September 25, 2014
On September 24, 2014, FDA approved Tybost (cobicistat) 150 mg tablets. Tybost is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection. The recommended dosages of Tybost and atazanavir or darunavir given with food are presented below.
|Tybost Dosage||Coadministered Agent Dosage||Patient Populations|
|150 mg orally once daily||atazanavir 300 mg orally once daily||Treatment-naive or experienced|
|darunavir 800 mg orally once daily||Treatment-naive|
Treatment-experienced with no darunavir resistance associated substitutions
The data to support the use of atazanavir and Tybost were from a phase 2 and 3 trial in treatment-naïve adults comparing atazanavir/cobicistat 300/150 mg and atazanavir/ritonavir 300/100 mg once daily each in combination with Truvada. The atazanavir/cobicistat based regimen was non-inferior to the atazanavir/ritonavir based regimen. The data to support the use of cobicistat with darunavir is from a multiple dose trial in healthy subjects comparing the relative bioavailability of darunavir/cobicistat 800/150 mg to darunavir/ritonavir 800/100 mg.
The most common adverse drug reactions observed with Tybost in combination with atazanavir (incidence greater than 10%, all Grades) are jaundice, ocular icterus, and nausea.
The following limitations of use were included section 1 Indications and Usage:
Prior to starting Tybost, assess estimated creatinine clearance because Tybost decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. When coadministering Tybost with tenofovir disoproxil fumarate (tenofovir DF) assess estimated creatinine clearance, urine glucose, and urine protein at baseline.
Tybost coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with Tybost.
|Drug Class||Drugs Within Class That Are Contraindicated||Clinical Comment|
|Alpha 1-Adrenoreceptor Antagonist||alfuzosin||Potential for increased alfuzosin concentrations, which can result in serious or life threatening reactions such as hypotension.|
|Antiarrhythmic||dronedarone||Potential for increased dronedarone concentrations.|
|Antimycobacterial||rifampin||Rifampin is a potent inducer of CYP metabolism and coadministration may cause a significant decrease in the plasma concentrations of atazanavir or darunavir and result in loss of therapeutic effect and development of resistance.|
|Antineoplastics||irinotecan||Contraindicated with Tybost coadministered with atazanavir only: Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicity.|
|Potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.|
|GI Motility Agent||cisapride||Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.|
|Herbal Products||St. Johns wort (Hypericum perforatum)||Products containing St. Johns wort may result in reduced plasma concentrations of atazanavir or darunavir, which may result in loss of therapeutic effect and development of resistance.|
|HMG-CoA Reductase Inhibitors||lovastatin,|
|Potential for serious reactions such as myopathy including rhabdomyolysis.|
|Neuroleptic||pimozide||Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.|
|Non-nucleoside Reverse Transcriptase Inhibitor||nevirapine||Contraindicated with Tybost coadministered with atazanavir only: Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures.|
|Phosphodiesterase-5 (PDE5) Inhibitor||sildenafila when administered as REVATIO® for the treatment of pulmonary arterial hypertension||Potential for sildenafil-associated adverse reactions (which include visual disturbances, hypotension, priapism, and syncope).|
|Protease Inhibitor||indinavir||Contraindicated with Tybost coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.|
orally administered midazolamb
|Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Co-administration of triazolam or orally administered midazolam may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening benzodiazepine reactions such as prolonged or increased sedation or respiratory depression.|
A summary of the Warnings and Precautions follows.
Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:
The potential for drug interactions must be considered by healthcare providers prior to and during therapy with Tybost coadministered with atazanavir or darunavir.
Healthcare providers should carefully evaluate whether dosage adjustments of concomitant medications or antiretroviral drugs are necessary in:
Under these circumstances, healthcare providers should also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.
Tybost increases the systemic exposure of CYP3A substrates, including atazanavir and darunavir, by inhibiting CYP3A. Concomitant use of Tybost with atazanavir or darunavir and other medications metabolized by CYP3A may result in increased plasma concentrations of these medications, which may result in increased adverse reactions and severe, life-threatening or fatal reactions.
Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A. Concomitant use of drug products that act as CYP3A inducers may result in decreased plasma concentrations of cobicistat, atazanavir, or darunavir, and to loss of efficacy of atazanavir or darunavir, and possible resistance.
Labeling for Tybost will be posted soon at Drugs@FDA.
Tybost is a product of Gilead Sciences, Foster City, CA.
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