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Fostemsavir

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
Brands: Rukobia

Medically reviewed by Drugs.com. Last updated on Aug 3, 2020.

Introduction

Fostemsavir tromethamine is an HIV fusion inhibitor.

Uses for Fostemsavir

Fostemsavir tromethamine has the following uses:

Fostemsavir tromethamine, a human immunodeficiency virus type 1 (HIV-1) gp120-directed attachment inhibitor, in combination with other antiretroviral(s), is indicated for the 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.1

Fostemsavir Dosage and Administration

General

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

Extended-release tablets: 600 mg (of fostemsavir).1

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

One tablet taken twice daily with or without food.1

Cautions for Fostemsavir

Contraindications

  • Hypersensitivity to fostemsavir or any of the components of the formulation.1

  • Coadministration with strong cytochrome P450 (CYP)3A inducers as significant decreases in temsavir (active moiety of fostemsavir tromethamine) plasma concentrations may occur, which may result in loss of virologic response.1

Warnings/Precautions

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including fostemsavir tromethamine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.1

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.1

QTc Prolongation with Higher than Recommended Dosages

Fostemsavir tromethamine at 2.4 g twice daily, 4 times the recommended daily dosage, has been shown to significantly prolong the QTc interval of the electrocardiogram. Fostemsavir tromethamine should be used with caution in patients with a history of QTc-interval prolongation, when coadministered with a drug with a known risk of torsades de pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT-interval prolongation.1

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

Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting fostemsavir tromethamine in patients co-infected with hepatitis B.1

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

The concomitant use of fostemsavir tromethamine and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:1

  • Loss of therapeutic effect of fostemsavir tromethamine and possible development of resistance due to reduced exposure of temsavir.1

  • Possible prolongation of QTc interval from increased exposure to temsavir.1

Consider the potential for drug interactions prior to and during therapy with fostemsavir tromethamine, review concomitant medications during therapy with fostemsavir tromethamine, and monitor for the adverse reactions associated with the concomitant drugs.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to fostemsavir tromethamine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.1

Risk Summary: There are insufficient human data on the use of fostemsavir tromethamine during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures.1

The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.1

Animal Data: Fostemsavir was administered orally to pregnant rats (50, 200, 600 mg/kg/day) and rabbits (25, 50, or 100 mg/kg/day) during Gestation Days 6 to 15 (rat) and 7 to 19 (rabbit). No fetal abnormalities were observed at temsavir exposures of approximately 180 (rat) and 30 (rabbit) times those in humans at the maximum recommended human dose (MRHD). In rabbits, increased embryonic death associated with maternal toxicity was observed at temsavir exposures approximately 60 times those in humans at the MRHD. In a separate rat study conducted at drug exposures approximately 200 times those in humans at the MRHD, fetal abnormalities (cleft palate, open eyes, shortened snout, microstomia, misaligned mouth/jaw, and protruding tongue) and reductions in fetal body weights occurred in the presence of maternal toxicity.1

In a rat pre- and postnatal development study, fostemsavir was administered orally at doses of 10, 50, or 300 mg/kg/day from Gestation Day 6 through Lactation Day 20. Reduced neonatal survival (7 to 14 days after birth) in the absence of other adverse fetal or neonatal effects was observed at maternal temsavir exposures approximately 130 times those in humans at the MRHD. No adverse fetal or neonatal effects were observed at maternal temsavir exposures approximately 35 times those in humans at the MRHD.1

In a distribution study in pregnant rats, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) crossed the placenta and were detectable in fetal tissue.1

Lactation

Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.1

It is not known whether fostemsavir tromethamine is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk.1

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving fostemsavir tromethamine.1

Data: In a distribution study, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) were excreted in rat milk following a single dose of fostemsavir administered to lactating rats 7 to 9 days postpartum. In the pre- and postnatal development study in rats, temsavir was present in milk at concentrations similar to those measured in maternal plasma, as determined 11 days postpartum. In addition, lactational exposure was associated with reduced offspring survival at maternal temsavir exposures not thought to be clinically relevant.1

Pediatric Use

The safety and effectiveness of fostemsavir tromethamine have not been established in pediatric patients.1

Geriatric Use

Clinical trials of fostemsavir tromethamine did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of fostemsavir tromethamine in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to drug-induced QT-interval prolongation.1

Renal Impairment

No dosage adjustment is required for patients with renal impairment or those on hemodialysis.1

Hepatic Impairment

No dosage adjustment is required in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C).1

Common Adverse Effects

The most common adverse reaction (all grades) observed in ≥5% of subjects was nausea.1

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:

  • See full prescribing information for complete list of significant drug interactions.1

