Isavuconazole

Usage

Isavuconazole is prescribed for the treatment of invasive aspergillosis and invasive mucormycosis, particularly in patients for whom amphotericin B is inappropriate. It is classified as a triazole antifungal agent. Its mechanism of action involves inhibiting the synthesis of ergosterol, a crucial component of the fungal cell membrane, leading to fungal cell death.

Alternate Names

Isavuconazole is also known as isavuconazonium sulfate (the prodrug form). Cresemba is the prominent brand name under which this medication is marketed.

How It Works

Pharmacodynamics: Isavuconazole exerts its antifungal effect by inhibiting lanosterol 14α-demethylase, a key enzyme in fungal ergosterol biosynthesis. This inhibition disrupts the fungal cell membrane integrity, leading to cell death.

Pharmacokinetics:

• Absorption: Isavuconazole exhibits high oral bioavailability (98%), allowing for interchangeable use between intravenous and oral administration when clinically indicated. Absorption is minimally affected by food.
• Metabolism: Isavuconazole is primarily metabolized in the liver by CYP3A4 and CYP3A5 enzymes.
• Elimination: Isavuconazole is predominantly eliminated via hepatic metabolism, with minimal renal excretion. Thus, no dose adjustment is necessary in patients with renal impairment.

Mode of Action: Isavuconazole inhibits the fungal cytochrome P450 enzyme lanosterol 14α-demethylase, thereby blocking ergosterol synthesis. Ergosterol is an essential component of the fungal cell membrane. This disruption compromises the structural and functional integrity of the fungal cell membrane, ultimately resulting in fungal cell death.

Dosage

Standard Dosage

Adults:

The recommended loading dose is 200 mg (equivalent to 372 mg isavuconazonium sulfate) every 8 hours for 48 hours (6 doses total), administered either intravenously or orally. Following the loading dose, the maintenance dose is 200 mg once daily.

Children (≥1 year):

• IV:

  • 1 to <3 years (<18 kg): Loading dose: 15 mg/kg IV every 8 hours x 6 doses (48 hours). Maintenance: 15 mg/kg IV daily.
  • 3 to <18 years (<37 kg): Loading dose: 10 mg/kg IV every 8 hours x 6 doses (48 hours). Maintenance: 10 mg/kg IV daily.
  • 3 to <18 years (≥37 kg): Loading dose: 372 mg IV every 8 hours x 6 doses (48 hours). Maintenance: 372 mg IV daily.

• Oral (≥6 years):

  • 16 to <18 kg: Loading dose: 149 mg PO every 8 hours x 6 doses (48 hours). Maintenance: 149 mg PO daily.
  • 18 to <25 kg: Loading dose: 223.5 mg PO every 8 hours x 6 doses (48 hours). Maintenance: 223.5 mg PO daily.
  • 25 to <32 kg: Loading dose: 298 mg PO every 8 hours x 6 doses (48 hours). Maintenance: 298 mg PO daily.
  • ≥32 kg: Loading dose: 372 mg PO every 8 hours x 6 doses (48 hours). Maintenance: 372 mg PO daily.

Special Cases:

• Elderly Patients: No dose adjustment is typically necessary. However, clinical experience in this population is limited.
• Patients with Renal Impairment: No dose adjustment required.
• Patients with Hepatic Dysfunction (Mild to Moderate): No dose adjustment required. Severe hepatic impairment: Not studied, use with caution if benefits outweigh risks.
• Patients with Comorbid Conditions: Dose adjustments may be necessary based on specific comorbidities and concomitant medications.

Clinical Use Cases:

Dosage remains consistent across various clinical settings, including intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations. The standard loading and maintenance doses apply, with adjustments as needed based on individual patient factors such as hepatic or renal function and concomitant medications.

Dosage Adjustments:

Dose modification may be necessary based on drug interactions, especially with strong CYP3A4 inhibitors or inducers. Therapeutic drug monitoring (TDM) can be useful to guide dosing and ensure optimal plasma concentrations.

Side Effects

Common Side Effects:

Nausea, vomiting, diarrhea, headache, elevated liver enzymes, hypokalemia, constipation, dyspnea, and cough.

Rare but Serious Side Effects:

Hepatotoxicity (including hepatitis and hepatic failure), Stevens-Johnson syndrome, severe skin reactions, QT interval shortening, and anaphylaxis.

