AHFS Class:

• HIV Entry and Fusion Inhibitors 8:18.08.04

Generic Name(s):

• Fostemsavir Tromethamine

Fostemsavir tromethamine, an antiretroviral agent, is a human immunodeficiency virus type (HIV-1) gp120-directed attachment inhibitor.1

Treatment of HIV-1 Infection

Fostemsavir is used in combination with other antiretroviral(s) 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

Clinical Experience

The efficacy and safety of fostemsavir in adults with HIV-1, in combination with other antiretrovirals, is based principally on the results of a multicenter, partially-randomized, placebo-controlled, 96-week study (BRIGHTE) in heavily treatment-experienced HIV-1 patients.1,2 For study entry, patients were required to have a viral load of ≥400 copies/mL with ≤2 antiretroviral drug classes remaining as treatment options due to resistance, intolerability, contraindications, or other safety issues.1,2 Patients were enrolled in either a randomized (n=272) or non-randomized cohort (n=99) based on the number of remaining antiretrovirals regimens available (1-2 or zero, respectively). 1,2 In the randomized cohort, patients were assigned in a 3:1 ratio to receive blinded fostemsavir twice daily or placebo in addition to their failing antiviral regimen for 8 days, after which all patients received open-label fostemsavir plus a different optimized background therapy (OBT).1,2 Patients in the nonrandomized cohort received open-label fostemsavir with a new OBT regimen from the first day of the study onward.1,2 In the nonrandomized cohort, investigational antiretrovirals were allowed.1,2 The primary efficacy endpoint was the adjusted mean decline in HIV-1 RNA over the first 8 days of therapy in the randomized cohort. 1,2 The median age of patients enrolled in the study was 49 years (range 17-73 years); 78% were male, and 69.3% were white. 1 At baseline, the median HIV-1 RNA was 4.6 log10 copies/mL and the median CD4⁺ cell count was 80 cells/mm³ (100 and 41 cells/mm³ for randomized and non-randomized patients, respectively).1,2 The majority of patients (71%) had been treated for HIV for >15 years; 85% had been exposed to ≥5 HIV antiviral regimens prior to study entry.1

Patients were evaluated over a 96-week period.1,2 The decline in plasma HIV-1 RNA in the randomized cohort from Day 1-Day 8 was reduced with fostemsavir (adjusted mean, -0.791 HIV-1 RNA log₁₀ copies/mL) compared to placebo (adjusted mean, -0.166 HIV-1 RNA log₁₀ copies/mL). 1,2 In the randomized group, the proportion of patients achieving an HIV-1 RNA <40 copies/mL was 53% at week 24 and 60% at week 96.1 In patients with a viral load of <100,000 copies/mL at baseline, 60% achieved an HIV-1 RNA <40 copies/mL at week 24 and 65% at week 96. 1 In patients with a viral load of ≥100,000 copies/mL at baseline, 35% and 49% achieved HIV-1 RNA <40 copies/mL at week 24 and week 96, respectively.1 The majority of patients (84%) received dolutegravir as a component of OBT, of which 51% also received darunavir with ritonavir or cobicistat. 1,2 In the nonrandomized cohort, HIV-1 RNA <40 copies/mL was achieved in 37% of patients at weeks 24 and 96. 1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving as the result of expanded knowledge concerning the immunopathogenesis of HIV, availability of several different classes of antiretrovirals, and improvements in laboratory methods used to evaluate the rate of disease progression and response to antiretroviral therapy.200,201,202 The primary goals of antiretroviral therapy in the management of HIV infection are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels), restore and/or preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent secondary transmission of HIV.200,201,202 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,200 HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV,201 and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission,202 have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection. These guidelines are based on current knowledge regarding the pathogenesis of HIV, results of clinical studies, and expert opinion.200,201,202

General

Pretreatment Screening

• Review concomitant medications and adjust dosages of drugs that interact accordingly prior to initiating treatment with fostemsavir.1

Patient Monitoring

• Monitor liver chemistries in patients with hepatitis B virus and/or hepatitis C virus co-infection.1
• Monitor for adverse reactions due to drug interactions from concomitant medications taken with fostemsavir.1

Other General Considerations

• Initiate or maintain effective hepatitis B treatment (referring to treatment guidelines) in patients coinfected with hepatitis B.1

Administration

Fostemsavir is administered orally twice daily with or without food.1 Swallow tablets whole; do not chew, crush, or split tablets.1

If a dose of fostemsavir is missed, the prescribed dose should be taken as soon as the patient remembers.1 Patients should avoid missing doses due to the development of resistance.1 Do not double the next dose or take more than the prescribed dose.1