  • Doses of oral contraceptives should not contain more than 30 mcg of ethinyl estradiol per day.1

Actions and Spectrum

Mechanism of Action

Fostemsavir tromethamine is an HIV-1 antiretroviral agent.1

Fostemsavir is a prodrug without significant biochemical or antiviral activity that is hydrolyzed to the active moiety, temsavir, which is an HIV-1 attachment inhibitor. Temsavir binds directly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and cellular CD4 receptors, thereby preventing attachment. Additionally, temsavir can inhibit gp120-dependent post-attachment steps required for viral entry into host cells. Temsavir inhibited the binding of soluble CD4 to surface immobilized gp120 with an IC50 value of 14 nM using an enzyme-linked immunosorbent assay (ELISA).1

Spectrum

Antiviral Activity in Cell Culture: Temsavir exhibited antiviral activity against 3 CCR5-tropic laboratory strains of subtype B HIV-1, with EC50 values ranging from 0.4 to 1.7 nM. The range of susceptibility to temsavir was broader for CXCR4-tropic laboratory strains with 2 strains having EC50 values of 0.7 and 2.2 nM and 3 strains having EC50 values of 14.8, 16.2, and >2,000 nM. Antiviral activity of temsavir against HIV-1 subtype B clinical isolates varied depending on tropism with median EC50 values against the CCR5-tropic viruses, CXCR4-tropic viruses, and dual/mixed viruses of 3.7 nM (n = 9; range: 0.3 to 345 nM), 40.9 nM (n = 4; range: 0.6 to >2,000 nM), and 0.8 nM (n = 2; range: 0.3 to 1.3), respectively, showing a broad range of EC50 values for temsavir across the different tropic strains.1

Analysis of data from 1,337 clinical samples from the fostemsavir clinical development program (881 subtype B samples, 156 subtype C samples, 43 subtype A samples, 17 subtype A1 samples, 48 subtype F1 samples, 29 subtype BF1 samples, 19 subtype BF samples, 5 CRF01_AE samples, and 139 other) showed temsavir susceptibility is highly variable across subtypes with a wide range in EC50 values from 0.018 nM to >5,000 nM. The majority of subtype B isolates (84%, 740/881) had EC50 values below 10 nM, with 6% of isolates having EC50 values >100 nM. Of all isolates from all subtypes tested, 9% exhibited EC50 values >100 nM. Subtypes BF, F1 and BF1 had higher proportions (21% to 38%) of isolates with EC50 values >100 nM, and all 5 of 5 subtype AE isolates had EC50 values >100 nM. From an additional panel of clinical isolates with non-B subtypes, temsavir EC50 values were greater than the upper limits of the concentrations tested (>1,800 nM) in all subtype E (AE; 3 of 3), Group O (2 of 2), and HIV-2 (1 of 1) isolates, and some subtype D (1 of 4) and subtype G (1 of 3) isolates.1

Reduced Antiviral Activity against Subtype AE: Temsavir showed reduced antiviral activity against 14 different subtype AE isolates in peripheral blood mononuclear cell (PBMC) assays and the Phenosense Entry assay indicating that subtype AE (or E) viruses are inherently less sensitive to temsavir. Genotyping of subtype AE viruses identified polymorphisms at amino acid positions S375H and M475I in gp120, which have been associated with reduced susceptibility to fostemsavir. Subtype AE is a predominant subtype in Southeast Asia, but it is not found in high frequencies elsewhere throughout the world.1

There were 2 subjects with subtype AE virus at screening in the randomized cohort of the clinical trial. One subject (EC50 fold change >4,747-fold and gp120 substitutions at S375H and M475I at baseline) did not respond to fostemsavir tromethamine at Day 8. A second subject (EC50 fold change 298-fold and gp120 substitution at S375N at baseline) received placebo during functional monotherapy. Both subjects were virologically suppressed at Week 96 while receiving OBT (with dolutegravir) plus fostemsavir tromethamine.1

Antiviral Activity in Combination with Other Antiviral Agents: The antiviral activity of temsavir was not antagonistic in cell culture when combined with the CD4-directed post-attachment HIV-1 inhibitor ibalizumab, the CCR5 co-receptor antagonist maraviroc, the gp41 fusion inhibitor enfuvirtide, integrase strand transfer inhibitors (INSTIs) (dolutegravir, raltegravir), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine, rilpivirine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), or protease inhibitors (PIs) (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir). In addition, temsavir antiviral activity was not antagonistic in cell culture with the anti-HBV drug entecavir and the anti-HCV drug ribavirin.1