Long-Term Effects:

Potential for chronic liver damage with prolonged use.

Adverse Drug Reactions (ADR):

Anaphylaxis, hepatotoxicity, Stevens-Johnson Syndrome, and QT prolongation.

Contraindications

• Hypersensitivity to isavuconazole or other azole antifungals.
• Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) or strong CYP3A4 inducers (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, St. John’s wort).
• Familial short QT syndrome.

Drug Interactions

Isavuconazole is metabolized by CYP3A4/5 and can interact with numerous medications:

• CYP3A4/5 Inhibitors: Co-administration can increase isavuconazole concentrations.
• CYP3A4/5 Inducers: Co-administration can decrease isavuconazole concentrations.
• QT Prolonging Drugs: Use with caution.
• Consult a comprehensive drug interaction resource before co-prescribing.

Pregnancy and Breastfeeding

• Pregnancy: Isavuconazole is classified as Pregnancy Category D. It should not be used during pregnancy unless the potential benefit outweighs the risk to the fetus. Animal studies have shown evidence of teratogenicity.
• Breastfeeding: Isavuconazole is excreted in breast milk and may cause harm to the nursing infant. Breastfeeding is not recommended during treatment.

Drug Profile Summary

• Mechanism of Action: Inhibits fungal ergosterol synthesis by blocking lanosterol 14α-demethylase.
• Side Effects: Nausea, vomiting, diarrhea, headache, elevated liver enzymes, hypokalemia. Serious side effects: hepatotoxicity, Stevens-Johnson syndrome, QT shortening.
• Contraindications: Hypersensitivity, strong CYP3A4 inhibitors/inducers, familial short QT syndrome.
• Drug Interactions: Numerous, particularly with CYP3A4/5 substrates, inhibitors, and inducers.
• Pregnancy & Breastfeeding: Category D; not recommended.
• Dosage: Loading dose: 200 mg every 8 hours for 48 hours; Maintenance dose: 200 mg daily.
• Monitoring Parameters: Liver function tests, serum creatinine, potassium levels, QT interval, drug levels (if TDM is employed).

Popular Combinations

Information on commonly used drug combinations with isavuconazole is limited. It is crucial to consult specialized literature or guidelines for recommendations in specific clinical scenarios. Always consider potential drug interactions when combining medications.

Precautions

• Monitor liver function, renal function, and electrolyte levels.
• Observe for hypersensitivity reactions.
• Patients with familial short QT syndrome should not receive isavuconazole.
• Assess for potential drug interactions.
• Caution during pregnancy and breastfeeding.
• For patients with severe liver dysfunction, assess potential benefit against risks.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Isavuconazole?

A: Adults: Loading dose: 200 mg every 8 hours for 48 hours; Maintenance dose: 200 mg daily. Pediatric dosages are weight-based; see detailed pediatric guidelines above.

Q2: What are the common side effects of Isavuconazole?

A: Common side effects include nausea, vomiting, diarrhea, headache, and elevated liver enzymes.

Q3: Is Isavuconazole safe to use during pregnancy?

A: No, Isavuconazole is Pregnancy Category D and is generally avoided during pregnancy due to potential risks to the fetus.

Q4: How does Isavuconazole interact with other medications?

A: Isavuconazole interacts with numerous medications, particularly those metabolized by CYP3A4/5. Consult a drug interaction resource for specific interactions.

Q5: What should be monitored in patients receiving Isavuconazole?

A: Monitor liver function tests, serum creatinine, potassium levels, and QT interval.

Q6: Can Isavuconazole be used in patients with renal impairment?

A: Yes, no dose adjustment is necessary for patients with renal impairment.

Q7: What are the contraindications for Isavuconazole use?

A: Hypersensitivity to isavuconazole, co-administration with strong CYP3A4/5 inhibitors or inducers, and familial short QT syndrome.

Q8: Is Isavuconazole effective against all fungi?

A: No, although isavuconazole has broad-spectrum activity, it is not effective against all fungi. Susceptibility testing may be necessary to guide treatment.

Q9: What is the route of administration for Isavuconazole?

A: Isavuconazole can be administered both orally (capsules) and intravenously.

Q10: How long should Isavuconazole treatment last?

A: The duration of therapy depends on the clinical response and should be determined on a case-by-case basis. The benefit-risk balance should be carefully considered for long-term treatment beyond 6 months.