Store fostemsavir tablets at 20-25°C (may be exposed to 15-30°C).1

Dosage

Dosage of fostemsavir tromethamine is expressed in terms of fostemsavir.1

Treatment of HIV-1 Infection

For heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations, the recommended dosage of fostemsavir is 600 mg twice daily.1

Special Populations

Hepatic Impairment

In patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C), no dosage adjustment is needed.1

Renal Impairment

In patients with any degree of renal impairment or on dialysis, no dosage adjustment is needed.1

Geriatric Patients

While there are no specific dosage recommendations for geriatric patients, use caution during administration of fostemsavir due to the greater frequency of renal, hepatic, and cardiac dysfunction in these patients, as well as concomitant diseases and other drug therapy.1

Contraindications

• Hypersensitivity to fostemsavir or any of the components of the formulation.1
• Coadministration with strong cytochrome P-450 (CYP) 3A inducers.1

Warnings/Precautions

Immune Reconstitution Syndrome

During the initial phase of combination antiretroviral therapy, patients who respond to such therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.1 In the BRIGHTE study, 3 cases of severe immune reconstitution syndrome occurred.1

In the setting of immune reconstitution, autoimmune disorders such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis have also been reported, with variable onset.1 Some cases have occurred many months after initiating treatment.1

QTc Prolongation with Higher than Recommended Dosages

Fostemsavir has been shown to significantly prolong the QT_c interval at a dosage of 2.4 g twice daily (4 times the recommended daily dosage).1 Use fostemsavir with caution in patients with a history of QT_c-interval prolongation, patients with relevant pre-existing cardiac disease, and those who may be more susceptible to drug-induced QT_c interval prolongation, such as elderly patients.1 Caution is also advised when fostemsavir is coadministered with drugs known to increase the risk of torsades de pointes.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 virus (HBV) and/or hepatitis C virus (HCV) co-infection.1 Hepatic transaminase elevations were observed in a greater proportion of subjects in the BRIGHTE study who were coninfected with HBV and/or HCV compared with those with HIV mono-infection.1 Grade 3 and 4 AST and ALT elevations occurred in 14% of these patients compared to 3% (ALT) and 2% (AST) of patients without HBV and/or HCV co-infection. 1 Some elevations were consistent with hepatitis B reactivation, particularly when anti-hepatitis therapy was withdrawn.1 Pay special attention to the initiation and maintenance of hepatitis B treatments when starting fostemsavir in patients with hepatitis B co-infection.1

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

Concomitant use of fostemsavir with certain drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of fostemsavir and possible development of resistance due to reduced exposure of temsavir, and possible QT_c interval prolongation from increased temsavir exposure.1

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

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to fostemsavir during pregnancy.1 Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263or [Web].1

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

Lactation

It is not known whether fostemsavir is present in human breast milk, affects milk production, or has effects on the breastfed infant.1 When administered to lactating rats, fostemsavir-related drug was present in rat milk at concentrations similar to those in maternal plasma.1 When a drug is present in animal milk, it is likely to be present in human milk.1

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

There were no clinically relevant differences in the pharmacokinetics of total and unbound temsavir in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C).1

Renal Impairment

There were no clinically relevant differences in the pharmacokinetics of total and unbound temsavir in patients with mild to severe renal impairment.1 No clinically relevant differences were noted in the pharmacokinetics of temsavir in patients with end-stage renal disease (ESRD) on hemodialysis compared with those not on hemodialysis.1 Temsavir was not readily cleared during hemodialysis, with 12.3% of the total dose removed during a 4-hour hemodialysis session.1

Common Adverse Effects

The most common adverse effect (all grades) observed in ≥5% of patients receiving fostemsavir was nausea.1

Temsavir is a substrate of cytochrome P-450 (CYP) isoenzyme 3A4, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and uridine diphosphate glucuronosyltransferase (UGT).1 Drugs that induce or inhibit CYP3A, P-gp, or BCRP may have an impact on temsavir concentrations.1

Temsavir is an inhibitor of organic anion transporter polypeptide (OATP)1B1 and OATP1B3.1 Additionally, temsavir and 2 of tis metabolites are inhibitors of BCRP.1

At clinically relevant concentrations, significant interactions are not expected based on in vitro and clinical drug interaction results when fostemsavir is administered with substrates 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 transporters (OAT)1 and OAT3; and organic cation transporters (OCT)1 and OCT2.1

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A

Coadministration of fostemsavir with drugs that are strong CYP3A inducers is contraindicated.1 Such concomitant administration can significantly decrease temsavir plasma concentrations, which may lead to loss of virologic efficacy.1

