Isavuconazole (Cresemba) is a triazole antifungal drug that is available as an oral and intravenous formulation. It is indicated for the treatment of patients with invasive aspergillosis and mucormycosis.

Isavuconazole (Cresemba)  Uses:

• Aspergillosis:
  • It is indicated for the treatment of adult patients with invasive aspergillosis.
• Mucormycosis:
  • It is indicated for the treatment of adult patients with invasive mucormycosis.

Isavuconazole (Cresemba) Dose in Adults

Note:

• The doses are expressed here as milligrams of isavuconazonium sulfate.
• Oral and intravenous formulations can be switched.
• When switching from one formulation to another, restarting with the same initial dosing regimen is not necessary.

Isavuconazole (Cresemba) Dose in the treatment of Invasive Aspergillosis:

• IV:
  • Initial: 372 mg (isavuconazole 200 mg) intravenously three times a day (8 hours apart) for six doses.
  • Maintenance dose: 372 mg (isavuconazole 200 mg) intravenously once a day.
  • Initiate the maintenance dose 12 to 24 hours after the last loading dose.
• Oral:
  • Initial: 372 mg (isavuconazole 200 mg) orally three times a day (8 hours apart) for six doses
  • Maintenance dose: 372 mg (isavuconazole 200 mg) orally once a day.
  • Initiate the maintenance dose 12 to 24 hours after the last loading dose.
• Treatment Duration:
  • For at least 6 to 12 weeks, the treatment must be continued.
  • The extent and persistence of immunosuppression, the location of the infection, and the clinical response to medication all affect how long the course of treatment will last.

Isavuconazole (Cresemba) Dose in the treatment of Invasive Mucormycosis:

• IV:
  • Initial: 372 mg (isavuconazole 200 mg) intravenously three times a day (8 hours apart) for six doses.
  • Maintenance dose: 372 mg (isavuconazole 200 mg) intravenously once a day.
  • Initiate the maintenance dose 12 to 24 hours after the last loading dose.
• Oral:
  • Initial: 372 mg (isavuconazole 200 mg) orally three times a day (8 hours apart) for six doses
  • Maintenance dose: 372 mg (isavuconazole 200 mg) orally once a day.
  • Initiate the maintenance dose 12 to 24 hours after the last loading dose.

Dose in Children:

Not indicated.   

Pregnancy Risk Category: D

• Studies on animal reproduction have shown that in utero exposure to the drug can cause fetal harm.
• Before treatment can begin, it is important to perform a pregnancy test.
• Effective contraception should be used during treatment and for 28 days after the last dose.

Use during breastfeeding:

• It is unknown whether breastmilk is contaminated with the drug.
• The manufacturer suggests that you stop breastfeeding while taking the drug.

Dose in Kidney Disease:

Adjustment in the dose is not necessary.   

Dose in Liver Disease:

• Mild or moderate impairment (Child-Pugh class A or B):
  • Adjustment in the dose is not necessary.
• Severe impairment (Child-Pugh class C):
  • Dose adjustment in the manufacturer's labeling has not been provided.
  • It has not been studied in patients with severe hepatic impairment.
  • It should be used with caution.

Side Effects of Isavuconazole (Cresemba):

• Cardiovascular:
  • Peripheral Edema
• Central Nervous System:
  • Headache
  • Fatigue
  • Insomnia
• Endocrine & Metabolic:
  • Hypokalemia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Diarrhea
  • Abdominal Pain
  • Constipation
• Hepatic:
  • Increased Liver Enzymes
• Respiratory:
  • Dyspnea
  • Cough

Less Common Side Effects of Isavuconazole (Cresemba):

• Cardiovascular:
  • Chest Pain
  • Hypotension
  • Atrial Fibrillation
  • Atrial Flutter
  • Bradycardia
  • Cardiac Arrest
  • Catheter Site Thrombosis
  • Extrasystoles
  • Palpitations
  • Shortened QT Interval
  • Supraventricular Extrasystole
  • Supraventricular Tachycardia
  • Syncope
  • Thrombophlebitis
  • Ventricular Premature Contractions
• Central Nervous System:
  • Delirium
  • Anxiety
  • Brain Disease
  • Chills
  • Confusion
  • Convulsions
  • Depression
  • Drowsiness
  • Falling
  • Hallucination
  • Hypoesthesia
  • Malaise
  • Migraine
  • Peripheral Neuropathy
  • Stupor
  • Vertigo
  • Dizziness
  • Hypoesthesia
  • Paresthesia
• Dermatologic:
  • Skin Rash
  • Pruritus
  • Alopecia
  • Dermatitis
  • Erythema
  • Exfoliative Dermatitis
  • Urticaria
• Endocrine & Metabolic:
  • Hypomagnesemia
  • Hypoalbuminemia
  • Hypoglycemia
  • Hyponatremia
• Gastrointestinal:
  • Decreased Appetite
  • Dyspepsia
  • Abdominal Distention
  • Cholecystitis
  • Cholelithiasis
  • Cholestasis
  • Dysgeusia
  • Gastritis
  • Gingivitis
  • Stomatitis
• Genitourinary:
  • Hematuria
  • Proteinuria
• Hematologic & Oncologic:
  • Agranulocytosis
  • Leukopenia
  • Pancytopenia
  • Petechia
• Hepatic:
  • Hepatitis
  • Hepatomegaly
  • Increased Serum ALT
  • Increased Serum AST
  • Hepatic Failure
  • Increased Serum Transaminases
• Hypersensitivity:
  • Hypersensitivity
• Local:
  • Injection Site Reaction
• Neuromuscular & Skeletal:
  • Back Pain
  • Myositis
  • Neck Pain
  • Ostealgia
  • Tremor
• Ophthalmic:
  • Optic Neuropathy
• Otic:
  • Tinnitus
• Respiratory:
  • Acute Respiratory Tract Failure
  • Bronchospasm
  • Tachypnea

