FDA News: Issue 19, July 2020

Author: [AUTHOR] Published on 7/16/2020 8:02:00 AM

FDA Approves RUKOBIA (Fostemsavir) in Combination with Other Antiretroviral(s), for HIV-1 Infection in Heavily Treatment-Experienced Adults with Multidrug-Resistant HIV-1 Infection Failing Their Current Antiretroviral Regimen

On July 02, 2020, the US Food and Drug Administration (FDA) approved RUKOBIA (fostemsavir),in combination with other antiretroviral(s), for the treatment of a human immunodeficiency virus type (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. The approved recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food.

RUKOBIA is contraindicated in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA or with coadministration with strong CYP3A inducers.

Additional information regarding dosage and administration as well as warnings and precautions about immune reconstitution syndrome, QTc prolongation, and elevations in hepatic transaminases in patients with hepatitis B or C virus coinfection can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: Fostemsavir is a human immunodeficiency virus type 1 (HIV-1) gp120-directed attachment inhibitor.
  • General PK: Fostemsavir is a prodrug of temsavir, its active moiety. Plasma temsavir Cmax and AUCtau increases in a dose proportional or slightly greater than dose proportional manner over the range 600 mg to 1,800 mg of RUKOBIA.
  • Absorption: The absolute bioavailability of temsavir was 26.9% and Tmax was 2 h.
  • Distribution: Protein binding of temsavir is 88.4%, primarily to HSA. The blood-to-plasma ratio is 0.74. The steady-state volume of distribution is 29.5 L.
  • Elimination: The half-life of temsavir is 11 h, and apparent clearance is 66.6 L/h. Temsavir was not readily cleared by hemodialysis.
  • Metabolism: Temsavir is metabolized by esterases (36.1% of dose), CYP3A4 (21.2% of dose), and UGT (< 1% of dose).
  • Excretion: Following a single-dose administration of radiolabeled fostemsavir oral solution, 51% of the dose was excreted in urine (< 2% unchanged) and 33% in feces (1.1% unchanged).
  • Cardiac Electrophysiology: At therapeutic doses, RUKOBIA does not prolong the QT interval to any clinically relevant extent. At 4 times the recommended dose, the mean (upper 90% confidence interval) QTcF increase was 11.2 milliseconds (13.3 milliseconds). The observed increase in QTcF was temsavir concentration-dependent.
Drug Interactions
  • Androgen receptor inhibitors, anticonvulsants, antineoplastic agents, herbal products: coadministration of RUKOBIA with enzalutamide, carbamazepine, phenyltoin, mitotane, or St. John's wort is contraindicated. Coadministration with these drugs can cause significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations, which may result in loss of virologic response to RUKOBIA.
  • Strong CYP3A4 Inducers: Coadministration of RUKOBIA with a strong CYP3A4 inducer (e.g. rifampin) is contraindicated. Rifampin significantly decreases temsavir plasma concentrations, which may lead to loss of virologic response.
  • Hepatitis C Virus Direct-Acting Antivirals: Coadministration may increase exposures of grazoprevir or voxilaprevir through (OATP)1B1/3 inhibition; however, the magnitude of increase in exposure is unknown. Increased exposures of grazoprevir may increase the risk of ALT elevations. Use an alternative HCV regimen if possible.
  • Oral Contraceptives Containing Ethinyl Estradiol: Ethinyl estradiol daily dose should not exceed 30 mcg. Caution is advised particularly in patients with additional risk factors for thromboembolic events. When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol.
  • Statins (rosuvastatin, atorvastatin, fluvastatin, pitavastatin, simvastatin): Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.
  • Drugs that Prolong QT Interval: Coadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes. Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes.
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (white, black/African American, Asian, or other), HIV-1 infection aged up to 73 years, renal impairment with or without hemodialysis, or hepatic impairment. The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown. The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older.

Efficacy and Safety
Efficacy of RUKOBIA was demonstrated in a Phase 3, partially-randomized, international, double-blind, placebo-controlled trial of heavily treatment-experienced adult subjects with HIV-1 infection. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

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

Full prescribing information is available at https://go.usa.gov/xfCWH.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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