Concomitant use of fostemsavir with strong CYP3A inducers such as rifampin, enzalutamide, carbamazepine, phenytoin, mitotane, and St John's wort (Hypericum perforatum) is contraindicated.1

The manufacturer states that coadministration of fostemsavir with moderate CYP3A inducers is not likely to have a clinically relevant effect on plasma concentrations of temsavir.1

Inhibitors of CYP3A

The manufacturer states that coadministration of fostemsavir with strong CYP3A inhibitors is not likely to have clinically relevant effects on the plasma concentrations of temsavir.1

Inducers or Inhibitors of P-gp or BCRP

The manufacturer states that clinically significant effects of P-gp or BCRP inhibitors on the pharmacokinetics of temsavir are not likely.1

Drugs Affecting or Affected by Transport Proteins

Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to OAT1B1/3 inhibition.1 Increased systemic exposure of grazoprevir may increase the risk of ALT elevations.1 Use an alternative HCV regimen if possible.1

Temsavir inhibits BCRP; therefore, concomitant use of fostemsavir and BCRP substrates may result in increased concentrations of the BCRP substrate, and an increased risk of adverse effects from the substrate.1

Oral Contraceptives

Administration of fostemsavir with ethinyl estradiol can result in increased plasma concentrations of ethinyl estradiol.1 When ethinyl estradiol/norethindrone 0.030 mg/1.5 mg combination tablet was administered concomitantly with fostemsavir, peak plasma concentrations and AUC of ethinyl estradiol increased by 39% and 40%, respectively.1 Dosages of oral contraceptives should not contain more than 30 mcg of ethinyl estradiol per day.1 Use caution in patients with additional risk factors for thromboembolic events.1

Statins

Coadministration of fostemsavir with rosuvastatin, atorvastatin, fluvastatin, pitavastatin, or simvastatin can result in increased plasma concentrations of the statin.1 When a single dose of rosuvastatin 10 mg was administered concomitantly with fostemsavir, peak plasma concentrations and AUC of rosuvastatin increased by 78%, and 69%, respectively 1 Use the lowest possible starting dosage of the statin and monitor for statin-associated adverse events.1

Drugs that Prolong the QT Interval

Concomitant use of fostemsavir with drugs that have a known risk of torsades de pointes may further increase the risk of torsades de pointes.1 Use caution when these drugs are used concomitantly.1

Drugs without Clinically Significant Interactions

The manufacturer states that based on drug interaction studies with fostemsavir, 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.1

Description

Fostemsavir is an HIV-1 gp 120-directed attachment inhibitor.1 Fostemsavir tromethamine is a prodrug that does not have significant biochemical or antiviral activity until it is hydrolyzed to the active moiety temsavir.1 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 to host cells.1 Additionally, temsavir can inhibit gp120-dependent post-attachment steps required for viral entry into host cells.1 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

In vitro studies indicated that temsavir is active against various strains of HIV-1.1 HIV-1 variants with reduced susceptibility to temsavir have been produced in vitro and have emerged during fostemsavir therapy.1 Temsavir remained active against laboratory-derived CD4-independent viruses and temsavir-resistant viruses showed no evidence of a CD4-independent phenotype.1 Therefore, treatment with fostemsavir is unlikely to promote resistance to temsavir via generation of CD4-independent virus.1 In the randomized cohort of the BRIGHTE trial, approximately 50% of patients with virologic failure had treatment-emergent gp120 genotypic substitutions at 4 key sites (S375, M426, M434, and M475).1

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

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).1
• Inform patients that if they had a hypersensitivity reaction to fostemsavir or any of its components, they should not take the drug.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 is started.1
• Advise patients that fostemsavir may produce changes in their EKG (i.e., QT prolongation).1 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
• Advise patients that fostemsavir tablets may have a slight vinegar-like odor.1
• Advise patients to avoid missing doses as it can result in development of resistance.1 Instruct patients that if they miss a dose of fostemsavir, to take it as soon as they remember.1 Advise patients not to double their next dose or take more than the prescribed dose.1
• Stress 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.1
• Stress importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to fostemsavir during pregnancy.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Rukobia^® (fostemsavir tromethamine) ORAL prescribing information. ViiV Healthcare. Durham, NC: 2024 Feb.

2. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2020;382(13):1232-1243. doi:10.1056/NEJMoa1902493

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents with HIV (Last updated February 27, 2024). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Department of Health and Human Services (Updated June 27, 2024) Updates may be available at HIV.gov website [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States (Updated January 31, 2024). Updates may be available at HIV.gov website. [Web]