These Highlights Do Not Include All The Information Needed To Use Tybost Safely And Effectively. See Full Prescribing Information For Tybost.

Adult Patients:

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 [see Dosage and Administration (2.1)].

• TYBOST tablets, 150 mg, are orange, round, biconvex, film-coated, and debossed with “GSI” on one side and plain faced on the other side. (NDC 61958-1401-1).
• TYBOST tablets, 90 mg, are white, round, biconvex, film-coated, and debossed with “TYB” on one side and “90” on the other side. (NDC 61958-1402-1).

Store at 25 °C (77 °F); excursions permitted to 15°C –30 °C (59–86 °F) (see USP Controlled Room Temperature).

• Keep container tightly closed.
• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing.

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.

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. It has the following structural formula:

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 or 90 mg of cobicistat. The 150 mg and 90 mg tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 150 mg 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. The 90 mg tablets are film-coated with a coating material containing the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

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 pediatric patients weighing at least 14 kg [see Indications and Usage (1.1) and Dosage and Administration (2.2)].

Use of TYBOST and Darunavir

Adolescent Patients Weighing at Least 40 kg

Use of TYBOST and darunavir for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial (Trial 128; cohort 1 [Part A]) in virologically suppressed pediatric participants with HIV-1 aged 12 years and older (n=7). The safety, pharmacokinetics, and effectiveness in these participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing at Least 15 kg to Less than 40 kg:

Use of TYBOST and darunavir in combination with other ARVs is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and efficacy data from an open-label trial (Trial 128; cohorts 2 and 3) in pediatric participants with HIV-1 at least 2 years of age and weighing at least 15 kg to less than 40 kg (n=20, all of whom were virologically suppressed at baseline).

The safety, pharmacokinetics, and effectiveness of TYBOST when administered with darunavir in pediatric patients weighing at least 15 kg to less than 40 kg were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing Less than 15 kg:

Safety, pharmacokinetics, and effectiveness of TYBOST in combination with darunavir in pediatric patients weighing less than 15 kg have not been established.

Use of TYBOST and Atazanavir

Adolescent Patients Weighing at Least 35 kg:

Use of TYBOST and atazanavir is supported by evidence from adequate and well-controlled studies in adults, and by safety, pharmacokinetic, and efficacy data from an open-label trial (Trial 128; cohort 1 [Part A]) in pediatric participants with HIV-1 at least 12 years of age (n=14). The safety, pharmacokinetics, and effectiveness in these participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing at Least 14 kg to Less than 35 kg:

• Use of TYBOST and Atazanavir with Tenofovir Alafenamide (TAF)

The use of TYBOST in combination with atazanavir and TAF in pediatric patients weighing less than 35 kg is not recommended.

•  
  The use of TYBOST with atazanavir and emtricitabine/tenofovir alafenamide (FTC/TAF) was studied in pediatric participants weighing at least 14 kg to less than 35 kg. In Trial 128, patients who received ATV +cobicistat in cohort 2 (25 kg to <40 kg, n=14) and cohort 3 (14 kg to <25 kg, n=15) showed TAF exposures (C_max and AUC) that exceeded adult exposures by 4-5-fold in cohort 2 and 2-3-fold in cohort 3. Limited safety data were available to support the increased TAF exposures. Therefore, the use of TYBOST with atazanavir and TAF is not recommended in pediatric participants weighing at least 14 kg to less than 35 kg [see Drug Interactions (7.3)].
• •
  Use of TYBOST and Atazanavir with other antiretrovirals other than TAF
•  
  Use of TYBOST and atazanavir is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic data from Trial 128 in pediatric participants weighing at least 14 kg to less than 35 kg. In this population, the pharmacokinetics of atazanavir and cobicistat were similar to adults [see Clinical Pharmacology (12.3)].

Pediatric Patients Weighing Less than 14 kg:

Safety, pharmacokinetics, and effectiveness of TYBOST in combination with atazanavir in pediatric participants weighing less than 14 kg have not been established.

