Home › Drugs › Fostemsavir Tromethamine

Fostemsavir Tromethamine

FDA Drug Information • Also known as: Rukobia

Brand Names
Rukobia
Route
ORAL
Dosage Form
TABLET, FILM COATED, EXTENDED RELEASE
Product Type
HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Fostemsavir tromethamine is a prodrug of temsavir, an HIV-1 gp120-directed attachment inhibitor. The chemical name of fostemsavir tromethamine is (3-((4-benzoyl-1-piperazinyl)(oxo)acetyl)-4-methoxy-7-(3-methyl-1 H -1,2,4-triazol-1-yl)-1 H -pyrrolo[2,3-c]pyridin-1-yl)methyl dihydrogen phosphate, 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). The empirical formula is C 25 H 26 N 7 O 8 P

  • C 4 H 11 NO 3 . The molecular weight is 704.6 g/mol (583.5 as free acid). It has the following structural formula: Fostemsavir tromethamine is a white powder and is soluble to greater than 250 mg/mL in aqueous solutions with a pH greater than 3.7. RUKOBIA extended-release tablets are for oral administration. Each film-coated tablet contains 600 mg of fostemsavir (equivalent to 725 mg fostemsavir tromethamine), and the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, and magnesium stearate. The tablet film-coating contains the inactive ingredients iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Fostemsavir tromethamine chemical structure

    • What Is Fostemsavir Tromethamine Used For?

    1 INDICATIONS AND USAGE RUKOBIA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (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 [see Clinical Studies ( 14 )]. RUKOBIA, 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 , 12.4 )

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION The recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food [see Clinical Pharmacology ( 12.3 )] . Swallow tablets whole. Do not chew, crush, or split tablets. One tablet taken twice daily with or without food. ( 2 )

    Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Immune reconstitution syndrome [see Warnings and Precautions ( 5.1 )] .
  • QTc prolongation [see Warnings and Precautions ( 5.2 )] .
  • Elevations in hepatic transaminases in patients with hepatitis B or C virus co-infection [see Warnings and Precautions ( 5.3 )]. The most common adverse reaction (all grades) observed in ≥5% of subjects was nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial. The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatment-experienced adult subjects [see Clinical Studies ( 14 )] . In the randomized cohort, 203 subjects received at least one dose of blinded RUKOBIA 600 mg twice daily and 69 subjects received placebo in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, all randomized subjects except one received open-label RUKOBIA 600 mg twice daily plus an optimized background therapy (OBT). In the nonrandomized cohort, 99 subjects received open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward. A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of subjects and included 3 cases of severe immune reconstitution inflammatory syndrome. Data from the randomized cohort form the basis of the safety assessment of RUKOBIA because the presence of significant comorbid illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all grades) reported in ≥2% of subjects in the randomized cohort in the Week 96 analysis are listed in Table 1 . Table 1. Adverse Reactions a (Grades 1 to 4) Reported in ≥2% of Subjects Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis) OBT = Optimized background therapy. a Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator. b Of the 272 subjects enrolled in the randomized cohort, 1 subject who received placebo withdrew from the trial prior to receiving RUKOBIA in the open-label phase of the trial. c Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes pooled terms: fatigue and asthenia. e Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic. f Includes pooled terms: insomnia, sleep deficit, sleep disorder, abnormal dreams. Adverse Reaction RUKOBIA plus OBT (n = 271) b Nausea 10% Diarrhea 4% Headache 4% Abdominal pain c 3% Dyspepsia 3% Fatigue d 3% Rash e 3% Sleep disturbance f 3% Immune Reconstitution Inflammatory Syndrome 2% Somnolence 2% Vomiting 2% Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • See full prescribing information for complete list of significant drug interactions. ( 4 , 7 )
  • Doses of oral contraceptives should not contain more than 30 mcg of ethinyl estradiol per day. ( 7.3 ) 7.1 Potential for RUKOBIA to Affect Other Drugs Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition [see Drug Interactions ( 7.3 )] . When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol ( Table 3 ) [see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )] . 7.2 Potential for Other Drugs to Affect RUKOBIA Coadministration of RUKOBIA with rifampin, a strong CYP3A4 inducer, significantly decreases temsavir plasma concentrations. The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can significantly decrease temsavir plasma concentrations which may lead to loss of virologic response [see Contraindications ( 4 ), Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )] . 7.3 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with RUKOBIA is provided in Table 3 . These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see Contraindications ( 4 ), Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )] . Table 3. Established and Other Potentially Significant Drug Interactions a ↑ = Increase; ↓ = Decrease; HCV = Hepatitis C virus. a This table is not all inclusive. b See Clinical Pharmacology ( 12.3 ) for magnitude of interaction. Concomitant Drug Class: Drug Name Effect on Concentration of Temsavir and/or Concomitant Drug Clinical Comment Androgen receptor inhibitor: Enzalutamide ↓Temsavir Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA [see Contraindications ( 4 )] . Anticonvulsants: Carbamazepine Phenytoin ↓Temsavir Antimycobacterial: Rifampin b ↓Temsavir Antineoplastic: Mitotane ↓Temsavir Herbal product: St John’s wort ( Hypericum perforatum ) ↓Temsavir Hepatitis C virus direct-acting antivirals: Grazoprevir Voxilaprevir ↑Grazoprevir ↑Voxilaprevir Coadministration may increase exposures of grazoprevir or voxilaprevir; 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 contraceptive: Ethinyl estradiol b ↑Ethinyl estradiol Ethinyl estradiol daily dose should not exceed 30 mcg . Caution is advised particularly in patients with additional risk factors for thromboembolic events. Statins: Rosuvastatin b Atorvastatin Fluvastatin Pitavastatin Simvastatin ↑Rosuvastatin ↑Atorvastatin ↑Fluvastatin ↑Pitavastatin ↑Simvastatin Use the lowest possible...

    • Contraindications

    4 CONTRAINDICATIONS RUKOBIA is contraindicated in patients:

  • with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
  • coadministered strong cytochrome P450 (CYP)3A inducers, as significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] : o Androgen receptor inhibitor: Enzalutamide o Anticonvulsants: Carbamazepine, phenytoin o Antimycobacterial: Rifampin o Antineoplastic: Mitotane o Herbal product: St John’s wort ( Hypericum perforatum )
  • Hypersensitivity to fostemsavir or any of the components of the formulation. ( 4 )
  • Coadministration with strong cytochrome P450 (CYP)3A inducers as significant decreases in temsavir plasma concentrations may occur, which may result in loss of virologic response. ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of RUKOBIA 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 (see Data) . 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%. Data 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. In a rat pre- and postnatal development study, fostemsavir was administered orally at doses of 10, 50, or 300...

    Overdosage

    10 OVERDOSAGE There is no known specific treatment for overdose with RUKOBIA. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING RUKOBIA extended-release tablets, 600 mg, are beige, oval, film-coated, biconvex tablets debossed with “SV 1V7” on one side. Bottle of 60 tablets with child-resistant closure. NDC 49702-250-18. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. RUKOBIA extended-release tablets may have a slight vinegar-like odor.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.