Fostemsavir

Dosages

Interactions

Contraindicated

• Enzalutamide
• Carbamazepine
• Phenytoin
• Rifampin
• MitotaneSt John’s wort (Hypericum perforatum)

Serious

• Grazoprevir
• Voxilaprevir

Monitor Closely

• Ethinyl estradiol
• Rosuvastatin
• Atorvastatin
• Fluvastatin
• Pitavastatin
• Simvastatin

Adverse Effects

• Nausea 10%
• Diarrhoea 4%
• Headache 4%
• Abdominal pain 3%
• Dyspepsia 3%
• Fatigued 3%
• Rash 3%
• Sleep disturbance 3%
• Immune Reconstitution Inflammatory Syndrome 2%
• Somnolence 2%
• Vomiting 2%
• Elevations in hepatic transaminases in patients with hepatitis B or C virus 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.
• Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of fostemsavir 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 and possible development of resistance due to reduced exposure of temsavir 2) Possible prolongation of QTc interval from increased exposure to temsavir.

Less common adverse reactions

• Cardiac Disorders: Electrocardiogram QT prolonged, Torsade de Pointes
• Musculoskeletal Disorders: Myalgia.
• Nervous System Disorders: Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy).
• Skin and Subcutaneous Tissue Disorders: Pruritus.

Contraindications & Warnings

Immune Reconstitution Syndrome

• Immune reconstitution syndrome has been reported in patients. 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.
• 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

QTc Prolongation

• Seen with higher than recommended dosages at 2,400 mg twice daily, 4 times the recommended daily dose, has been shown to significantly prolong the QTc interval of the electrocardiogram

Safety Advice

🍺   Alcohol: Caution

Pharmacology

Mechanism of Action

• Fostemsavir tromethamine is a prodrug of temsavir is a first-in-class HIV-1 attachment inhibitor. After oral administration, fostemsavir is converted to temsavir, which is then absorbed and exerts antiviral activity by attaching directly to the glycoprotein 120 (gp120) subunit on the surface of the virus, thereby blocking HIV from attaching to host immune system CD4+ T-cells and preventing the virus from infecting those cells and multiplying. As fostemsavir is the first antiretroviral therapy to target this step of the viral cycle, there is no demonstrated resistance to other classes of antiretrovirals, which may help patients who have become resistant to most other medicines.

About Temsavir

• Temsavir  is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP).
• Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir.
• Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir. Temsavir is an inhibitor of OATP1B1 and OATP1B3.

Pharmacokinetic properties of Temsavir

• Absolute bioavailability: 26.9%
• Distribution: Plasma protein binding 88.4%
• Major route of elimination: Metabolism
• Half-life: 11 hours
• Metabolic pathwayse: Hydrolysis (esterases) [36.1% of oral dose], Oxidation (CYP3A4) [21.2% of oral dose], UGT [<1% of oral dose]
• Excretion: Urine (unchanged drug) 51 %, feces (unchanged drug) 33%, bile 5%

General Considerations

• Advise the patient to read the FDA-approved patient labeling (Patient Information).
• Hypersensitivity Reactions
• Immune Reconstitution Syndrome: Advice patients to inform their healthcare provider immediately of any signs and symptoms of
  infection, as inflammation from the previous infection, may occur soon after combination antiretroviral therapy, including when fostemsavir is started
• QTc Interval Prolongation: Advise patients that it 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
• Patients with Hepatitis B or C Virus Co-infection: Advise patients that it is recommended to have laboratory testing and to take medications for
  HBV or HCV as prescribed
• Drug Interactions: 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
• Pregnancy Registry: Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to fostemsavir during pregnancy.
• Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk
• Potential Odor of Tablets: Tablets may have a slight vinegar-like odour
• Missed Dosage: Advise patients to avoid missing doses as it can result in the 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

General Monitoring Parameters

• ECG for estimation of QT interval
• CBC at baseline with periodic tests for liver function, renal function, blood glucose level
• CD4 count