Clinical trials of TYBOST did not include sufficient numbers of participants aged 65 years and older to determine whether they respond differently from younger participants.

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 [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

• Alpha 1-adrenoreceptor antagonist: alfuzosin
• Antianginal: ranolazine
• Antiarrhythmic: dronedarone
• Anticonvulsants: carbamazepine, phenobarbital, phenytoin
• Anti-gout: colchicine
• Antimycobacterial: rifampin
• Antineoplastics: irinotecan
  These contraindications apply only to TYBOST coadministered with atazanavir
• 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

The following adverse reaction is described in greater detail in another section of the labeling:

• New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.2)].

TYBOST, in combination with atazanavir or darunavir, can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of TYBOST, atazanavir and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.3, 7, 12.3)

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 [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

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 participants with severe renal impairment and healthy participants. 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 [see Clinical Pharmacology (12.3)].

TYBOST has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with TYBOST [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].

• 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 [see Warnings and Precautions (5.4)].
• 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 [see Warnings and Precautions (5.3), Drug Interactions (7), and Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

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 14 kg. (1.1)

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. (1.2, 5.4)
• 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. (1.2, 5.3, 7, 12.3)

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.

• Assess creatinine clearance (CLcr) before initiating treatment. (5.1)
• When TYBOST is used in combination with a TDF-containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. (5.2)
• Use with TDF: 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)
• 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. (5.4)
• Use with HIV-1 protease inhibitors other than atazanavir or darunavir administered once daily is not recommended. (5.4)
• Coadministration with drugs or regimens containing ritonavir is not recommended. (5.4)

• TYBOST must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents. (2.1, 2.2)
• Recommended dosage in adults: (2.1)

• Recommended dosage in pediatric patients: TYBOST 150 mg or TYBOST 90 mg orally once daily based on body weight. For dosage recommendations for TYBOST and the coadministered protease inhibitor atazanavir or darunavir in pediatric patients, refer to Table 2 and Table 3 of the full prescribing information respectively. (2.2)
• Prior to starting TYBOST, assess estimated creatinine clearance. (2.3)
• Coadministration with tenofovir disoproxil fumarate (TDF): assess estimated creatinine clearance, urine glucose, and urine protein at baseline. (2.3)
• 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. (2.4)

TYBOST, 150 mg: Orange, round, biconvex, film-coated tablets debossed with "GSI" on one side and plain faced on the other side of the tablet.

TYBOST, 90 mg: White, round, biconvex, film-coated tablets debossed with "TYB" on one side and "90" on the other side of the tablet.

• Pregnancy: TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy. TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. (2.5, 8.1, 12.3)
• Pediatrics: Not recommended for patients weighing less than 14 kg. (8.4)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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.

Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see Dosage and Administration (2.3)]. Dosage recommendations are not available for drugs that require dosage adjustments in TYBOST-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.

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.

Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are presented in Table 1. TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

TYBOST tablets are available in bottles containing 30 tablets and a silica gel desiccant, with a child-resistant closure.

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 [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

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.

Prior to or when initiating TYBOST and during treatment with TYBOST, on a clinically appropriate schedule, assess estimated creatinine clearance because TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1)]. When coadministering TYBOST with TDF, assess estimated creatinine clearance, urine glucose, and urine protein at baseline. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2)].

Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of pediatric patients with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are based on weight and presented in Table 2 and Table 3, respectively. TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir.

NDC 61958-1402-1

30 tablets

Tybost ^®

(cobicistat) tablets

90 mg

Note to pharmacist:

Do not cover ALERT box

with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Tybost

Rx only

NDC 61958-1401-1

30 tablets

Tybost^®

(cobicistat) tablets

150 mg

Rx only

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Tybost

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.

Table 7 provides dosing recommendations as a result of drug interactions with TYBOST coadministered with atazanavir or darunavir. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].

