Product Information
Registration Status: ActiveCRESEMBA CAPSULES 100MG is approved to be sold in Singapore with effective from 2019-06-13. It is marketed by PFIZER PTE LTD, with the registration number of SIN15716P.
This product contains Isavuconazole 100 mg in the form of CAPSULE. It is approved for ORAL use.
This product is manufactured by SwissCo Services AG in SWITZERLAND, andAlmac Pharma Services Limited (Primary and Secondary packager) in UNITED KINGDOM.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Description
Isavuconazole is an triazole antifungal with broad spectrum of activity and good safety profile [A32026]. It is approved by the FDA and EMA for the treatment of invasive aspergillosis and mucormycosis. It works by inhibiting fungal cell membrane synthesis. Invasive fungal infections pose significant clinical challenges for patients, especially those who are immunocompromised. In vitro, most of the _Candida_ species, most _Aspergillus_ species, Mucorales, _Cryptococcus_ spp., _Fusarium_ species, dermatophytes and dimorphic fungi displayed susceptibility to isavuconzaole [A32029]. Resistance to isavuconazole has been associated with the mutation in the target gene CYP51 [FDA Label]. Cross-resistance between isavuconazole and other azoles was also proposed although the clinical relevance is unclear [FDA Label]. Its prodrug, [DB06636], is commonly used as an active ingredient in commercially available formulations due to low water solubility of isavuconazole. The prodrug formulation of isavuconazole is FDA- and EMA-approved and is marketed under the trade name Cresemba for the treatment of invasive aspergillosis and mucormycosis as oral or intravenous administration. The intravenous formulation is cyclodextrin-free which gives isavuconazole an advantage over other azole antifungals that requires cyclodextrin for facilitating drug solubility; this is because cyclodextrin has a potential for nephrotoxicity [A32029]. It is proposed that the intravenous and oral dosing can be used interchangeably [L1482], without the need for a repeat loading dose when transitioning from an IV to an oral formulation [A32026]. Isavuconazonium displays excellent water solubility for intravenous formulations, good absorption, and enhanced oral bioavailability [A32026]. Following administration, isavuconazonium undergoes biotransformation to form the active moiety, isavuconazole, for the antifungal actions.
Indication
- Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis [FDA Label]. - Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis [FDA Label], including patients where treatment amphotericin B is inappropriate [L1482].
Mechanism of Action
Isavuconazole displays fungicidal actions by disrupting the biosynthesis of ergosterol, which is a key component of fungal cell membrane. It inhibits cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase that mediates the conversion of lanosterol to ergosterol. The side arm of of the active isavuconazole molecule allows for greater affinity for the binding pocket in the fungal CYP51 protein by orienting the triazole ring of the molecule to engage with the heme moiety at the bottom of the binding pocket [A32026, A32029]. This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles [A32026, A32029]. As a result of lanosterol 14-alpha-demethylase inhibition, toxic methylated sterol precursors such as 14-α-methylated lanosterol, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol alter the function of fungal membrane and accumulate within the fungal cytoplasm [A32029]. Depletion of ergosterol within the fungal cell membrane leads to decreased structural integrity and function of the cell membrane, inhibited fungal cell growth and replication [A32026], and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition [FDA Label]. Mechanism of resistance and reduced susceptibility to isavuconazole arises from mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase [L1482]. Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded [FDA Label].
Pharmacokinetics
- Absorption
- Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL [FDA Label]. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole [FDA Label]. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h*ng/mL and 193906.8 h*ng/mL, respectively [L1482]. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9% [FDA Label]. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98% [FDA Label].
- Distribution
- The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration [FDA Label].
- Metabolism
- Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material [FDA label]. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of _in vivo_ and _in vitro_ studies [FDA Label].
- Elimination
Clearance
The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously [A32028].
Toxicity
At three times the recommended maintenance dose of isavuconazole, treatment-emergent adverse reactions included headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. As there is no specific antidote or effective method of hemodialysis for isavuconazole, supportive treatment with appropriate monitoring is recommended in case of overdose [FDA Label]. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats [FDA Label]. However, isavuconazole was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay without any significant evidence of increased frequency of micronuclei in an in vivo rat micronucleus test [L1482]. While carcinogenicity studies isavuconazole have not been performed, other drugs in the azole class at near human recommended doses were associated with the development of hepatocellular adenomas and carcinomas in mice and rat carcinogenicity studies [FDA Label]. At doses up to 90 mg/kg/day, oral isavuconazole did not affect the fertility in male or female rats. Isavuconazole at systemic exposures of subtherapeutic levels was associated with dose-related increases in the incidence of skeletal anomalies in rat and rabbit offsprings [L1482]. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring [L1482].
Active Ingredient/Synonyms
isavuconazol | isavuconazole | isavuconazolum | Isavuconazole |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.