fostemsavir (Rx)

>10%

Creatinine >1.8 x ULN or 1.5 x baseline (19%)

1-10%

Nausea (10%)

Direct bilirubin >ULN (7%)

Hemoglobin <9 g/dL (6%)

Cholesterol ≥300 mg/dL) (5%)

Lipase >3x ULN (5%)

Triglycerides >500 mg/dL (5%)

ALT >5x ULN (5%)

AST >5x ULN (4%)

Hyperglycemia >250 mg/dL (4%)

LDL cholesterol ≥190 mg/dL

Neutrophils ≤599 cells/mm³ (4%)

Diarrhea (4%)

Headache (4%)

Bilirubin ≥2.6x ULN (3%)

Urate >12 mg/dL (3%)

Abdominal pain (3%)

Dyspepsia (3%)

Fatigue (3%)

Rash (3%)

Sleep disturbance (3%)

Immune reconstitution inflammatory syndrome (2%)

Somnolence (2%)

Vomiting (2%)

Creatinine kinase ≥10x ULN (2%)

<2%

• Cardiac disorders: ECG QT prolonged (asymptomatic)
• Musculoskeletal disorders: Myalgia
• Nervous system disorders: Dizziness, dysgeusia, peripheral neuropathy
• Skin and subcutaneous tissue disorders: Pruritus

Contraindications

Hypersensitivity to fostemsavir or any of its components

Coadministered strong CYP3A inducers (eg, enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, St John’s wort), as significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations may occur, which may result in loss of virologic response

Cautions

Immune reconstitution syndrome reported with combination antiretroviral therapy; an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis) may occur, which may necessitate further evaluation and treatment; autoimmune disorders (eg, Grave disease, polymyositis, Guillain-Barré) also reported

Monitor liver enzymes in patients coinfected with hepatitis B or C virus; elevated hepatic transaminases observed in greater proportion of coinfected individuals; maintain/initiate effective hepatitis B therapy when initiating fostemsavir to avoid hepatitis B reactivation

Drug interaction overview

• CYP3A4 inducers

  • Contraindicated
  • Temsavir (active moiety) is a CYP3A4 substrate
  • Coadministration with strong CYP3A4 inducers significantly decreases temsavir plasma concentrations, which may lead to loss of virologic response and resistance

• QT prolongation

  • Caution with history of prolonged QT, torsade de Pointes, or cardiac disease prone to arrhythmias
  • Caution if coadministered with other drugs known to prolong QT interval
  • QTc prolongation reported with higher than recommended doses
  • Geriatric patients may be more prone to QT prolongation

• OATP and BCRP substrates

  • Temsavir inhibits OATP1B1, OATP1B3, and BCRP
  • Caution; OATP1B1/3 or BCRP substrates (eg, grazoprevir, voxilaprevir, ethinyl estradiol, statins) may need to be avoided or require dosage modification
  • Temsavir inhibits organic anion transporting polypeptide (OATP)1B1/3, which may increase plasma concentration of substrate

Pregnancy

Antiretroviral pregnancy registry (APR): Clinicians are encouraged to register patients by calling 1-800-258-4263

Human data are insufficient regarding use during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage

Animal studies

• Oral administration to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures

Lactation

The CDC recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection

Unknown if excreted in breast milk, affects milk production, or effects breastfed infants

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Prodrug of temsavir; first-in-class HIV-1 attachment inhibitor that works by binding directly to the glycoprotein 120 (gp120) subunit on the surface of the virus

By binding to this location on the virus, fostemsavir blocks HIV from attaching to host immune system CD4+ T cells and other immune cells, thereby preventing HIV from infecting those cells and multiplying

Absorption

Bioavailability: 26.9%

Peak plasma time: 2 hr

Peak plasma concentration: 1700 ng/mL

Trough concentration: 478 ng/mL

AUC: 12,900 ng⋅h/mL

Distribution

Protein bound: 88.4% (primarily to albumin)

Vd: 29.5 L

Metabolism

Hydrolysis (esterases): 36.1%

Oxidation (CYP3A4): 21.2%

UGT: <1%

Elimination

Half-life: 11 hr

Clearance: 17.9 L/hr

Excretion: Urine (51%; <2% unchanged); feces (33%; 1.1 unchanged)

Oral Administration

May take with or without food

Swallow tablets whole; do not chew, crush, or split

Missed dose

• Advise patients to avoid missing doses as it can result in development of resistance
• If dose is missed; take as soon as remembered
• Do not double next dose or take more than prescribed dose owing to risk of QT prolongation

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

Tablets may have slight vinegarlike odor