In Table 7, if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir [see Clinical Pharmacology (12.3)].

In addition to the drug interactions noted in Table 7, TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see Warnings and Precautions (5.4)].

Evaluate whether dosing adjustments of concomitant medications or coadministered 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, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.

No dose adjustment is required when TDF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir.

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.

Trial 128 was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of TYBOST coadministered with atazanavir or darunavir in pediatric participants with HIV-1 and baseline estimated creatinine clearance ≥90 mL/min/1.73 m², including virologically-suppressed pediatric participants between the ages of 12 to less than 18 years (cohort 1 [Part A], N=22), pediatric participants between the ages of 6 to less than 12 years (cohort 2, N=23, 9 of whom switched to TYBOST co-administered with darunavir and were all virologically-suppressed at baseline), and pediatric participants at least 2 years of age (cohort 3, N=26, 11 of whom switched to TYBOST co-administered with darunavir and were all virologically-suppressed at baseline). Participants in cohort 1 (Part A) were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir or darunavir, both administered with ritonavir combined with 2 NRTIs or consisting of a third agent administered with 2 NRTIs (cohorts 2 and 3 only). TYBOST 150 mg was given once daily with atazanavir or darunavir in cohort 1 (Part A) and cohort 2. TYBOST 90 mg was given once daily with atazanavir or darunavir in cohort 3. For all cohorts, participants were administered a background regimen containing 2 NRTIs.

Cohort 1 (Part A): 12 to <18 years; ≥35 kg

In cohort 1 (Part A), the mean age of participants was 14 years (range 12 to 17 years); median weight was 55 kg; 62% were male, 38% were Asian, 33% were White, 19% were Black, and 67% were not Hispanic or Latino. At baseline, 20/21 participants had plasma HIV-1 RNA <50 copies/mL and 1 participant had plasma HIV-1 RNA of 50 copies/mL.

In participants who switched to TYBOST coadministered with atazanavir, 93% (13/14) of participants were suppressed (HIV-1 RNA <50 copies/mL) at Week 48 and 1 evaluable participant experienced virologic failure at Week 24 without significant emergent resistance associated substitutions in reverse transcriptase or protease. From a median baseline CD4+ cell count and CD4+% of 770 cells/mm³ (range 486 to 1765 cells/mm³) and 33% (range 23% to 45%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -60 cells/mm³ (range -500 to 705 cells/mm³) and -0.3% (range -6% to 8%), respectively.

In participants who switched to TYBOST coadministered with darunavir, 86% (6/7) of participants remained suppressed (HIV-1 RNA <50 copies/mL), and 1 subject had missing data at Week 48. From a median baseline CD4+ cell count and CD4+% of 1117 cells/mm³ (range 658 to 2416 cells/mm³) and 45% (range 28% to 56%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -342 cells/mm³ (range -1389 to 219 cells/mm³) and -6% (range -12% to 5%), respectively. All 6 participants with available data had CD4+ cell counts above 800 cells/mm³ at Week 48.

Cohort 2: 6 to <12 years; ≥25 kg to <40 kg

Participants in cohort 2 who switched to TYBOST coadministered with darunavir (n=9) had a mean age of 10 years (range 9 to 11 years); median weight was 29 kg; 11% were male, and 89% were Black. At baseline, all participants had plasma HIV-1 RNA <50 copies/mL.

In these participants who switched to TYBOST coadministered with darunavir, 100% (9/9) of participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 48. From a mean (SD) baseline CD4+ count of 898 (209), the mean (SD) change from baseline in CD4+ cell count was 10 (199) cells/mm³ and the mean (SD) change in CD4% was 1.26% (6.2%) at Week 48.

Cohort 3: ≥2 years; ≥14 kg to <25 kg

Participants in cohort 3 who switched to TYBOST coadministered with darunavir (n=11) had a mean age of 5 years (range 3 to 7 years); median weight was 17 kg; 45% were male, and 100% were Black. At baseline, all participants had plasma HIV-1 RNA <50 copies/mL.

