Treatment for overdosage with EVOTAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient's clinical status. There is no specific antidote for overdose with EVOTAZ. Since atazanavir is extensively metabolized by the liver and both atazanavir and cobicistat are highly bound plasma proteins, it is unlikely that EVOTAZ will be significantly removed by hemodialysis or peritoneal dialysis.
Atazanavir: Human experience of acute overdose with atazanavir is limited. A single self-administered overdose of 29.2 g of atazanavir in an HIV-infected patient (73 times the 400-mg recommended dose of atazanavir administered without a CYP3A inhibitor) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At atazanavir doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed.
EVOTAZ is contraindicated:
Table 1 displays drugs that are contraindicated with EVOTAZ.
Table 1: Drugs that are
Contraindicated with EVOTAZ
| Drug Class | Drugs within class that are contraindicated with EVOTAZ | Clinical Comment |
| Alpha 1- Adrenoreceptor Antagonist | Alfuzosin | Potential for increased alfuzosin concentrations, which can result in hypotension. |
| Antianginal | Ranolazine | Potential for serious and/or life-threatening reactions. |
| Antiarrhythmics | Dronedarone | Potential for increased dronedarone concentrations. |
| Anticonvulsants | Carbamazepine, phenobarbital, phenytoin | Potential for decreased atazanavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. |
| Antigout | Colchicine | Contraindicated in patients with renal and/or hepatic impairment due to the potential for serious and/or life-threatening reactions. |
| Antimycobacterials | Rifampin | Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance. |
| Antineoplastics | Irinotecan | Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities. |
| Antipsychotic | Lurasidone Pimozide |
Potential for serious and/or life-threatening reactions. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Benzodiazepines | Triazolam, orally administered midazolama | Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with atazanavir may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. |
| Ergot Derivatives | Dihydroergotamine, ergotamine, methylergonovine | Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI Motility Agent | Cisapride | Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Hepatitis C Direct-Acting Antivirals | Elbasvir/grazoprevir | May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. |
| Herbal Products | St. John’s wort (Hypericum perforatum) | Coadministration of products containing St. John’s wort and EVOTAZ may result in loss of therapeutic effect and development of resistance. |
| HMG-CoA Reductase Inhibitors | Lovastatin, simvastatin | Potential for serious reactions such as myopathy including rhabdomyolysis. |
| Non-nucleoside Reverse Transcriptase Inhibitors | Nevirapine | Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures. |
| Phosphodiesterase-5 (PDE-5) Inhibitors | Sildenafilb when administered for the treatment of pulmonary arterial hypertension | Potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope). |
| Protease Inhibitors | Indinavir | Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. |
| a See DRUG
INTERACTIONS, Table 5 for parenterally administered midazolam. b See DRUG INTERACTIONS, Table 5 for sildenafil when administered for erectile dysfunction. |
The following adverse reactions are discussed in greater detail in other sections of the labeling:
For additional safety information about atazanavir and cobicistat, consult the full prescribing information for these individual products.
Clinical Trial Experience In AdultsBecause 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.
The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naive subjects received:
The most common adverse reactions (Grades 2-4) and reported in ≥5% of subjects in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%).
The proportion of subjects who discontinued study treatment due to adverse events regardless of severity was 11% in both the atazanavir coadministered with cobicistat and atazanavir coadministered with ritonavir groups. Table 2 lists the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study 114.
Table 2: Selected Adverse Reactionsa (Grades 2-4)
Reported in ≥2% of HIV1 Infected Treatment-Naive Adults in
the Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144
analysis)
| Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344) |
Atazanavir coadministered with ritonavir and emtricitabine /tenofovir DF (n=348) |
|
| Jaundice | 6% | 3% |
| Rashb | 5% | 4% |
| Ocular icterus | 4% | 2% |
| Nausea | 2% | 2% |
| Diarrhea | 2% | 1% |
| Headache | 2% | 1% |
| a Frequencies of adverse reactions are based
on Grades 2-4 adverse events attributed to study drugs. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, and urticaria. |
Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF are listed below. These events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with atazanavir coadministered with cobicistat, and reported with greater frequency compared with the atazanavir coadministered with ritonavir group.
