Tybost

5 WARNINGS AND PRECAUTIONS 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 ) 5.1 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. 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. 5.2 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 [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. 5.3 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. 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) ]. 5.4 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.

6 ADVERSE REACTIONS 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) ]. The most common adverse drug reactions observed with TYBOST in combination with atazanavir (incidence greater than 5%, Grades 2−4) are jaundice and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trials Experience in Adults The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 antiretroviral treatment-naïve participants with HIV-1 received: TYBOST coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=344) or ritonavir coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=348). The most common adverse reactions (Grades 2−4) and reported in >5% of participants in the TYBOST group were jaundice (6%) and rash (5%). The proportion of participants who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups. Table 4 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of participants in the TYBOST group in Trial 114. Table 4 Selected Adverse Reactions Frequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs. (Grades 2−4) Reported in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST Coadministered with Atazanavir + TRUVADA N=344 Ritonavir Coadministered with Atazanavir + TRUVADA N=348 Jaundice 6% 3% Rash Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria. 5% 4% Ocular icterus 4% 2% Nausea 2% 2% Diarrhea 2% 1% Headache 2% 1% Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of participants receiving TYBOST coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir. Gastrointestinal Disorders: vomiting, upper abdominal pain General Disorders and Administration Site Conditions: fatigue Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Psychiatric Disorders: depression, abnormal dreams, insomnia Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3−4) occurring in at least 2% of participants in the TYBOST group in Trial 114 is presented in Table 5 . Table 5 Laboratory Abnormalities (Grades 3−4) in ≥2% of Treatment-Naïve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Laboratory Parameter Abnormality N=344 N=348 Total Bilirubin (>2.5 × ULN) 73% 66% Creatine Kinase (≥10.0 × ULN) 8% 9% Urine RBC (Hematuria) (>75 RBC/HPF) 6% 3% ALT (>5.0 × ULN) 6% 3% AST (>5.0 × ULN) 4% 3% GGT (>5.0 × ULN) 4% 2% Serum Amylase For participants with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3−4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively. (>2.0 × ULN) 4% 2% Urine Glucose (Glycosuria) (≥1000 mg/dL) 3% 3% Neutrophils (<750/mm 3 ) 3% 2% Serum Glucose (Hyperglycemia) (>250 mg/dL) 2% 2% Increase in Serum Creatinine : TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group. Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 6 . In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown. Table 6 Lipid Values, Mean Change from Baseline, Reported in Treatment-Naïve Adults with HIV-1 Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis) TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA Baseline Week 144 Baseline Week 144 mg/dL Change from baseline The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes participants receiving an HMG-CoA reductase inhibitor drug. mg/dL Change from baseline Total Cholesterol (fasted) 163 [N=219] +11 [N=219] 165 [N=227] +13 [N=227] HDL-cholesterol (fasted) 43 [N=218] +7 [N=218] 43 [N=228] +6 [N=228] LDL-cholesterol (fasted) 102 [N=218] +11 [N=218] 104 [N=228] +16 [N=228] Triglycerides (fasted) 130 [N=219] +14 [N=219] 131 [N=227] +14 [N=227] Adverse Reactions from Clinical Trials Experience in Pediatric Participants The safety of TYBOST was evaluated in an open-label clinical trial (Trial 128) of pediatric participants with HIV-1 administered TYBOST-boosted atazanavir or darunavir plus two nucleoside reverse transcriptase inhibitors; this study included 22 virologically-suppressed participants between the ages of 12 to less than 18 years (weighing ≥35 kg) administered atazanavir (N=14) or darunavir (N=7) through Week 48; 9 virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg to less than 40 kg administered darunavir (N=9) through Week 48; and 11 virologically-suppressed participants at least 2 years of age (weighing ≥14 kg to <25 kg) administered darunavir through Week 48 [see Drug Interactions (7.3) , Use in Specific Populations (8.4) , Clinical Studies (14.2) ] . In this trial, the safety profile of TYBOST was similar to that in adults.