In these participants who switched to TYBOST coadministered with darunavir, 91% (10/11) of participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 48. From a mean (SD) CD4+ count of 1185 (317), the mean (SD) change from baseline in CD4+ cell count was -122 (329) cells/mm³ and the mean (SD) change in CD4% was 1.4% (2.5%) at Week 48.

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 [see Dosage and Administration (2.3, 2.4)].
• Document urine glucose and urine protein at baseline [see Dosage and Administration (2.3)] 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.

In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) participants treated with TYBOST coadministered with atazanavir and TRUVADA^® and 11 (3.2%) participants treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Seven of the 10 participants (2.0% overall) in the TYBOST group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 participants (2.0% overall) in the ritonavir group. One participant in the TYBOST group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 participants with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of TYBOST coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any participant.

The activity of TYBOST as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with TYBOST 150 mg was consistent with those observed with ritonavir 100 mg [see Clinical Pharmacology (12.2)]. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir.

The safety and efficacy of TYBOST coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Trial 114) in treatment-naïve participants with HIV-1 and baseline estimated creatinine clearance above 70 mL/min (N=692). In Trial 114, participants were randomized in a 1:1 ratio to receive either atazanavir 300 mg + TYBOST 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All participants received concomitant treatment with 300 mg of TDF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).

The mean age of participants was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀ copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm³ (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm³.

Virologic outcomes in Trial 114 through Week 144 are presented in Table 13. In Trial 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm³ in the TYBOST group and 297 cells/mm³ in the ritonavir group.

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.

These interactions may lead to:

• clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications.
• clinically significant adverse reactions from higher exposures of TYBOST and atazanavir or darunavir.

These interactions may lead to:

• 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).

See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during TYBOST with atazanavir or darunavir therapy; review concomitant medications during TYBOST with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].

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 [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

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.

Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.

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 as shown in Table 7.

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 (see Table 7).

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 (see Table 7).

Adult Patients:

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 [see Dosage and Administration (2.1)].

• TYBOST tablets, 150 mg, are orange, round, biconvex, film-coated, and debossed with “GSI” on one side and plain faced on the other side. (NDC 61958-1401-1).
• TYBOST tablets, 90 mg, are white, round, biconvex, film-coated, and debossed with “TYB” on one side and “90” on the other side. (NDC 61958-1402-1).

Store at 25 °C (77 °F); excursions permitted to 15°C –30 °C (59–86 °F) (see USP Controlled Room Temperature).

• Keep container tightly closed.
• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing.

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.

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. It has the following structural formula:

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 or 90 mg of cobicistat. The 150 mg and 90 mg tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 150 mg 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. The 90 mg tablets are film-coated with a coating material containing the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

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 pediatric patients weighing at least 14 kg [see Indications and Usage (1.1) and Dosage and Administration (2.2)].

Use of TYBOST and Darunavir

Adolescent Patients Weighing at Least 40 kg

Use of TYBOST and darunavir for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial (Trial 128; cohort 1 [Part A]) in virologically suppressed pediatric participants with HIV-1 aged 12 years and older (n=7). The safety, pharmacokinetics, and effectiveness in these participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing at Least 15 kg to Less than 40 kg:

Use of TYBOST and darunavir in combination with other ARVs is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and efficacy data from an open-label trial (Trial 128; cohorts 2 and 3) in pediatric participants with HIV-1 at least 2 years of age and weighing at least 15 kg to less than 40 kg (n=20, all of whom were virologically suppressed at baseline).

The safety, pharmacokinetics, and effectiveness of TYBOST when administered with darunavir in pediatric patients weighing at least 15 kg to less than 40 kg were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing Less than 15 kg:

Safety, pharmacokinetics, and effectiveness of TYBOST in combination with darunavir in pediatric patients weighing less than 15 kg have not been established.