Resistance

Cell Culture: HIV-1 variants with reduced susceptibility to temsavir were selected following 14 to 49 days passage in cell culture of NL4-3, LAI, and BaL viruses in a T-cell line. Selected viruses exhibited 18- to 159-fold decreased temsavir susceptibility and genotypic analysis identified the following emerging amino acid substitutions in gp120: L116P/Q, L175P, A204D, V255I, A281V, M426L, M434I, and M475I (S375 substitutions were identified based on in vivo data with a related attachment inhibitor). In general, most substitutions mapped to the conserved regions (C1, C2, C4, and C5) of the gp120 envelope, confirming temsavir targets the viral envelope protein during infection.1

Single-substitution recombinant viruses at these amino acid positions were engineered into the HIV-1 LAI viral background and the resultant recombinants demonstrated reduced susceptibility to temsavir (L116P [>340-fold], A204D [>340-fold], S375M [47-fold], S375V [5.5-fold], S375Y [>10,000-fold], M426L [81-fold], M426V [3.3-fold], M434I [11-fold], M434T [15-fold], M475I [5-fold], M475L [17-fold], and M475V [9.5-fold]).1

Temsavir remained active against laboratory-derived CD4-independent viruses and temsavir-resistant viruses showed no evidence of a CD4-independent phenotype. Therefore, treatment with fostemsavir tromethamine is unlikely to promote resistance to temsavir via generation of CD4-independent virus.1

Resistance in Clinical Subjects: The percentage of subjects who experienced virologic failure through the Week 96 analysis was 25% (69/272) in the randomized cohort (including 25% [51/203] among subjects who received blinded fostemsavir functional monotherapy and 26% [18/69] among subjects who received blinded placebo during the 8-day double-blind period). Virologic failure = confirmed ≥400 copies/mL after prior confirmed suppression to <400 copies/mL, ≥400 copies/mL at last available prior to discontinuation, or >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level (≥40 copies/mL). Overall, 51% (27/53) of evaluable subjects with virologic failure in the randomized cohorts had treatment-emergent gp120 genotypic substitutions at 4 key sites (S375, M426, M434, and M475).1

The median temsavir EC50 fold change at failure in randomized evaluable subject isolates with emergent gp120 substitutions at positions 375, 426, 434, or 475 (n = 26) was 1,755-fold. In randomized evaluable subject isolates with no emergent gp120 substitutions at those positions (n = 27), the median temsavir EC50 fold change at failure was 3.6-fold.1

Cross-resistance: Both the CD4-directed post-attachment inhibitor ibalizumab and the gp120-directed attachment inhibitor fostemsavir develop resistance in gp120. Five of 7 viruses resistant to ibalizumab retained susceptibility to temsavir while the other 2 viruses had reduced susceptibility to both temsavir (>1,400-fold decreased susceptibility) and ibaluzimab. Resistance to the CCR5 coreceptor antagonist maraviroc can also develop in the gp120 envelope. Some CCR5-tropic maraviroc-resistant viruses showed reduced susceptibility to temsavir. Viruses resistant to the gp41 fusion inhibitor enfuvirtide retained susceptibility to temsavir.1

Temsavir retained wild-type activity against viruses resistant to the INSTI raltegravir; the NNRTI rilpivirine; the NRTIs abacavir, lamivudine, tenofovir, zidovudine; and the PIs atazanavir and darunavir.1

Additionally, ibalizumab, maraviroc, enfuvirtide, the INSTI raltegravir, NNRTIs (efavirenz, rilpivirine), NRTIs (abacavir, tenofovir), and PIs (atazanavir, darunavir) retained activity against site-directed mutants with reduced temsavir susceptibility (S375M, M426L, or M426L plus M475I) or against clinical envelopes that had decreased baseline susceptibility to temsavir.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Inform patients that if they have had a hypersensitivity reaction to fostemsavir tromethamine or any of its components, they should not take fostemsavir tromethamine.1

Risk of immune reconstitution syndrome.1 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 tromethamine is started.1

Advise patients that fostemsavir tromethamine may produce changes in their electrocardiogram (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.1

Advise patients that it is recommended to have laboratory testing and to take medications for HBV or HCV as prescribed.1

Fostemsavir tromethamine 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.1

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to fostemsavir tromethamine during pregnancy.1

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

Fostemsavir tromethamine tablets may have a slight vinegar-like odor.1

Advise patients to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss a dose of fostemsavir tromethamine, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.1

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.

Fostemsavir Tromethamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

600 mg (of fostemsavir)

Rukobia

ViiV Healthcare Company

AHFS Drug Information. © Copyright 2021, Selected Revisions August 3, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. ViiV Healthcare Company. Rukobia (fostemsavir tromethamine) ORAL prescribing information. 2020 Jul. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a21006b7-6d6f-4f06-81b4-17978756452b