Fostemsavir (Monograph)

Brand name: Rukobia
Drug class: HIV Entry and Fusion Inhibitors
Chemical name: [3-[2-(4-Benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate
Molecular formula: C₂₅H₂₆N₇O₈P
CAS number: 864953-29-7

Medically reviewed by Drugs.com on Nov 27, 2022. Written by ASHP.

Introduction

Antiretroviral; HIV-1 gp120-directed attachment inhibitor.

Uses for Fostemsavir

Treatment of HIV-1 Infection

Treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations; used in combination with other antiretroviral(s).

Therapeutic options for the management of HIV infection and use of antiretrovirals are continuously evolving. While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines on selection and use of antiretrovirals for the treatment or prevention of HIV infection.

Fostemsavir Dosage and Administration

General

Pretreatment Screening

• Review concomitant medications and adjust dosages of drugs that interact accordingly prior to initiating treatment with fostemsavir.

Patient Monitoring

• Monitor liver chemistries in patients with hepatitis B virus and/or hepatitis C virus co-infection.

• Monitor for adverse reactions due to drug interactions from concomitant medications taken with fostemsavir.

Other General Considerations

• Initiate or maintain effective hepatitis B treatment (referring to treatment guidelines) in patients coinfected with hepatitis B.

Oral Administration

Administer orally twice daily without regard to food. Swallow tablets whole; do not chew, crush, or split tablets.

Dosage

Adults

Treatment of HIV-1 Infection

Oral

600 mg twice daily.

Special Populations

Hepatic Impairment

Mild to severe hepatic impairment (Child-Pugh Score A, B, or C): No dosage adjustment required.

Renal Impairment

Any degree of renal impairment or on dialysis: No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations.

Cautions for Fostemsavir

Contraindications

• Hypersensitivity to fostemsavir or any of components of the formulation.

• Coadministration with strong CYP3A inducers.

Warnings/Precautions

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], tuberculosis); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) reported to occur in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

QTc Prolongation with Higher than Recommended Dosages

Significantly prolongs the QT_c interval at 4 times the recommended daily dosage. Use caution when coadministering with drugs that have a known risk of torsades de pointes, in patients with a history of QT_c-interval prolongation or relevant pre-existing cardiac disease, and in elderly patients.

Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection

Monitor liver chemistries in patients with hepatitis B and/or hepatitis C co-infection; hepatic transaminase elevations were observed in clinical trials, some of which were consistent with hepatitis B reactivation.

Pay special attention to the initiation and maintenance of hepatitis B treatments when starting fostemsavir in patients with hepatitis B co-infection.

Risk of Adverse Reactions or Loss of Virologic Response due to Drug Interactions

Concomitant use with certain drugs may result in QT_c interval prolongation or loss of therapeutic effect of fostemsavir with possible development of resistance.

Consider drug interaction potential, review concomitant medications, and monitor for adverse reactions.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Insufficient data on use in pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. No adverse developmental effects at clinically relevant temsavir exposures observed in animal studies.

Lactation

Fostemsavir-related drug distributed into milk in animals; not known if present in human breast milk, affects milk production, or has effects on the breastfed infant.

Instruct HIV-infected lactating patients not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger adults.

Use caution because of age-related decreases in hepatic, renal, or cardiac function and potential for concomitant disease and drug therapy.

May be more susceptible to drug-induced QT-interval prolongation.

Hepatic Impairment

Mild to severe hepatic impairment (Child-Pugh Score A, B, or C): Exposure not altered; no dosage adjustment needed.

Renal Impairment

Mild to severe renal impairment: Exposure not altered; no dosage adjustment needed.

End-stage renal disease (ESRD) on hemodialysis or not on hemodialysis: Exposure not altered; no dosage adjustment needed.

Common Adverse Effects

Adverse effects (all grades) observed in ≥5% of patients in clinical studies was nausea.

Drug Interactions

Substrate of CYP3A, P-glycoprotein (P-gp), UGT, and breast cancer resistance protein (BCRP). Inducers or inhibitors of CYP3A, P-gp, or BCRP may impact temsavir (active moiety of fostemsavir) concentrations.

Inhibits organic anion transporter polypeptide (OATP)1B1 and OATP1B3 and BRCP.