Use of TYBOST and Atazanavir

Adolescent Patients Weighing at Least 35 kg:

Use of TYBOST and atazanavir is supported by evidence from adequate and well-controlled studies in adults, and by safety, pharmacokinetic, and efficacy data from an open-label trial (Trial 128; cohort 1 [Part A]) in pediatric participants with HIV-1 at least 12 years of age (n=14). The safety, pharmacokinetics, and effectiveness in these participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing at Least 14 kg to Less than 35 kg:

• Use of TYBOST and Atazanavir with Tenofovir Alafenamide (TAF)

The use of TYBOST in combination with atazanavir and TAF in pediatric patients weighing less than 35 kg is not recommended.

•  
  The use of TYBOST with atazanavir and emtricitabine/tenofovir alafenamide (FTC/TAF) was studied in pediatric participants weighing at least 14 kg to less than 35 kg. In Trial 128, patients who received ATV +cobicistat in cohort 2 (25 kg to <40 kg, n=14) and cohort 3 (14 kg to <25 kg, n=15) showed TAF exposures (C_max and AUC) that exceeded adult exposures by 4-5-fold in cohort 2 and 2-3-fold in cohort 3. Limited safety data were available to support the increased TAF exposures. Therefore, the use of TYBOST with atazanavir and TAF is not recommended in pediatric participants weighing at least 14 kg to less than 35 kg [see Drug Interactions (7.3)].
• •
  Use of TYBOST and Atazanavir with other antiretrovirals other than TAF
•  
  Use of TYBOST and atazanavir is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic data from Trial 128 in pediatric participants weighing at least 14 kg to less than 35 kg. In this population, the pharmacokinetics of atazanavir and cobicistat were similar to adults [see Clinical Pharmacology (12.3)].

Pediatric Patients Weighing Less than 14 kg:

Safety, pharmacokinetics, and effectiveness of TYBOST in combination with atazanavir in pediatric participants weighing less than 14 kg have not been established.

Clinical trials of TYBOST did not include sufficient numbers of participants aged 65 years and older to determine whether they respond differently from younger participants.

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 [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

• Alpha 1-adrenoreceptor antagonist: alfuzosin
• Antianginal: ranolazine
• Antiarrhythmic: dronedarone
• Anticonvulsants: carbamazepine, phenobarbital, phenytoin
• Anti-gout: colchicine
• Antimycobacterial: rifampin
• Antineoplastics: irinotecan
  These contraindications apply only to TYBOST coadministered with atazanavir
• 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

The following adverse reaction is described in greater detail in another section of the labeling:

• New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.2)].

TYBOST, in combination with atazanavir or darunavir, can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of TYBOST, atazanavir and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.3, 7, 12.3)

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 [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

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 participants with severe renal impairment and healthy participants. 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 [see Clinical Pharmacology (12.3)].

TYBOST has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with TYBOST [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].

• 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 [see Warnings and Precautions (5.4)].
• 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 [see Warnings and Precautions (5.3), Drug Interactions (7), and Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

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 14 kg. (1.1)

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. (1.2, 5.4)
• 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. (1.2, 5.3, 7, 12.3)

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.

• Assess creatinine clearance (CLcr) before initiating treatment. (5.1)
• When TYBOST is used in combination with a TDF-containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. (5.2)
• Use with TDF: 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)
• 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. (5.4)
• Use with HIV-1 protease inhibitors other than atazanavir or darunavir administered once daily is not recommended. (5.4)
• Coadministration with drugs or regimens containing ritonavir is not recommended. (5.4)

• TYBOST must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents. (2.1, 2.2)
• Recommended dosage in adults: (2.1)

• Recommended dosage in pediatric patients: TYBOST 150 mg or TYBOST 90 mg orally once daily based on body weight. For dosage recommendations for TYBOST and the coadministered protease inhibitor atazanavir or darunavir in pediatric patients, refer to Table 2 and Table 3 of the full prescribing information respectively. (2.2)
• Prior to starting TYBOST, assess estimated creatinine clearance. (2.3)
• Coadministration with tenofovir disoproxil fumarate (TDF): assess estimated creatinine clearance, urine glucose, and urine protein at baseline. (2.3)
• 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. (2.4)

TYBOST, 150 mg: Orange, round, biconvex, film-coated tablets debossed with "GSI" on one side and plain faced on the other side of the tablet.