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
Laboratory AbnormalitiesThe frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study 114 is presented in Table 3.
Table 3: Laboratory Abnormalities (Grades 3-4)
Reported in ≥2% of HIV-1 Infected Treatment-Naive Adults in the
Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144
analysis)
| Laboratory Parameter Abnormality | 144 weeks Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344) |
144 weeks Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF (n=348) |
| Total Bilirubin (>2.5 x ULN) | 73% | 66% |
| Creatine Kinase (≥10.0 x ULN) | 8% | 9% |
| Urine RBC (Hematuria) (>75 RBC/HPF) | 6% | 3% |
| ALT (>5.0 x ULN) | 6% | 3% |
| AST (>5.0 x ULN) | 4% | 3% |
| GGT (>5.0 x ULN) | 4% | 2% |
| Serum Amylasea (>2.0 x ULN) | 4% | 2% |
| Urine Glucose (Glycosuria ≥1000 mg/dL) | 3% | 3% |
| Neutrophils (<750/mm³) | 3% | 2% |
| Serum Glucose (Hyperglycemia) (≥250 mg/dL) | 2% | 2% |
| a For subjects with serum amylase >1.5 x upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in the atazanavir coadministered with cobicistat group (N=46) and atazanavir coadministered with ritonavir group (N=35) was 7% and 3%, respectively. |
Cobicistat, a component of EVOTAZ, has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. In Study 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment in the atazanavir coadministered with cobicistat group, 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 atazanavir coadministered with cobicistat group and -8.0 ± 16.8 mL/min in the atazanavir coadministered with ritonavir group.
Serum LipidsChanges from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. In both groups, mean values for serum lipids remained within the normal range for each laboratory test. The clinical significance of these changes is unknown.
Table 4: Lipid Values, Mean Change from Baseline,
Reported in HIV-1 Infected Treatment-Naive Adults Receiving Atazanavir
Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir
Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study 114 (Week
144 analysis)
| Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF | Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF | |||
| Baseline mg/dL | Week 144 change from baselinea | Baseline mg/dL | Week 144 change from baselinea | |
| 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] |
| a The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values and excludes subjects receiving an HMG-CoA reductase inhibitor drug. |
See the full prescribing information for atazanavir for postmarketing information on atazanavir.
EVOTAZ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults.
Limitations Of UseAtazanavir: In a thorough QT/QTc study in 72 healthy subjects, atazanavir 400 mg and 800 mg (Cmax was 1.2 times and 2.4 times the Cmax observed with the recommended dosage of EVOTAZ, respectively) without a CYP3A inhibitor did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving atazanavir. The mean (±SD) maximum change in PR interval from the predose for atazanavir 400 mg (n=65), atazanavir 800 mg (n=66), and placebo (n=67) was 24 (±15) msec, 60 (±25) msec, and 13 (±11) msec, respectively. Steady state atazanavir exposures (Cmax and AUCtau) observed in this healthy volunteer study exceeded those observed in patients treated with atazanavir coadministered with cobicistat. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram.
In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir-containing and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval > 500 msec.
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 CreatinineThe 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 (eGFRCG) 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 eGFRCG 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 eGFRCG, without affecting the actual glomerular filtration rate.
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 | |
| Absorption | ||
| Tmax (h) | 2.0 | 2.0 |
| Effect of light meal (relative to fasting) AUC ratiob | 1.28 (1.17,1.40) | 1.24 (1.15,1.34) |
| Effect of high fat meal(relative to fasting) AUC ratiob | 0.96 (0.81,1.13) | 1.12 (1.01,1.23) |
| Effect of light meal(relative to fasting) C24 ratiob | 1.35 (1.22,1.50) | ND |
| Effect of high fat meal (relative to fasting) C24 ratiob | 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 |
| t½ (h) | 7.2a | 3.5 |
| % Of dose excreted in urine | ND | 8.2c |
| % Of dose excreted in feces | ND | 86.2c |
| 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. |
||
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.
