negative [750/mm:500 msec [see Warnings and Precautions (5.1) ] . Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, cobicistat 250 mg (1.7 times the recommended dosage in Evotaz) and 400 mg (2.7 times the recommended dosage in Evotaz) did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg dose of cobicistat . Effects on Serum Creatinine The effect of cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR 80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50-79 mL/min, N=18). A statistically significant change in estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFR CG ) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function ( 9.9 13.1 mL/min) and mild-to-moderate renal impairment ( 11.9 7.0 mL/min). No statistically significant changes in eGFR CG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFR CG , without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.3) ] . Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of the components of Evotaz (atazanavir 300 mg and cobicistat 150 mg) were evaluated in healthy adult volunteers. Results are summarized in Table 6. Table 6: Pharmacokinetic Properties of the Components of Evotaz Atazanavir Cobicistat a Following Evotaz dosing under fasted conditions. b Values refer to geometric mean ratio (fed / fasted) and (90% confidence interval). c Dosing in mass balance study: cobicistat (single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days). ND = not determined. Absorption T max (h) 2.0 2.0 Effect of light meal (relative to fasting) AUC ratio b 1.28 (1.17,1.40) 1.24 (1.15,1.34) Effect of high fat meal (relative to fasting) AUC ratio b 0.96 (0.81,1.13) 1.12 (1.01,1.23) Effect of light meal (relative to fasting) C24 ratio b 1.35 (1.22,1.50) ND Effect of high fat meal (relative to fasting) C24 ratio b 1.23 (1.02,1.48) ND Distribution % Bound to human plasma proteins 86 ~98 Source of protein binding data In vitro In vitro Blood-to-plasma ratio ND 0.5 Metabolism Metabolism CYP3A (major) Glucuronidation, N-dealkylation, hydrolysis, oxygenation with dehydrogenation (minor) CYP3A (major) CYP2D6 (minor) Elimination Major route of elimination Metabolism Metabolism t 1/2 (h) 7.2 a 3.5 % Of dose excreted in urine ND 8.2 c % Of dose excreted in feces ND 86.2 c The pharmacokinetics of atazanavir was evaluated in HIV-1 infected subjects who received atazanavir 300 mg coadministered with cobicistat 150 mg in combination with emtricitabine/tenofovir DF. The steady-state pharmacokinetic parameters of atazanavir coadministered with cobicistat are shown in Table 7 [see Clinical Studies (14) ] . Table 7: Pharmacokinetic Parameters (Mean SD) of Atazanavir in the Pharmacokinetic Substudy of Study 114 Parameter Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=22) AUC (µg h/mL) 46.13 26.18 C max (µg/mL) 3.91 1.94 C tau (µg/mL) 0.80 0.72 Specific Populations Renal Impairment Atazanavir: In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C max was 9% lower, AUC was 19% higher, and C min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C max , AUC, and C min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Cobicistat: A study of the pharmacokinetics of cobicistat was performed in non HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects [see Use in Specific Populations (8.6) ] . Hepatic Impairment Evotaz has not been studied in patients with hepatic impairment. Atazanavir: Atazanavir is primarily metabolized and eliminated by the liver. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function. Cobicistat: Cobicistat is primarily metabolized and eliminated by the liver. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7) ] . Gender and Age Atazanavir: There were no clinically important pharmacokinetic differences observed due to age or gender. Cobicistat: No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat. Assessment of Drug Interactions Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. Drug interaction studies were not conducted for Evotaz or for atazanavir coadministered with cobicistat. Drug interaction studies of cobicistat were conducted with desipramine, digoxin, and efavirenz. Drug interaction studies of cobicistat coadministered with elvitegravir included rosuvastatin and rifabutin. The effects of cobicistat on the exposure of coadministered drugs are summarized in Table 8. For information regarding clinical recommendations, [see Drug Interactions (7) ] . Table 8: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat a Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat-containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information. Coadministered Drug Coadministered Drug Dose/Schedule Cobicistat Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without cobicistat; No Effect = 1.00 C max AUC C min a All interaction studies conducted in healthy volunteers. NC = not calculated desipramine 50 mg single dose (n=8) 150 mg QD (n=8) 1.24 (1.08, 1.44) 1.65 (1.36, 2.02) NC digoxin 0.5 mg single dose (n=22) 150 mg QD (n=22) 1.41 (1.29, 1.55) 1.08 (1.00, 1.17) NC efavirenz 600 mg single dose (n=17) 150 mg QD (n=17) 0.87 (0.80, 0.94) 0.93 (0.89, 0.97) NC Microbiology Mechanism of Action Evotaz is a fixed-dose combination of atazanavir (ATV) and the CYP3A inhibitor cobicistat. ATV is an azapeptide HIV-1 protease inhibitor (PI) that selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of the CYP3A substrate atazanavir. Antiviral Activity in Cell Culture Atazanavir exhibits anti HIV-1 activity with a mean 50% effective concentration (EC 50 value) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT 2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat. Resistance In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir coadministered with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant. Clinical Studies: Resistance to Evotaz is driven by atazanavir as cobicistat lacks antiviral activity. For the complete atazanavir resistance-associated substitutions, refer to the atazanavir full prescribing information. Clinical Studies of Treatment-Naive Patients Receiving Atazanavir 300 mg Coadministered with Cobicistat 150 mg: n an analysis of treatment-failure subjects who received atazanavir coadministered with cobicistat in Study 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in this group (6%, 21/344). Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures (5%, 19/348). Among the 19 subjects, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir- or protease inhibitor-associated resistance substitutions. Cross-Resistance Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs. International AIDS Society (IAS)-defined PI resistance substitutions, depending on the number and type, may confer a reduced virologic response to atazanavir. Please refer to the Baseline Genotype/Phenotype and Virologic Outcome Analyses section in the atazanavir full prescribing information. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Atazanavir: Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir coadministered with 100 mg/day ritonavir, nonpregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose. Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose. Mutagenesis Atazanavir: Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Cobicistat: Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays. Impairment of Fertility Atazanavir: At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir coadministered with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed. Cobicistat: Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose. Clinical Studies The safety and efficacy of atazanavir coadministered with cobicistat were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naive subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg coadministered with cobicistat 150 mg once daily or atazanavir 300 mg coadministered with ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as a single tablet. Randomization was stratified by screening HIV-1 RNA level ( 100,000 copies/mL or >100,000 copies/mL). The mean age of subjects 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 log 10 copies/mL (range: 3.2-6.4). The mean baseline CD4+ cell count was 352 cells/mm 3 (range: 1-1455) and 17% had CD4+ cell counts 200 cells/mm 3 . Forty percent (40%) of patients had baseline viral loads >100,000 copies/mL. Virologic outcomes in Study 114 through Week 144 are presented in Table 9. In Study 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm3 in patients receiving atazanavir coadministered with cobicistat and 297 cells/mm3 in patients receiving atazanavir coadministered with ritonavir. Table 9: Virologic Outcomes of Randomized Treatment of Study 114 in HIV-1 Infected Treatment-Naive Adults at Week 144 a Atazanavir 300 mg coadministered with cobicistat 150 mg (once daily) + emtricitabine/tenofovir disoproxil fumarate (n=344) Atazanavir 300 mg coadministered with ritonavir 100 mg + emtricitabine/tenofovir disoproxil fumarate (n=348) a Week 144 window is between Day 967 and 1050 (inclusive). b Includes subjects who had 50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of 50 copies/mL. c Includes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. There were no deaths reported in Study 114. d Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy (e.g., withdrew consent, lost to follow-up, etc). HIV-1 RNA]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only B Pregnancy Category No proven risk in humans N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturer Bristol-Myers Squibb Company Drug Class Antiviral combinations Related Drugs antiviral combinations Harvoni , Truvada , Atripla , Genvoya , Triumeq , Stribild HIV Infection Truvada , Atripla , Norvir , Viread , Isentress , Prezista , Stribild , lamivudine , abacavir , tenofovir , Epzicom , Reyataz , ritonavir , Complera , darunavir , emtricitabine , Kaletra , Intelence , Sustiva , Epivir , efavirenz , nevirapine , atazanavir , raltegravir , Selzentry , More... Evotaz Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first! Evotaz Images Evotaz atazanavir 300 mg / cobicistat 150 mg (3641 ) View larger images} } that offer
let you Evotaz learning
EmoticonEmoticon