Oteseconazole (Monograph)

Brand name: Vivjoa
Drug class: Azoles
Chemical name: (2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl]propan-2-ol
Molecular formula: C₂₃H₁₆F₇N₅O₂
CAS number: 1340593-59-0

Introduction

Oteseconazole is an azole antifungal agent.

Uses for Oteseconazole

Oteseconazole has the following uses:

Oteseconazole is an azole antifungal indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are NOT of reproductive potential. If specimens for fungal culture are obtained prior to therapy, antifungal therapy may be instituted before the results of the cultures are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Oteseconazole Dosage and Administration

General

Oteseconazole is available in the following dosage form(s) and strength(s):

Capsules: 150 mg of oteseconazole (fluconazole is not supplied in the carton).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer oteseconazole orally with food.

• There are two recommended oteseconazole dosage regimens: a oteseconazole-only regimen and a fluconazole/oteseconazole regimen. Use one of these two dosage regimens.

• Oteseconazole-only Dosage Regimen:

  • On Day 1: Administer oteseconazole 600 mg (as a single dose), then

  • On Day 2: Administer oteseconazole 450 mg (as a single dose), then

  • Beginning on Day 14: Administer oteseconazole 150 mg once a week (every 7 days) for 11 weeks (weeks 2 through 12).

• Fluconazole/oteseconazole Dosage Regimen:

  • On Day 1, Day 4, and Day 7: Administer fluconazole 150 mg orally, then

  • On Days 14 through 20: Administer oteseconazole 150 mg once daily for 7 days, then

  • Beginning on Day 28: Administer oteseconazole 150 mg once a week (every 7 days) for 11 weeks (weeks 4 through 14).

Related/similar drugs

fluconazole, nystatin topical, clotrimazole topical, Diflucan, itraconazole, miconazole topical

Cautions for Oteseconazole

Contraindications

• Females of reproductive potential.

• Pregnant and lactating women.

• Hypersensitivity to oteseconazole.

Warnings/Precautions

Embryo-fetal Toxicity

Oteseconazole is contraindicated in females of reproductive potential, and in pregnant and lactating women. Based on animal studies, oteseconazole may cause fetal harm. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks. Ocular abnormalities were observed in the offspring of pregnant rats dosed at 7.5-mg/kg/day during organogenesis through lactation in pre and postnatal developmental studies. The observed ocular abnormalities included cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration and hemorrhage. Ocular abnormalities occurred at doses about 3.5 times the steady state clinical exposure seen with patients being treated for RVVC. Advise patients that oteseconazole is contraindicated in females of reproductive potential, and in pregnant and lactating women because of potential risks to a fetus or breastfed infant.

Specific Populations

Pregnancy

Oteseconazole is contraindicated in females of reproductive potential and in pregnant women. Based on animal studies, oteseconazole may cause fetal harm when administered to pregnant women. In addition, the drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks.

Ocular abnormalities were observed in a pre and postnatal animal study in the offspring of rats administered oteseconazole from Gestation Day 6 through Lactation Day 20 at doses about 3.5 times the recommended human dose based on AUC comparisons. The observed ocular abnormalities included cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration and hemorrhage.

There are limited human data in pregnant women who were exposed to oteseconazole during the clinical trials; these data are insufficient to exclude a potential risk of cataracts or other eye abnormalities in human infants.

Rat and rabbit embryofetal development was assessed after oral administration of oteseconazole. There was no embryofetal toxicity or malformations at 40 mg/kg/day following administration of oteseconazole during organogenesis in pregnant rats at doses about 10 times the maximum human exposure for RVVC based on AUC comparisons. Abortions occurred in rabbits in the presence of maternal toxicity (reduced bodyweight gain with reduced food consumption) but there were no malformations at 15 mg/kg/day following administration of oteseconazole during organogenesis in pregnant rabbits about 6 times the maximum human exposure for RVVC based on AUC comparisons.

Ocular abnormalities including cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration, and hemorrhage were observed in the offspring of rats administered oteseconazole from Gestation Day 6 through Lactation Day 20 at 7.5 mg/kg day (about 3.5 times the recommended human dose based on AUC comparisons). There were no effects on pregnancy or parturition in these pre and postnatal studies at any dose.

