HIV/AIDS Update - Approval of Tybost (cobicistat) 150 mg tablets

"U.S. Food & Drug Administration (FDA)" <fda@xxxxxxxxxxxxxxxxxxxxxxx> · Thu, 25 Sep 2014 08:40:40 -0500

Title:     HIV/AIDS Update - Approval of Tybost (cobicistat) 150 mg tablets

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  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.

 Recommended Dosing Regimens

 Tybost Dosage  
Coadministered Agent Dosage

Patient    Populations

150 mg orally once daily

atazanavir    300 mg orally once daily

Treatment-naïve    or experienced

darunavir    800 mg orally once daily

Treatment-naïve 
 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:

Tybost is not interchangeable with       ritonavir to increase systemic exposure of darunavir 600 mg twice daily,       fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The       use of Tybost is not recommended with darunavir 600 mg twice daily,       fosamprenavir, saquinavir or tipranavir.
Complex or unknown mechanisms       of drug interactions preclude extrapolation of ritonavir drug interactions       to certain Tybost interactions. Tybost and ritonavir when administered       with either atazanavir or darunavir may result in different drug       interactions when used with concomitant medications.

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.
Drugs that are Contraindicated with  Concomitant use with Tybost and Atazanavir or Darunavir 

 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.

Ergot Derivatives

dihydroergotamine,
 ergotamine,
 methylergonovine

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. John’s wort (Hypericum perforatum)

Products containing    St. John’s 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,
 simvastatin

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.

Sedative/hypnotics

triazolam,
 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.

Effects on Serum Creatinine: Assess  creatinine clearance (CLcr) before initiating treatment. 
New onset or worsening renal  impairment when used with tenofovir disoproxil fumarate: When Tybost is used in  combination with a tenofovir disoproxil fumarate (tenofovir DF) containing  regimen, cases of acute renal failure and Fanconi syndrome have been reported.  (5.2)
Use with tenofovir DF: Assess urine  glucose and urine protein at baseline and monitor CLcr, urine glucose, and  urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment.  (5.2) 

Risk of Serious Adverse  Reactions or Loss of Virologic Response Due to Drug Interactions:

Initiation of Tybost, a CYP3A inhibitor, in patients receiving  medications metabolized by CYP3A, or initiation of medications metabolized by  CYP3A in patients already receiving Tybost may increase plasma concentration of  these medications which may increase the risk of clinically significant adverse  reactions (including life-threatening or fatal reactions) associated with the  concomitant medications.   Coadministration of Tybost with atazanavir or darunavir in combination  with CYP3A inducers may lead to lower exposure of cobicistat and atazanavir or  darunavir and loss of efficacy of atazanavir or darunavir and possible  resistance. Therefore, consider the potential for drug interactions prior to  and during Tybost therapy; review concomitant medications during Tybost  therapy; and monitor for the adverse reactions associated with the concomitant  drugs 
Tybost or ritonavir when administered with either atazanavir or  darunavir may result in different drug interactions when used with concomitant  medications. Complex or unknown mechanisms of drug interactions preclude  extrapolation of ritonavir drug interactions to certain Tybost interactions 
Antiretrovirals that are not  recommended: Tybost in combination with more than one antiretroviral that  requires pharmacokinetic enhancement (i.e., two protease inhibitors or  elvitegravir in combination with a protease inhibitor) is not recommended. Additionally,  darunavir in combination with efavirenz, nevirapine or etravirine. Atazanavir  in combination with etravirine or in combination with efavirenz in  treatment-experienced patients. 
Use with HIV-1 protease inhibitors  other than atazanavir or darunavir administered once daily are not recommended. 
Coadministration with  cobicistat-containing drugs, including STRIBILD®, is not  recommended. 
Coadministration with drugs or  regimens containing ritonavir is not recommended. 

Use of Tybost with concomitant medications
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:

Patients       on a stable concomitant medication who initiate or switch to a Tybost-containing       regimen
Patients       on a Tybost-containing regimen who initiate a new concomitant medication
Patients       initiating a Tybost-containing regimen and a new concomitant medication       simultaneously  

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.
Richard Klein
 Office of Health and Constituent Affairs
 Food and Drug Administration
Kimberly Struble
 Division of Antiviral Products
 Food and Drug Administration
Steve Morin
 Office of Health and Constituent Affairs
 Food and Drug Administration

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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.
Ergot Derivatives	dihydroergotamine, ergotamine, methylergonovine	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. John’s wort (Hypericum perforatum)	Products containing St. John’s 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, simvastatin	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.
Sedative/hypnotics	triazolam, 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.