FDA approves new anti fungal drug Isavuconazonium sulfate

  • The U.S. Food and Drug Administration, on March 6, 2015, approved  isavuconazonium sulfate, a new antifungal drug  used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.
  • As part of its QIDP designation, isavuconazonium sulfate was given priority review, which provides an expedited review of the drug’s application
  • Aspergillosis is a fungal infection caused by Aspergillus species, and mucormycosis is caused by the Mucorales fungi. These infections occur most often in people with weakened immune systems.
  • CRESEMBA contains isavuconazonium sulfate, which is the prodrug of isavuconazole, an azole antifungal drug.
  • Isavuconazonium sulfate drug substance is an amorphous, white to yellowish-white powder.
  • The chemical name of isavuconazonium sulfate is glycine, N-methyl-, [2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5­ difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1). The empirical formula is C35H35F2N8O5S·HSO4, the molecular weight is 814.84 and the structural formula is:

isavuconazonium sulfate

                      ——————————–Mechanism of Action ———————-

  • Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase.
  • This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition.
  • Activity in vitro and in clinical infections:
  • Isavuconazole has activity against most strains of the following microorganisms, both in vitro and in clinical infections: Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae and Mucormycetes species.

——————————————-Drug Resistance ——————————————–

  • There is a potential for development of resistance to isavuconazole. The mechanism of resistance to isavuconazole, like other azole antifungals, is likely due to multiple mechanisms that include substitutions in the target gene CYP51.
  • Changes in sterol profile and elevated efflux pump activity were observed, however, the clinical relevance of these findings is unclear.
  • In vitro and animal studies suggest cross-resistance between isavuconazole and other azoles. The relevance of crossresistance to clinical outcome has not been fully characterized. However, patients failing prior azole therapy may require alternative antifungal therapy.

 —————————DOSAGE AND ADMINISTRATION——————————

  • CRESEMBA for injection must be administered through an in-line filter over a minimum of 1 hour.
  • Loading Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for 6 doses (48 hours) via oral (2 capsules) or intravenous administration (1 reconstituted vial).
  • Maintenance Dose: 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily via oral (2 capsules) or intravenous administration (1 reconstituted vial) starting 12 to 24 hours after the last loading dose.
  • Capsules can be taken with or without food.

 ——————————CONTRAINDICATIONS——————————

  • Hypersensitivity
  • Coadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir.
  • Coadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbituratess.
  • Use in patients with familial short QT syndrome

 ————————WARNINGS AND PRECAUTIONS———————————-

  • Hepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapy
  • Infusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.
  • Hypersensitivity Reactions: Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA for exfoliative cutaneous reactions.
  • Drug Particulates: Intravenous formulation may form insoluble particulates following reconstitution. Administer CRESEMBA through an in-line filter.

 ——————————ADVERSE REACTIONS——————————

  • Most frequent adverse reactions: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

 ——————————DRUG INTERACTIONS——————————

  • CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole.
  • Appropriate therapeutic drug monitoring and dose adjustment of immunosuppressants (i.e., tacrolimus, sirolimus, and cyclosporine) may be necessary when co-administered with CRESEMBA.
  • Drugs with a narrow therapeutic window that are P-gp substrates, such as digoxin, may require dose adjustment when administered concomitantly with CRESEMBA.

     ———————–USE IN SPECIFIC POPULATIONS——————————

  • Pregnancy: should not be used
  • Mothers should not breast feed children while taking CRESEMBA.
  • Cautiously used in hepatic insufficiency.

Cresemba is marketed by Astellas Pharma US, Inc., based in Northbrook, Illinois.

For more information Click Here