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 |
| Cmax (μg/mL) | 3.91 ± 1.94 |
| Ctau (μg/mL) | 0.80 ± 0.72 |
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk SummaryProspective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Cobicistat use in women during pregnancy has not been evaluated; however, atazanavir use during pregnancy has been evaluated in a limited number of women. The pharmacokinetics of EVOTAZ have not been evaluated in pregnant patients. Available data from the APR show no difference in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits. During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsDose Adjustment During Pregnancy and the Postpartum Period
Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of EVOTAZ cannot be predicted from studies of other atazanavir-containing products in pregnant women.
Maternal Adverse Reactions
Atazanavir
Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.
Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.
Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.
Fetal/Neonatal Adverse Reactions
Atazanavir
All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life. Advise pregnant women of the potential risk to newborn infants. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.
DataHuman Data
Atazanavir
Based on prospective reports from the interim APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference in the overall rate for birth defects for atazanavir (2.3%) compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Based on prospective reports to the APR, the prevalence of birth defects in live births was 2.1% following first trimester exposure to atazanavir-containing regimens.
Cobicistat
Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.
Animal Data
Atazanavir
Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre-and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD.
Cobicistat
Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD.
In a pre-and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD.
EVOTAZ tablets contain 342 mg atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat and are oval, biconvex, pink, film-coated, and debossed with “3641” on one side and plain on the other side.
Storage And HandlingEVOTAZ ™ tablets, 300 mg atazanavir and 150 mg cobicistat, are oval, biconvex, pink, film-coated, debossed with “3641” on one side and plain on the other side. Each bottle contains 30 tablets (NDC-0003-3641-11), a silica gel desiccant and is closed with a child-resistant closure.
Store EVOTAZ tablets at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep container tightly closed.
Manufactured for: Bristol-Myers Squibb Company Princeton, NJ 08543 USA, Revised: Jan 2017
Included as part of the PRECAUTIONS section.
PRECAUTIONS Cardiac Conduction AbnormalitiesAtazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities. In clinical trials of atazanavir that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of atazanavir-treated patients (n=920) and 5% of patients (n=118) treated with atazanavir coadministered with ritonavir. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second-or third-degree AV block), consider ECG monitoring in these patients.
Severe Skin ReactionsCases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir. EVOTAZ should be discontinued if severe rash develops.
Mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials. These reactions had a median time to onset of 7.3 weeks and median duration of 1.4 week and generally did not result in treatment discontinuation.
Effects On Serum CreatinineCobicistat 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 EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with EVOTAZ, assess estimated creatinine clearance. Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
New Onset Or Worsening Renal Impairment When Used With Tenofovir DFRenal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF. Therefore, coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min.
In a clinical trial over 144 weeks (N=692), 10 (2.9%) subjects treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) subjects treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any subject.
Nephrolithiasis And CholelithiasisCases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered.
HepatotoxicityPatients with underlying hepatitis B or C viral infections or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with EVOTAZ and during treatment.
Risk Of Serious Adverse Reactions Or Loss Of Virologic Response Due To Drug InteractionsInitiation of EVOTAZ, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving EVOTAZ, may increase plasma concentrations of medications metabolized by CYP3A.
Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of EVOTAZ, respectively.
Increased concentrations of EVOTAZ may lead to:
Decreased concentrations of EVOTAZ may lead to:
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during EVOTAZ therapy; review concomitant medications during EVOTAZ therapy; and monitor for the adverse reactions associated with the concomitant medications.
When used with concomitant medications, EVOTAZ may result in different drug interactions than those observed or expected with atazanavir coadministered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with atazanavir coadministered with ritonavir to certain EVOTAZ interactions.