Contraindications to Isavuconazole (Cresemba):

• Allergy reactions to any component of the drug or the drug itself
• Strong CYP3A4 inhibitors like ketoconazole and high-dose ritonavir used together (400 mg twice daily)
• simultaneous use of potent CYP3A4 inducers, such as carbamazepine, rifampin, St. John's wort, and long-acting barbiturates.
• Familial short QT syndrome

Canadian labeling: Additional contraindications

• Concurrent use moderate CYP3A4/5 inducers such as efavirenz and etravirine

Warnings and precautions

• Hepatic effects
  • Hepatotoxicity can be severe and even fatal. Patients with underlying medical conditions, such as hematological malignancies, are more likely to experience hepatotoxic reactions.
  • Hepatitis and cholestasis can be caused by patients. This may manifest as an increase in AST, ALT or alkaline phosphatase and total bilirubin.
  • Asymptomatic elevations of liver enzymes are not usually a sign that treatment should be stopped. They can also be reversed after treatment is stopped.
  • It is important to monitor the liver function test results at baseline, and as often thereafter, if indicated.
  • Patients with transaminitis need to be regularly watched for symptoms of liver damage.
• Hypersensitivity
  • Treatment may end if patients exhibit clinical symptoms of liver damage.
  • If severe reactions occur, discontinue treatment.
  • Cross-reactions with other azole drug have not been investigated. Patients with hypersensitivity reactions to other drugs should be cautious when using it.
• Hepatic impairment
  • Patients with liver disease should use it with caution.
  • At baseline, liver function tests should always be performed.

Monitoring parameters:

• Monitor for an allergic reaction during and following the infusion. Infusion reactions may occur and manifest as shortness of breath, chills, dizziness, hypotension, paraesthesias and hypoesthesias.
• AST, ALT, alkaline phosphatase, and total bilirubin levels should be checked before starting treatment and as needed at regular intervals thereafter.

How to administer Isavuconazole (Cresemba)?

IV:

• The infusion should be administered over a minimum period of one hour.
• It must be administered through an infusion set with an in-line filter (pore size 0.2 to 1.2 micron).
• The line should be flushed with NS or D5W before and after infusion.
• Avoid administering the drug as an intravenous bolus injection.

Oral:

• The capsules should be swallowed whole without crushing, chewing, dissolving, breaking, or opening it.
• It may be administered with or without meals.

Mechanism of action of Isavuconazole (Cresemba):

• Isavuconazonium sulfurate is a drug that is rapidly hydrolyzed to its active form (isavuconazole in the blood).
• It inhibits the synthesis of ergosterol, which is an essential component in the fungal cell membrane.
• It blocks the synthesis and activity of ergosterol-forming enzyme lanosterol 14 alpha-demethylase, a cytochrome P450 dependent enzyme.
• This enzyme is responsible for the conversion lanosterol into ergosterol.
• This causes an increase in methylated sterol precursors and membrane depletion ergosterol in the fungal cell membrane, which results in weakening the cell membrane structure.

Protein binding:

• Greater than 99% of the drug is bound to plasma proteins, primarily to albumin.

Metabolism:

• Isavuconazonium sulfate is a prodrug and is hydrolyzed in the blood by esterases to active isavuconazole and an inactive cleavage product.
• It is metabolized by CYP3A4, CYP 3A5, and UGT.

Bioavailability of the oral capsules:

• 98%

Half-life elimination: IV:

• 130 hours

Time to peakserum levels after oral administration:

• 2 to 3 hours

Excretion:

• Oral: 46.1% (feces),
• 45.5% (urine)

International Brand Names of Isavuconazole:

• Cresemba

Isavuconazole brand names in Pakistan:

No Brands Available in Pakistan.