TYBOST, 90 mg: White, round, biconvex, film-coated tablets debossed with "TYB" on one side and "90" on the other side of the tablet.

• Pregnancy: TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy. TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. (2.5, 8.1, 12.3)
• Pediatrics: Not recommended for patients weighing less than 14 kg. (8.4)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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.

Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see Dosage and Administration (2.3)]. Dosage recommendations are not available for drugs that require dosage adjustments in TYBOST-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.

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.

Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are presented in Table 1. TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

TYBOST tablets are available in bottles containing 30 tablets and a silica gel desiccant, with a child-resistant closure.

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 [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

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.

Prior to or when initiating TYBOST and during treatment with TYBOST, on a clinically appropriate schedule, assess estimated creatinine clearance because TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1)]. When coadministering TYBOST with TDF, assess estimated creatinine clearance, urine glucose, and urine protein at baseline. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2)].

Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of pediatric patients with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are based on weight and presented in Table 2 and Table 3, respectively. TYBOST must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir.

NDC 61958-1402-1

30 tablets

Tybost ^®

(cobicistat) tablets

90 mg

Note to pharmacist:

Do not cover ALERT box

with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Tybost

Rx only

NDC 61958-1401-1

30 tablets

Tybost^®

(cobicistat) tablets

150 mg

Rx only

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Tybost

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.

Table 7 provides dosing recommendations as a result of drug interactions with TYBOST coadministered with atazanavir or darunavir. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].

In Table 7, if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir [see Clinical Pharmacology (12.3)].

In addition to the drug interactions noted in Table 7, TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see Warnings and Precautions (5.4)].

Evaluate whether dosing adjustments of concomitant medications or coadministered 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, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.

No dose adjustment is required when TDF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir.

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.

Trial 128 was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of TYBOST coadministered with atazanavir or darunavir in pediatric participants with HIV-1 and baseline estimated creatinine clearance ≥90 mL/min/1.73 m², including virologically-suppressed pediatric participants between the ages of 12 to less than 18 years (cohort 1 [Part A], N=22), pediatric participants between the ages of 6 to less than 12 years (cohort 2, N=23, 9 of whom switched to TYBOST co-administered with darunavir and were all virologically-suppressed at baseline), and pediatric participants at least 2 years of age (cohort 3, N=26, 11 of whom switched to TYBOST co-administered with darunavir and were all virologically-suppressed at baseline). Participants in cohort 1 (Part A) were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir or darunavir, both administered with ritonavir combined with 2 NRTIs or consisting of a third agent administered with 2 NRTIs (cohorts 2 and 3 only). TYBOST 150 mg was given once daily with atazanavir or darunavir in cohort 1 (Part A) and cohort 2. TYBOST 90 mg was given once daily with atazanavir or darunavir in cohort 3. For all cohorts, participants were administered a background regimen containing 2 NRTIs.

Cohort 1 (Part A): 12 to <18 years; ≥35 kg

In cohort 1 (Part A), the mean age of participants was 14 years (range 12 to 17 years); median weight was 55 kg; 62% were male, 38% were Asian, 33% were White, 19% were Black, and 67% were not Hispanic or Latino. At baseline, 20/21 participants had plasma HIV-1 RNA <50 copies/mL and 1 participant had plasma HIV-1 RNA of 50 copies/mL.