Antiretrovirals That Are Not RecommendedEVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) 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.
EVOTAZ is not recommended in combination with ritonavir or products containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.
See DRUG INTERACTIONS for additional recommendations on use with other antiretroviral agents.
HyperbilirubinemiaMost patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin greater than 5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to EVOTAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients.
Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Diabetes Mellitus/HyperglycemiaNew-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Fat RedistributionRedistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
HemophiliaThere have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Instructions For UseAdvise patients to take EVOTAZ with food every day and that EVOTAZ must always be used in combination with other antiretroviral drugs. Inform patients to avoid missing doses as it can result in development of resistance, and not to discontinue therapy without consulting with their healthcare provider. Advise patients if a dose of EVOTAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped, the patient should not double the next dose.
Drug InteractionsEVOTAZ may interact with many drugs; therefore, inform patients of the potential for serious drug interactions with EVOTAZ, and that some drugs are contraindicated with EVOTAZ and other drugs require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort.
Instruct patients receiving hormonal contraceptives to use additional or alternative non-hormonal contraceptive measures during therapy with EVOTAZ because no data are available to make recommendations regarding use of hormonal contraceptives and atazanavir coadministered with cobicistat.
Cardiac Conduction AbnormalitiesInform patients that EVOTAZ may produce changes in the electrocardiogram (e.g., PR prolongation). Advise patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness.
Severe Skin ReactionsInform patients that mild rashes without other symptoms have been reported with atazanavir use. These rashes go away within two weeks with no change in treatment. However, inform patients there have been reports of severe skin reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with atazanavir use. Advise patients to seek medical evaluation immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, or facial edema).
Nephrolithiasis And CholelithiasisInform patients that kidney stones and/or gallstones have been reported with atazanavir use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications.
HyperbilirubinemiaInform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving atazanavir, a component of EVOTAZ. Tell patients this may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if they have cosmetic concerns.
Fat RedistributionInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
Pregnancy RegistryInform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant women exposed to EVOTAZ.
LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisAtazanavir: 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.
MutagenesisAtazanavir: 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 FertilityAtazanavir: 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.
Use In Specific Populations Pregnancy Pregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk SummaryProspective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Cobicistat use in women during pregnancy has not been evaluated; however, atazanavir use during pregnancy has been evaluated in a limited number of women. The pharmacokinetics of EVOTAZ have not been evaluated in pregnant patients. Available data from the APR show no difference in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits. During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsDose Adjustment During Pregnancy and the Postpartum Period
Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of EVOTAZ cannot be predicted from studies of other atazanavir-containing products in pregnant women.
Maternal Adverse Reactions
Atazanavir
Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.
Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.
Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.
Fetal/Neonatal Adverse Reactions
Atazanavir
All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life. Advise pregnant women of the potential risk to newborn infants. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.
DataHuman Data
Atazanavir
Based on prospective reports from the interim APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference in the overall rate for birth defects for atazanavir (2.3%) compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Based on prospective reports to the APR, the prevalence of birth defects in live births was 2.1% following first trimester exposure to atazanavir-containing regimens.
Cobicistat
Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.
Animal Data
Atazanavir
Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre-and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD.
Cobicistat
Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD.
In a pre-and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD.
Lactation Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production.
Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Cobicistat is present in rat milk. There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct women not to breastfeed.
DataAnimal Data
Cobicistat: During the prenatal and postnatal development toxicology study at doses up 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation Day 10.
Pediatric UseAtazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.
The safety and efficacy of EVOTAZ in pediatric patients 3 months to less than 18 years of age have not been established.
Geriatric UseClinical studies with the components of EVOTAZ did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. In general, appropriate caution should be exercised in the administration and monitoring of EVOTAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal ImpairmentEVOTAZ is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis.
Hepatic ImpairmentEVOTAZ is not recommended for use in patients with any degree of hepatic impairment.
