TYBOST® (cobicistat) tablets

TYBOST® (cobicistat) tablets

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TYBOST® (cobicistat) tablets

TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor.

The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0.

Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20 °C.

TYBOST tablets are for oral administration. Each tablet contains 150 mg of cobicistat. The tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sunset yellow FCF (FD&C Yellow #6) aluminum lake, and iron oxide yellow.

Indications and usage

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 in adults and in pediatric patients:

  • weighing at least 35 kg coadministered with atazanavir or
  • weighing at least 40 kg coadministered with darunavir

Limitations of Use:

  • 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.

Dosage and administration

TYBOST must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents.

Recommended dosage in adults:

TYBOST DosageCoadministered Agent DosageAdult Patient Populations
150 mg orally once dailyatazanavir 300 mg orally once dailyTreatment-naïve or treatment-experienced
150 mg orally once dailydarunavir 800 mg orally once dailyTreatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions
  • Recommended dosage in pediatric patients: TYBOST 150 mg orally once daily. For dosage recommendations of the coadministered protease inhibitor atazanavir or darunavir, refer to Table 2 of the full prescribing information.
  • Prior to starting TYBOST, assess estimated creatinine clearance.
  • Coadministration with tenofovir disoproxil fumarate (TDF): assess estimated creatinine clearance, urine glucose, and urine protein at baseline.
  • TYBOST coadministered with TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST

Mechanism of Action

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.

Not Recommended During Pregnancy

TYBOST coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters.

TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters

TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with TYBOST coadministered with darunavir or atazanavir.

Contraindications

The concomitant use of TYBOST with atazanavir or darunavir and the following drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect

  • Alpha 1-adrenoreceptor antagonist: alfuzosin
  • Antianginal: ranolazine
  • Antiarrhythmic: dronedarone
  • Anticonvulsants: carbamazepine, phenobarbital, phenytoin
  • Anti-gout: colchicine
  • Antimycobacterial: rifampin
  • Antineoplastics: irinotecan*
  • Antipsychotics: lurasidone, pimozide
  • Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
  • Herbal Products: St. John’s wort (Hypericum perforatum)
  • Hormonal Contraceptives: drospirenone/ ethinyl estradiol*
  • Lipid-modifying Agents: lomitapide, lovastatin, simvastatin
  • Non-nucleoside Reverse Transcriptase Inhibitor: nevirapine*
  • Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio® for the treatment of pulmonary arterial hypertension
  • Protease Inhibitor: indinavir*
  • Sedative/hypnotics triazolam, orally administered midazolam

*These contraindications apply only to TYBOST coadministered with atazanavir

Adverse reactions

The most common adverse drug reactions observed with TYBOST in combination with atazanavir (incidence greater than 5%, Grades 2−4) are jaundice and rash.

Warnings and precautions

Effects on Serum Creatinine: TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating TYBOST, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.

Although TYBOST may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.

New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate:

Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST was used in an antiretroviral regimen that contained TDF.

  • Coadministration of TYBOST and TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST
  • Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when TYBOST is used with TDF. Measure serum phosphorus in patients with or at risk for renal impairment when used with TDF.
  • Coadministration of TYBOST and TDF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.

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 concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of TYBOST with atazanavir or darunavir.

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These interactions may lead to:

  • clinically significant adverse reactions, potentially leading to severe, lifethreatening, or fatal events from higher exposures of concomitant medications.
  • clinically significant adverse reactions from higher exposures of TYBOST and atazanavir or darunavir.
  • loss of therapeutic effect of TYBOST with atazanavir or darunavir and possible development of resistance.
  • loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).

Antiretrovirals that are Not Recommended in Combination with TYBOST:

The following antiretrovirals are not recommended in combination with TYBOST because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:

  • More than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or a protease inhibitor in combination with elvitegravir)
  • Darunavir in combination with efavirenz, nevirapine, or etravirine
  • Atazanavir in combination with etravirine
  • Atazanavir in combination with efavirenz in treatment-experienced patients
  • Darunavir 600 mg twice daily
  • Other HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavir

TYBOST in combination with fixed-dose combination tablets that contain cobicistat is not recommended.

TYBOST in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of TYBOST and ritonavir on CYP3A.

Drug interactions

Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs:

Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may be increased if those drugs are coadministered with TYBOST.

Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s). Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring .

Potential Effect of Concomitant Drugs on the Pharmacokinetics of Cobicistat (Coadministered with Atazanavir or Darunavir):

Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A.

Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir, and darunavir, which may lead to loss of therapeutic effect and development of resistance

Coadministration of TYBOST with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir, and darunavir.

Established and Other Potentially Significant Interactions:

Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir.

Use in specific populations

Pregnanacy: TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy. In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during the second and third trimesters of pregnancy.

Lactation: There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Contraception: TYBOST interacts with certain oral contraceptives.

Pediatric Use: The safety and effectiveness of TYBOST coadministered with atazanavir or darunavir and two nucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection have been established in virologically suppressed pediatric patients

  • weighing at least 35 kg for TYBOST coadministered with atazanavir or
  • weighing at least 40 kg for TYBOST coadministered with darunavir

Geriatric Use: Clinical trials of TYBOST did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Renal Impairment: No dosage adjustment of TYBOST is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. TYBOST is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment.

Hepatic Impairment: No dosing adjustment of TYBOST is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment

Overdosage

If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with TYBOST consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.

As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

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