<table width="75%" ID="table4"><caption>Table 4 Selected Adverse Reactions<footnote>Frequencies of adverse reactions are based on Grades 2&#x2013;4 adverse events attributed to study drugs.</footnote> (Grades 2&#x2212;4) Reported in &#x2265;2% of Treatment-Na&#xEF;ve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis) </caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">TYBOST Coadministered with Atazanavir + TRUVADA N=344</th><th styleCode="Rrule">Ritonavir Coadministered with Atazanavir + TRUVADA N=348</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Jaundice</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Lrule Rrule Toprule">Rash<footnote>Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria.</footnote></td><td styleCode="Rrule Toprule">5%</td><td styleCode="Rrule Toprule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule Toprule">Ocular icterus</td><td styleCode="Rrule Toprule">4%</td><td styleCode="Rrule Toprule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr></tbody></table>

<table width="75%" ID="table5"><caption>Table 5 Laboratory Abnormalities (Grades 3&#x2212;4) in &#x2265;2% of Treatment-Na&#xEF;ve Adults with HIV-1 in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis)</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule">TYBOST + Atazanavir + TRUVADA</th><th styleCode="Rrule">Ritonavir + Atazanavir + TRUVADA</th></tr><tr><th styleCode="Lrule Rrule">Laboratory Parameter Abnormality</th><th styleCode="Rrule" align="center" valign="middle">N=344</th><th styleCode="Rrule" align="center" valign="middle">N=348</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Total Bilirubin (&gt;2.5 &#xD7; ULN)</td><td styleCode="Rrule">73%</td><td styleCode="Rrule">66%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Creatine Kinase (&#x2265;10.0 &#xD7; ULN)</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">9%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urine RBC (Hematuria) (&gt;75 RBC/HPF)</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ALT (&gt;5.0 &#xD7; ULN)</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">AST (&gt;5.0 &#xD7; ULN)</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">GGT (&gt;5.0 &#xD7; ULN)</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Serum Amylase<footnote ID="foot31">For participants with serum amylase &gt;1.5 &#xD7; upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3&#x2212;4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively.</footnote> (&gt;2.0 &#xD7; ULN)</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urine Glucose (Glycosuria) (&#x2265;1000 mg/dL)</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophils (&lt;750/mm³)</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr><td styleCode="Lrule Rrule">Serum Glucose (Hyperglycemia) (&gt;250 mg/dL)</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr></tbody></table>

<table width="75%" ID="table6"><caption>Table 6 Lipid Values, Mean Change from Baseline, Reported in Treatment-Na&#xEF;ve Adults with HIV-1 Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis)</caption><col width="28%" align="left" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="18%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="3"/><th styleCode="Rrule" colspan="2">TYBOST + Atazanavir + TRUVADA</th><th styleCode="Rrule" colspan="2">Ritonavir + Atazanavir + TRUVADA</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" align="center">Baseline</th><th styleCode="Rrule">Week 144</th><th styleCode="Rrule">Baseline</th><th styleCode="Rrule">Week 144</th></tr><tr><th styleCode="Rrule" align="center">mg/dL</th><th styleCode="Rrule">Change from baseline<footnote ID="foot41">The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes participants receiving an HMG-CoA reductase inhibitor drug.</footnote></th><th styleCode="Rrule">mg/dL</th><th styleCode="Rrule">Change from baseline<footnoteRef IDREF="foot41"/></th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Total Cholesterol (fasted)</td><td styleCode="Rrule">163 [N=219]</td><td styleCode="Rrule">+11 [N=219]</td><td styleCode="Rrule">165 [N=227]</td><td styleCode="Rrule">+13 [N=227]</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">HDL-cholesterol (fasted)</td><td styleCode="Rrule">43 [N=218]</td><td styleCode="Rrule">+7 [N=218]</td><td styleCode="Rrule">43 [N=228]</td><td styleCode="Rrule">+6 [N=228]</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">LDL-cholesterol (fasted)</td><td styleCode="Rrule">102 [N=218]</td><td styleCode="Rrule">+11 [N=218]</td><td styleCode="Rrule">104 [N=228]</td><td styleCode="Rrule">+16 [N=228]</td></tr><tr><td styleCode="Lrule Rrule">Triglycerides (fasted)</td><td styleCode="Rrule">130 [N=219]</td><td styleCode="Rrule">+14 [N=219]</td><td styleCode="Rrule">131 [N=227]</td><td styleCode="Rrule">+14 [N=227]</td></tr></tbody></table>