Prior to starting EVOTAZ, assess estimated creatinine clearance because cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. When coadministering EVOTAZ with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline and routinely monitor during treatment.
Hepatic TestingIn patients with underlying hepatitis B or C viral infections, conduct hepatic laboratory testing prior to initiating therapy and during treatment with EVOTAZ.
Recommended DosageEVOTAZ is a fixed-dose combination product containing 300 mg of atazanavir and 150 mg of cobicistat. In treatment-naive and -experienced adults, the recommended dosage of EVOTAZ is one tablet taken once daily orally with food. Administer EVOTAZ in conjunction with other antiretroviral agents.
When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required.
Dosage In Patients With Renal ImpairmentEVOTAZ is not recommended in HIV-1 treatment-experienced patients with end-stage renal disease managed with hemodialysis.
EVOTAZ coadministered with tenofovir DF is not recommended in patients with estimated creatinine clearance below 70 mL/min. Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
Not Recommended In Patients With Any Degree Of Hepatic ImpairmentEVOTAZ is not recommended in patients with any degree of hepatic impairment.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
For additional safety information about atazanavir and cobicistat, consult the full prescribing information for these individual products.
Clinical Trial Experience In AdultsBecause 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.
The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naive subjects received:
The most common adverse reactions (Grades 2-4) and reported in ≥5% of subjects in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%).
The proportion of subjects who discontinued study treatment due to adverse events regardless of severity was 11% in both the atazanavir coadministered with cobicistat and atazanavir coadministered with ritonavir groups. Table 2 lists the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study 114.
Table 2: Selected Adverse Reactionsa (Grades 2-4)
Reported in ≥2% of HIV1 Infected Treatment-Naive Adults in
the Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144
analysis)
| Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344) |
Atazanavir coadministered with ritonavir and emtricitabine /tenofovir DF (n=348) |
|
| Jaundice | 6% | 3% |
| Rashb | 5% | 4% |
| Ocular icterus | 4% | 2% |
| Nausea | 2% | 2% |
| Diarrhea | 2% | 1% |
| Headache | 2% | 1% |
| a Frequencies of adverse reactions are based
on Grades 2-4 adverse events attributed to study drugs. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, and urticaria. |
Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF are listed below. These events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with atazanavir coadministered with cobicistat, and reported with greater frequency compared with the atazanavir coadministered with ritonavir group.
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
Laboratory AbnormalitiesThe frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study 114 is presented in Table 3.
Table 3: Laboratory Abnormalities (Grades 3-4)
Reported in ≥2% of HIV-1 Infected Treatment-Naive Adults in the
Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144
analysis)
| Laboratory Parameter Abnormality | 144 weeks Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344) |
144 weeks Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF (n=348) |
| Total Bilirubin (>2.5 x ULN) | 73% | 66% |
| Creatine Kinase (≥10.0 x ULN) | 8% | 9% |
| Urine RBC (Hematuria) (>75 RBC/HPF) | 6% | 3% |
| ALT (>5.0 x ULN) | 6% | 3% |
| AST (>5.0 x ULN) | 4% | 3% |
| GGT (>5.0 x ULN) | 4% | 2% |
| Serum Amylasea (>2.0 x ULN) | 4% | 2% |
| Urine Glucose (Glycosuria ≥1000 mg/dL) | 3% | 3% |
| Neutrophils (<750/mm³) | 3% | 2% |
| Serum Glucose (Hyperglycemia) (≥250 mg/dL) | 2% | 2% |
| a For subjects with serum amylase >1.5 x upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in the atazanavir coadministered with cobicistat group (N=46) and atazanavir coadministered with ritonavir group (N=35) was 7% and 3%, respectively. |
Cobicistat, a component of EVOTAZ, has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. In Study 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment in the atazanavir coadministered with cobicistat group, 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 atazanavir coadministered with cobicistat group and -8.0 ± 16.8 mL/min in the atazanavir coadministered with ritonavir group.