Does not affect metabolism of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp, multidrug resistance protein (MRP)2; bile salt export pump (BSEP), sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transports (OAT)1 and OAT3, and organic cation transporters (OCT)1 and OCT2 substrates.

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A: Coadministration with strong CYP3A inducers is contraindicated; results in decreased plasma concentrations of temsavir and potential loss of therapeutic efficacy. Coadministration with moderate CYP3A inducers is not likely to have clinically relevant effects.

Inhibitors of CYP3A: Coadministration with strong CYP3A inhibitors is not likely to have clinically relevant effects.

Inducers or Inhibitors of P-gp or BCRP

Inhibitors of P-gp or BCRP: Clinically important pharmacokinetic interactions unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of OATP1B1/3: Possible pharmacokinetic interaction (increased plasma concentrations of substrate).

Substrates of Drug Transport Systems

Substrates of BCRP: Possible pharmacokinetic interaction (increased plasma concentration of BCRP substrate).

Drugs that Prolong the QT Interval

Concomitant use of fostemsavir with drugs that have a known risk of torsades de pointes may increase the risk of torsades de pointes. Use caution when co-administering fostemsavir and drugs with a known risk of torsades de pointes.

Drugs without Clinically Significant Interactions

The manufacturer states that the following drugs can be coadministered without dosage adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with or without etravirine, etravirine, famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with or without ritonavir, tenofovir disoproxil fumarate.

Specific Drugs

Fostemsavir Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 26.9%

Peak plasma concentrations attained 2 hours following oral administration.

Systemic exposure to temsavir is dose proportional over the fostemsavir dose range of 600–1800 mg.

Food

Administration with a high-fat meal increased exposure by 81% relative to fasting. Administration with a standard meal increased exposure by 10%, which is not considered clinically significant.

Special Populations

Mild to severe hepatic impairment (Child-Pugh Score A, B, or C) does not affect temsavir exposure.

Mild to severe renal impairment and hemodialysis does not affect temsavir exposure.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

88.4% bound to human plasma protein.

Elimination

Metabolism

Principally metabolized by CYP3A4 and esterases.

Elimination Route

Following oral administration of radiolabeled drug, 51% eliminated in urine (<2% unchanged); 33% eliminated in feces (1.1% unchanged).

Half-life

11 hours.

Special Populations

Age, sex, or race/ethnicity do not substantially affect fostemsavir pharmacokinetics.

Not readily cleared by hemodialysis; approximately 12.3% of an administered dose is removed during a 4-hour hemodialysis session.

Stability

Storage

Oral

Extended-release tablets

Store at 20–25°C (excursions permitted to 15–30°C).

Actions and Spectrum

• Fostemsavir is a prodrug that is hydrolyzed to the active moiety, temsavir, an HIV-1 attachment inhibitor.

• Temsavir binds to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits interaction between the virus and cellular CD4 receptors, thereby preventing attachment.

• Temsavir also inhibits gp120-dependent post-attachment steps required for viral entry into host cells.

• HIV-1 variants with reduced susceptibility to temsavir have been produced in vitro and have emerged during fostemsavir therapy.

• Temsavir retained activity against viruses resistant to the HIV integrase strand transfer inhibitor (INSTI) raltegravir; the HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine; the HIV nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, lamivudine, tenofovir, zidovudine; and the protease inhibitors (PIs) atazanavir and darunavir.

• Both ibalizumab, a CD4-directed post-attachment inhibitor, and fostemsavir develop resistance in gp120.

• Some CCR5-tropic maraviroc-resistant viruses have shown reduced susceptibility to temsavir.

• Viruses resistant to the gp41 fusion inhibitor enfuvirtide retained susceptibility to temsavir.

Advice to Patients

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

• Inform patients that if they have had a hypersensitivity reaction to fostemsavir or any of its components, they should not take the drug.

• Risk of immune reconstitution syndrome. Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection, as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when fostemsavir is started.

• Advise patients that fostemsavir may produce changes in their EKG (i.e., QT prolongation). Instruct patients to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm, or loss of consciousness.

• Advise patients that it is recommended to have laboratory testing and to take medications for HBV or HCV as prescribed.

• Fostemsavir may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort.

• Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to fostemsavir during pregnancy.

• Instruct lactating patients with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

• Fostemsavir tablets may have a slight vinegar-like odor.

• Advise patients to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss a dose of fostemsavir, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information.

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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