketoconazole results in a significant increase in AUCtau by 422% and Cmax by 9% due to CYP3A4/5 inhibition. Therefore, the simultaneous use of isavuconazole and ketoconazole is contraindicated.

St. John's wort (strong CYP3A4/5 inducer):

• The effect of co-administering isavuconazole with St. John's wort has not been studied. However, isavuconazole concentrations are expected to significantly decrease due to CYP3A4 induction. Consequently, the concurrent use of isavuconazole and St. John's wort is contraindicated.

Prednisone

Prednisolone (CYP3A4 substrate) can be affected by co-administration with isavuconazole. Isavuconazole may lead to an increase in the exposure (AUCinf) of prednisolone (its active metabolite) by 8%, while the maximum concentration (Cmax) of prednisolone may decrease by 4% due to CYP3A4 inhibition.

On the other hand, isavuconazole is known to induce CYP3A4/5 enzymes, potentially leading to a decrease in its own concentrations.

The following are the side effects involving Isavuconazole:

• Nausea
• Vomiting
• Diarrhea
• Headache
• Rash
• Increased liver enzymes (seen in blood tests)
• Abnormal taste sensation (dysgeusia)
• Fatigue
• Fever
• Abdominal pain
• Decreased appetite
• Anemia

The use of Isavuconazole should be prudent in the following group of special populations:

Pregnancy:

Pregnancy Category D

There is a lack of data regarding the use of Isavuconazole in pregnant women. Animal studies have demonstrated reproductive toxicity , but the potential risk for humans remains uncertain. In general, Isavuconazole should not be used during pregnancy, except in cases of severe or potentially life-threatening fungal infections where the benefits of using isavuconazole may outweigh the potential risks to the fetus.

For women of child-bearing potential, it is advised to avoid using Isavuconazole unless they are using contraception to prevent pregnancy.

Pediatric:

The safety and effectiveness of Isavuconazole in pediatric patients under the age of 18 have not been determined or established.

Geriatric Use:

In the Phase 2 and 3 trials, a total of 547 patients received Isavuconazole. Among these patients, 86 (16%) were greater than 65 years of age, and 20 (4%) were greater than 75 years of age. The pharmacokinetics of isavuconazole were found to be similar in both young and elderly subjects (aged 65 years and older). Therefore, no dose adjustment of Isavuconazole is necessary for elderly patients.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Isavuconazole.

Symptoms

In a QT study evaluating supratherapeutic doses of isavuconazole (equivalent to isavuconazole 600 mg/day), certain symptoms were reported more frequently compared to the therapeutic dose group (equivalent to isavuconazole 200 mg/day). These symptoms included headache, dizziness, paraesthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoaesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia, as well as arthralgia.

Management of overdose

Isavuconazole is not effectively removed by haemodialysis, and there is no specific antidote for isavuconazole overdose. In case of an overdose, supportive treatment should be initiated.

Pharmacodynamics:

Isavuconazole demonstrates antifungal activity against a wide range of strains, including Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae as well as Mucormycetes species, both in vivo and in vitro.

In a cardiac electrophysiology study conducted with healthy subjects, isavuconazole was found to cause dose-related shortening of the QTc interval. However, the potential additive effect of isavuconazole when used with other drugs known to prolong the QTc interval remains unknown.

Pharmacokinetics:

Absorption:

● After taking 200 mg of isavuconazole by mouth, the average highest amount of the drug found in the bloodstream (known as Cmax) at a steady state was 7499 ng/mL. For 600 mg of isavuconazole, Cmax was 20028 ng/mL. It's recommended to take the drug at least 2-3 hours before reaching a steady state after a single or multiple doses of isavuconazole. Taking either 400 mg of oral or intravenous isavuconazole resulted in mean AUC (area under the curve) of 189462.8 hng/mL and 193906.8 hng/mL, respectively. Isavuconazole can be taken with or without food, but it's best to avoid high-fat meals if you're taking oral isavuconazole because it can reduce Cmax by 9% and increase AUC by 9%. Finally, when taking a single dose of isavuconazole by mouth, the drug's bioavailability is 98%.

Volume of distribution:

● The mean steady-state volume of distribution (Vss) was approximately 450 L following intravenous administration.

Protein binding:

● Isavuconazole is highly protein-bound, predominantly to albumin (greater than 99%).

Metabolism:

● Isavuconazole is rapidly converted from its prodrug form, isavuconazonium, to isavuconazole via esterase-mediated hydrolysis. Although minor metabolites were found, none of them showed an AUC greater than 10% of the total radio-labeled material. Studies conducted both in vivo and in vitro have indicated that the primary enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and uridine diphosphate-glucuronosyltransferases (UGT) in that order.

Route of elimination:

● Following oral administration, approximately 46.1% of total radiolabeled isavuconazole was detected in the feces, and about 45.5% was recovered in urine. The unchanged form of isavuconazole in the urine accounted for less than 1% of the total dose administered.

1. https://go.drugbank.com/drugs/DB11633
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3. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=97433
4. https://www.ema.europa.eu/en/documents/product-information/Isavuconazole-epar-product-information_en.pdf
5. https://www.drugs.com/monograph/isavuconazonium.html
6. https://labeling.pfizer.com/ShowLabeling.aspx?id=12203