Serum LipidsChanges from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. In both groups, mean values for serum lipids remained within the normal range for each laboratory test. The clinical significance of these changes is unknown.
Table 4: Lipid Values, Mean Change from Baseline,
Reported in HIV-1 Infected Treatment-Naive Adults Receiving Atazanavir
Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir
Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study 114 (Week
144 analysis)
| Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF | Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF | |||
| Baseline mg/dL | Week 144 change from baselinea | Baseline mg/dL | Week 144 change from baselinea | |
| 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] |
| a The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values and excludes subjects receiving an HMG-CoA reductase inhibitor drug. |
See the full prescribing information for atazanavir for postmarketing information on atazanavir.
DRUG INTERACTIONS Potential For EVOTAZ To Affect Other DrugsAtazanavir is an inhibitor of CYP3A and UGT1A1 and a weak inhibitor of CYP2C8. Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3.
Coadministration of EVOTAZ 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 of EVOTAZ and drugs primarily metabolized by CYP3A, UGT1A1 and/or CYP2D6 or drugs that are substrates of P-gp, BCRP, OATP1B1 and/or OATP1B3 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic effects and adverse reactions which may require dose adjustments and/or additional monitoring as shown in Table 5. Use of EVOTAZ is not recommended when coadministered with drugs highly dependent on CYP2C8 for clearance with narrow therapeutic indices (e.g., paclitaxel, repaglinide).
Potential For Other Drugs To Affect EVOTAZAtazanavir and cobicistat are CYP3A4 substrates; therefore, drugs that induce CYP3A4 may decrease atazanavir and cobicistat plasma concentrations and reduce the therapeutic effect of EVOTAZ, leading to development of resistance to atazanavir (see Table 5). Cobicistat is also metabolized by CYP2D6 to a minor extent.
Coadministration of EVOTAZ with other drugs that inhibit CYP3A4 may increase the plasma concentrations of cobicistat and atazanavir (see Table 5).
Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with EVOTAZ.
Established And Other Potentially Significant Drug InteractionsTable 5 provides dosing recommendations as a result of drug interactions with the components of EVOTAZ. These recommendations are based either on observed drug interactions in studies of cobicistat, atazanavir, or atazanavir coadministered with ritonavir or predicted drug interactions based on the expected magnitude of interaction and potential for serious events or loss of therapeutic effect of EVOTAZ.
Table 5: Established and Other Potentially Significant
Drug Interactions: Alteration in Dose or Regimen May Be Recommended
Based on Drug Interaction Studiesa or Predicted Interactions
| Concomitant Drug Class: Specific Drugs | Effectb on Concentration | Clinical Comment |
| HIV Antiretroviral Agents: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs) | ||
| didanosine buffered formulations enteric-coated (EC) capsules | ↓atazanavir ↓didanosine |
It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times. |
| tenofovir disoproxil fumarate | ↓atazanavir ↑ tenofovir |
Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir -associated adverse reactions. |
| HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) For contraindicated NNRTIs,. |
||
| efavirenz | ↓atazanavir ↓cobicistat ↔efavirenz |
Coadministration of EVOTAZ with efavirenz is not recommended because it because it atazanavir. |
| etravirine | ↓atazanavir ↓cobicistat |
Coadministration of EVOTAZ with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir. |
| HIV Antiretroviral Agents: CCR5 Antagonist | ||
| maraviroc | ↑ maraviroc | When coadministering maraviroc and EVOTAZ, patients should receive maraviroc 150 mg twice daily. |
| HIV Antiretroviral Agents: Protease Inhibitor For contraindicated protease inhibitors,. |
||
| ritonavir or products containing ritonavir | ↑ atazanavir | Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A . |
| HCV Antiviral Agents | ||
| boceprevir | atazanavir: effects unknown | No drug interaction data are available. Coadministration of EVOTAZ with boceprevir or simeprevir is not recommended. |
| simeprevir | boceprevir: effects unknown | |