In participants who switched to TYBOST coadministered with atazanavir, 93% (13/14) of participants were suppressed (HIV-1 RNA <50 copies/mL) at Week 48 and 1 evaluable participant experienced virologic failure at Week 24 without significant emergent resistance associated substitutions in reverse transcriptase or protease. From a median baseline CD4+ cell count and CD4+% of 770 cells/mm³ (range 486 to 1765 cells/mm³) and 33% (range 23% to 45%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -60 cells/mm³ (range -500 to 705 cells/mm³) and -0.3% (range -6% to 8%), respectively.

In participants who switched to TYBOST coadministered with darunavir, 86% (6/7) of participants remained suppressed (HIV-1 RNA <50 copies/mL), and 1 subject had missing data at Week 48. From a median baseline CD4+ cell count and CD4+% of 1117 cells/mm³ (range 658 to 2416 cells/mm³) and 45% (range 28% to 56%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -342 cells/mm³ (range -1389 to 219 cells/mm³) and -6% (range -12% to 5%), respectively. All 6 participants with available data had CD4+ cell counts above 800 cells/mm³ at Week 48.

Cohort 2: 6 to <12 years; ≥25 kg to <40 kg

Participants in cohort 2 who switched to TYBOST coadministered with darunavir (n=9) had a mean age of 10 years (range 9 to 11 years); median weight was 29 kg; 11% were male, and 89% were Black. At baseline, all participants had plasma HIV-1 RNA <50 copies/mL.

In these participants who switched to TYBOST coadministered with darunavir, 100% (9/9) of participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 48. From a mean (SD) baseline CD4+ count of 898 (209), the mean (SD) change from baseline in CD4+ cell count was 10 (199) cells/mm³ and the mean (SD) change in CD4% was 1.26% (6.2%) at Week 48.

Cohort 3: ≥2 years; ≥14 kg to <25 kg

Participants in cohort 3 who switched to TYBOST coadministered with darunavir (n=11) had a mean age of 5 years (range 3 to 7 years); median weight was 17 kg; 45% were male, and 100% were Black. At baseline, all participants had plasma HIV-1 RNA <50 copies/mL.

In these participants who switched to TYBOST coadministered with darunavir, 91% (10/11) of participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 48. From a mean (SD) CD4+ count of 1185 (317), the mean (SD) change from baseline in CD4+ cell count was -122 (329) cells/mm³ and the mean (SD) change in CD4% was 1.4% (2.5%) at Week 48.

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 [see Dosage and Administration (2.3, 2.4)].
• Document urine glucose and urine protein at baseline [see Dosage and Administration (2.3)] 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.

In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) participants treated with TYBOST coadministered with atazanavir and TRUVADA^® and 11 (3.2%) participants treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Seven of the 10 participants (2.0% overall) in the TYBOST group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 participants (2.0% overall) in the ritonavir group. One participant in the TYBOST group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 participants with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of TYBOST coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any participant.

The activity of TYBOST as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with TYBOST 150 mg was consistent with those observed with ritonavir 100 mg [see Clinical Pharmacology (12.2)]. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir.

The safety and efficacy of TYBOST coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Trial 114) in treatment-naïve participants with HIV-1 and baseline estimated creatinine clearance above 70 mL/min (N=692). In Trial 114, participants were randomized in a 1:1 ratio to receive either atazanavir 300 mg + TYBOST 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All participants received concomitant treatment with 300 mg of TDF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).

The mean age of participants was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀ copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm³ (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm³.

Virologic outcomes in Trial 114 through Week 144 are presented in Table 13. In Trial 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm³ in the TYBOST group and 297 cells/mm³ in the ritonavir group.

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.

These interactions may lead to:

• clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications.
• clinically significant adverse reactions from higher exposures of TYBOST and atazanavir or darunavir.

These interactions may lead to:

• 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).

See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during TYBOST with atazanavir or darunavir therapy; review concomitant medications during TYBOST with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].

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 [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

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.

Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.

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 as shown in Table 7.

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 (see Table 7).

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 (see Table 7).