Lactation

Oteseconazole is contraindicated in lactating women and females of reproductive potential. There are no data on the presence of oteseconazole in human or animal milk or data on the effects of oteseconazole on milk production. There were no reported adverse effects in breastfed infants following maternal exposure to oteseconazole during lactation; however, given the limited duration of follow-up of the oteseconazole-exposed infants during the post-natal period, no conclusions can be drawn from these data.

Ocular abnormalities were observed in a pre and postnatal study in the offspring of rats administered oteseconazole from Gestation Day 6 through Lactation Day 20 at doses approximately 3.5 times the recommended human dose based on AUC comparisons. The relationship between the observed animal findings and breastfed infants is unknown.

Females of Reproductive Potential

Oteseconazole is contraindicated in females of reproductive potential based on animal findings. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks.

Females who are NOT of reproductive potential are defined as: persons who are biological females who are postmenopausal or have another reason for permanent infertility (e.g., tubal ligation, hysterectomy, salpingo-oophorectomy).

Pediatric Use

Oteseconazole is contraindicated in females of reproductive potential. Based on animal studies, oteseconazole may cause fetal harm when administered to a pregnant woman or potential harm to the breastfed infant. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks associated with oteseconazole use.

The safety and effectiveness of oteseconazole have not been established in pre-menarchal pediatric females.

Geriatric Use

Clinical studies of oteseconazole did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Renal Impairment

No dosage adjustment of oteseconazole is recommended in patients with mild to moderate renal impairment (i.e., estimated glomerular filtration rate (eGFR) by the modification of diet in renal disease (MDRD) equation 30-89 mL/min). Clinical studies of oteseconazole did not include sufficient numbers of patients with severe renal impairment (eGFR 15-29 mL/min) or end-stage renal disease (ESRD), defined as eGFR <15 mL/min, to determine the safety of oteseconazole in this population. Therefore, oteseconazole is not recommended for use in patients with severe renal impairment or ESRD (with or without dialysis).

Hepatic Impairment

No dosage adjustment of oteseconazole is recommended in patients with mild hepatic impairment (Child-Pugh A). There is insufficient information to determine the safety of oteseconazole in patients with moderate or severe hepatic impairment (Child-Pugh B-C). Therefore, oteseconazole is not recommended for use in patients with moderate or severe hepatic impairment.

Common Adverse Effects

The most frequently reported adverse reactions (incidence > 2%) were headache and nausea.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

BCRP (Breast Cancer Resistance Protein) Substrates: Concomitant use of oteseconazole with BCRP substrates may increase the exposure of drugs that are BCRP substrates, which may increase the risk of adverse reactions associated with these drugs. Use the lowest possible starting dose of the BCRP substrate or consider reducing the dose of the substrate drugs and monitor for adverse reactions.

Actions and Spectrum

Mechanism of Action

Oteseconazole is an antifungal drug.

Oteseconazole is an azole metalloenzyme inhibitor targeting the fungal sterol, 14α demethylase (CYP51), an enzyme that catalyzes an early step in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane formation and integrity. Inhibition of CYP51 results in the accumulation of 14-methylated sterols, some of which are toxic to fungi. Through the inclusion of a tetrazole metal-binding group, oteseconazole has a lower affinity for human CYP enzymes.

Antifungal Activity

The following in vitro data is available, but their clinical significance is unknown. Oteseconazole has been shown to be active against most isolates of the following microorganisms associated with RVVC:

• Candida albicans

• Candida glabrata

• Candida krusei

• Candida parapsilosis

• Candida tropicalis

• Candida lusitaniae

• Candida dubliniensis

Resistance

The potential for increases in minimum inhibitory concentrations (MIC) to oteseconazole has been evaluated in vitro including specific mechanisms of resistance. Increases in oteseconazole MIC were associated with upregulation of the efflux pumps CDR1, MDR1, and the azole target, lanosterol 14-alpha-demethylase (CYP51). Against certain Candida spp. oteseconazole maintained meaningful in vitro activity against clinical isolates that were resistant to fluconazole.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients that oteseconazole is contraindicated in females of reproductive potential and in pregnant women because it may cause fetal harm.

• Advise patients that oteseconazole is contraindicated in lactating women because it may cause harm to the breastfed infant.

• Advise patients that oteseconazole must be taken with food, and that capsules must be swallowed whole and not chewed, crushed, dissolved, or opened.

• Advise patients to inform their health care provider if they are taking a BCRP substrate (e.g., rosuvastatin). Concomitant use with oteseconazole may increase the exposure of drugs that are BCRP substrates, which may increase the risk of adverse reactions associated with these drugs.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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