| Sofosbuvir/velpatasvir/ voxilaprevir | ↑ voxilaprevir | Coadministration with EVOTAZ is not recommended. |
| Other Agents | ||
| Antacids (please also see H2 receptor antagonists and proton-pump inhibitors below) | ↓atazanavir | With concomitant use, administer a minimum of 2 hours apart. |
| Antiarrhythmics: amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone | ↑ antiarrhythmics | For contraindicated antiarrhythmics,. Clinical monitoring is recommended upon coadministration with antiarrhythmics. |
| digoxin | ↑ digoxin | When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations. |
| Antibacterials (macrol | ↑ atazanavir ↑ cobicistat |
Consider alternative antibiotics. |
| clarithromycin | ↑ clarithromycin | |
| erythromycin | ↑ erythromycin | |
| telithromycin | ↑ telithromycin | |
| Anticancer Agents: (e.g., dasatinib, nilotinib, vinblastine, vincristine) | ↑ anticancer agents | A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with EVOTAZ. Consult the dasatinib and nilotinib full prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects. |
| Anticoagulant: apixaban, rivaroxaban | ↑ apixaban ↑ rivaroxaban |
Concomitant use of apixaban or rivaroxaban and EVOTAZ is not recommended. |
| dabigatran etexilate | ↑ dabigatran | Concomitant use of dabigatran etexilate and EVOTAZ is not recommended in specific renal impairment groups for certain indications. Refer to the dabigatran prescribing information for dosing recommendations for dabigatran etexilate when coadministered with P-gp inhibitors. |
| warfarin | warfarin: effect unknown | Monitor the International Normalized Ratio (INR) when coadministered with warfarin. |
| Anticonvulsants: Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine) | ↓atazanavir ↓cobicistat |
For contraindicated anticonvulsants,. Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response. |
| Anticonvulsants that are metabolized by CYP3A (e.g., clonazepam) | ↑ clonazepam | Clinical monitoring of anticonvulsants is recommended with EVOTAZ coadministration. |
| Other anticonvulsants (e.g., lamotrigine) | lamotrigine: effects unknown | Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration. |
| Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine) | SSRIs: effects unknown | When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended. |
| Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline) | ↑ TCAs | |
| Other Antidepressants (e.g., trazodone) | ↑ trazodone | |
| Antifungals: ketoconazole, itraconazole | ↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole |
Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole. |
| voriconazole | effects unknown | Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole. |
| Antigout: colchicine | ↑ colchicine | The coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated. Recommended dosage of colchicine when administered with EVOTAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course should be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterials: rifabutin | atazanavir: effect unknown | For contraindicated antimycobacterials,. |
| cobicistat: effect unknown ↑ rifabutin |
A rifabutin dose reduction of up to 75% (e.g., 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions, including neutropenia and uveitis, is warranted. | |
| Antipsychotics: quetiapine |
↑ quetiapine | For contraindicated antipsychotics,. Initiation of EVOTAZ in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking EVOTAZ: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| (e.g., perphenazine, risperidone, thioridazine) | ↑ antipsychotic | A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with EVOTAZ. |
| Beta-Blockers: (e.g., metoprolol, carvedilol, timolol) | ↔atazanavir ↑ beta-blockers |
Clinical monitoring is recommended when beta-blockers that are metabolized by CYP2D6 are coadministered with EVOTAZ. |
| Calcium channel blockers: (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) |
↑ calcium channel blocker | Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended. |
| Corticosteroids (systemic): dexamethasone and other corticosteroids | ↓atazanavir ↓cobicistat ↑ corticosteroids |
Concomitant use with dexamethasone or other corticosteroids that induceCYP3A may result in loss of therapeutic effect of EVOTAZ and development of resistance to atazanavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. |
| Endothelin receptor antagonists: bosentan | ↓atazanavir ↓cobicistat ↑ bosentan |
Initiation of bosentan in patients taking EVOTAZ: For patients who have been receiving EVOTAZ for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Initiation of EVOTAZ in patients taking bosentan: Discontinue bosentan at least 36 hours before starting EVOTAZ. After at least 10 days following initiation of EVOTAZ, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose. |
| H2-Receptor antagonists (H2RA): (e.g., famotidine) | ↓atazanavir | Coadministration of EVOTAZ with tenofovir DF and an H2RA in treatment-experienced patients is not recommended. Administer EVOTAZ either at the same time or at a minimum of 10 hours after a dose of the H2RA. The dose of the H2RA should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naive patients or 20 mg twice daily in treatment-experienced patients. |
| HMG-CoA reductase inhibitors: | ↑ HMG-CoA reductase inhibitors | For contraindicated HMG-CoA reductase inhibitors, |
| atorvastatin, fluvastatin, pravastatin, rosuvastatin | Coadministration of EVOTAZ with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with EVOTAZ, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with rosuvastatin are as follows. Rosuvastatin dose should not exceed 10 mg/day. |
|
| Hormonal contraceptives: (e.g., progestin/estrogen) | progestin and estrogen: effects unknown | For contraindicated hormonal contraceptives,. No data are available to make recommendations on the coadministration of EVOTAZ and oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered. |
| Immunosuppressants: (e.g., cyclosporine, everolimus, sirolimus, tacrolimus) | ↑ immunosuppressants | Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with EVOTAZ. |
| Inhaled beta-agonist: salmeterol | ↑ salmeterol | Coadministration with salmeterol is not recommended due to an increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| Inhaled/nasal steroids: budesonide, fluticasone and other inhaled or nasal steroids | ↑ corticosteroids | Coadministration with inhaled or nasal corticosteroids that are metabolized by CYP3A is not recommended unless the potential benefit to the patient outweighs the risks. Consider alternative corticosteroids, particularly for longterm use. |
| Narcotic analgesics: For treatment of opioid dependence: buprenorphine, naloxone, methadone |
buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown | Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking EVOTAZ: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. |
| fentanyl | ↑ fentanyl |
Initiation of EVOTAZ in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms. When EVOTAZ is coadministered with fentanyl, careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended. |
| tramadol | ↑ tramadol |
When EVOTAZ is coadministered with tramadol, a decreased dose of tramadol may be needed. |
| Phosphodiesterase-5 (PDE-5) inhibitors: avanafil, sildenafil, tadalafil, vardenafil | ↑ PDE-5 inhibitors | For contraindicated PDE-5 inhibitors,. Coadministration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established. Coadministration with EVOTAZ may result in an increase in PDE-5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil when used for the treatment of PAH is contraindicated with EVOTAZ. Tadalafil: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ: Initiation of tadalafil in patients taking EVOTAZ:
EVOTAZ:
Sildenafil: Reduced dosage to 25 mg every 48 hours with increased monitoring for adverse reactions. Tadalafil: Reduced dosage to 10 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil: Reduced dosage to no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. |
| Proton-pump inhibitors (PPI): (e.g., omeprazole) | ↓atazanavir | In treatment-naive patients, administer EVOTAZ a minimum of 12 hours after administration of the PPI. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration of EVOTAZ with PPI is not recommended. |
| Sedatives/Hypnotics: buspirone, diazepam, zolpidem, and parenterally administered midazolam | ↑ sedatives/hypnotics | For contraindicated sedatives/hypnotics,. Parenterally administered midazolam:Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Concomitant use with oral midazolam and triazolam is contraindicated. With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended. |
| a For magnitude of interactions see CLINICAL
PHARMACOLOGY, Table 7. b ↑ = Increase, ↓ = Decrease, ↔ = No change. |
||
Based on known metabolic profiles, clinically significant drug interactions are not expected between EVOTAZ and acetaminophen, atenolol, dapsone, fluconazole, trimethoprim/sulfamethoxazole, or azithromycin.
