Evotaz Drug Information
Generic name: ATAZANAVIR AND COBICISTAT
Cytochrome P450 3A Inhibitor [EPC]
Uses of Evotaz
Indications EVOTAZ ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in the following populations: • Adult patients • Pediatric patients weighing at least 35 kg.
Limitations of Use Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions.
Dosage & Administration of Evotaz
Laboratory Testing Prior to Initiation and During Treatment with EVOTAZ Renal Testing Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Renal laboratory testing should include estimated creatinine clearance, serum creatinine, and urinalysis with microscopic examination. 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. In patients with chronic kidney disease, also monitor serum phosphorus. Hepatic Testing Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ.
Recommended Dosage EVOTAZ is a fixed-dose tablet containing 300 mg of atazanavir and 150 mg of cobicistat. The recommended dosage of EVOTAZ is one tablet taken once daily orally with food in both treatment-naive and treatment-experienced patients with HIV-1: • Adult patients • Pediatric patients weighing at least 35 kg Administer EVOTAZ in conjunction with other antiretroviral agents. Dose separation may be required when taken with H 2 -receptor antagonists or proton-pump inhibitors.
Dosage in Patients with Renal Impairment EVOTAZ is not recommended in treatment-experienced patients with HIV-1 who have 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 Impairment EVOTAZ is not recommended in patients with any degree of hepatic impairment.
Not Recommended During Pregnancy EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals due to substantially lower exposures of cobicistat and consequently, lower exposures of atazanavir, during the second and third trimesters. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ.
Side Effects of Evotaz
Clinical Trial 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 Trial Experience in Adult Participants The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study GS-US-216-0114, in which 692 antiretroviral treatment-naive participants with HIV-1 received: • atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (N=344) or • atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (N=348). The proportion of participants 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 participants in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114. Table 2: Selected Adverse Reactions a (Grades 2-4) Reported in ≥2% of Treatment-Naive Adults with HIV-1 in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis) 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. Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of participants 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 participant 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 Abnormalities The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of participants in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114 is presented in Table 3. Table 3: Laboratory Abnormalities (Grades 3-4) Reported in ≥2% of Treatment-Naive Adults with HIV-1 in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis) Increase in Serum Creatinine: 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 GS-US-216-0114, 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 Lipids Changes 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 Treatment-Naive Adults with HIV-1 Receiving Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study GS-US-216-0114 (Week 144 analysis) Adverse Reactions from Clinical Trial Experience in Pediatric Participants Although no clinical trial with EVOTAZ as the fixed-dose tablet was conducted in a pediatric population, the safety of atazanavir coadministered with cobicistat plus two nucleoside reverse transcriptase inhibitors was evaluated in treatment-experienced virologically suppressed participants with HIV-1 between the ages of 12 to less than 18 years (N=14) through Week 48 in an open-label clinical trial (Study GS-US-216-0128).
Results from this study showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults.
Postmarketing Experience See the full prescribing information for atazanavir for postmarketing information on atazanavir.
| Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=344) | Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (n=348) | |
|---|---|---|
| Jaundice | 6% | 3% |
| Rash b | 5% | 4% |
| Ocular icterus | 4% | 2% |
| Nausea | 2% | 2% |
| Diarrhea | 2% | 1% |
| Headache | 2% | 1% |
| 144 weeks Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF | 144 weeks Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF | |
|---|---|---|
| Laboratory Parameter Abnormality | (n=344) | (n=348) |
| a 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 atazanavir coadministered with cobicistat group (N=46) and atazanavir coadministered with ritonavir group (N=35) was 7% and 3%, respectively. | ||
| 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 a (>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% |
| Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF | Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF | |||
|---|---|---|---|---|
| Baseline mg/dL | Week 144 change from baseline a | Baseline mg/dL | Week 144 change from baseline a | |
| a The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 144 values and excludes participants receiving an HMG-CoA reductase inhibitor drug. | ||||
| 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] |
Warnings & Cautions for Evotaz
Cardiac Conduction Abnormalities
Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy participants and in participants with HIV-1 treated with atazanavir, 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 in participants with HIV-1 that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of participants treated with atazanavir (n=920) and 5% of participants (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 Reactions Cases 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 Creatinine
Cobicistat 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 DF Renal 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. • When EVOTAZ is used with tenofovir DF, document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment. • Measure serum phosphorus in patients with or at risk for renal impairment. • Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended. In a clinical trial over 144 weeks (N=692), 10 (2.9%) participants treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) participants treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event.
One participant 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 participants treated with cobicistat, with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any participant.
Chronic Kidney Disease
Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease.
Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered.
Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 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.
Hepatotoxicity Patients with underlying hepatitis B or C virus 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 Interactions Initiation 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: • 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 EVOTAZ.
Decreased concentrations of EVOTAZ may lead to: • loss of therapeutic effect of EVOTAZ and possible development of resistance. 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 Recommended EVOTAZ 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.
Hyperbilirubinemia
Most 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 Syndrome
Immune 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, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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/Hyperglycemia
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 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.
Fat Redistribution Redistribution/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.
Hemophilia There 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.
Drug Interactions with Evotaz
Potential for EVOTAZ to Affect Other Drugs Atazanavir 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 EVOTAZ Atazanavir 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 H 2 -receptor antagonists are administered with EVOTAZ (see Table 5).
Established and Other Potentially Significant Drug Interactions Table 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 with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions. is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for is contraindicated.
Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. 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. Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension. Antacids and buffered medications (please also see H 2 -receptor antagonists and proton-pump inhibitors below) ↓ atazanavir With concomitant use, administer a minimum of 2 hours apart.
Antianginal: ranolazine ↑ ranolazine Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions. Antiarrhythmics: dronedarone ↑ dronedarone Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity.
Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance. Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). is contraindicated due to potential for loss of therapeutic effect and development of resistance.
Antineoplastics: apalutamide ↓ atazanavir ↓cobicistat Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors. Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide. ivosidenib ↓ atazanavir ↓ cobicistat ↑ ivosidenib Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. Mechanism: The mechanism of interaction is CYP3A4 induction by Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions. pimozide ↑ pimozide Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Coadministration of EVOTAZ with ergot derivatives is contraindicated due to the 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. Hepatitis C Direct-Acting Antivirals: elbasvir/grazoprevir ↑ grazoprevir Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations. Herbal Products: St.
John’s wort ( Hypericum perforatum) ↓ atazanavir ↓ cobicistat Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance. H 2 ‑Receptor antagonists (H 2 RA ): (e.g., famotidine) ↓ atazanavir Coadministration of EVOTAZ with tenofovir DF and an H 2 RA in treatment-experienced patients is not recommended.
Lipid-modifying agents: Other lipid-modifying agents: lomitapide ↑ lomitapide Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity. HMG-CoA reductase inhibitors: lovastatin simvastatin ↑lovastatin ↑simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis. Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin ↑ HMG-CoA reductase inhibitors Coadministration of EVOTAZ with atorvastatin is not recommended.
Hormonal contraceptives: drospirenone/ethinyl estradiol ↑ drospirenone Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope). Tadalafil: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ: Initiation of tadalafil in patients taking EVOTAZ: Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Other Benzodiazepines: clorazepate diazepam estazolam flurazepam parenterally administered midazolam ↑ 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. Other Sedatives/Hypnotics: buspirone, zolpidem With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.
Drugs with No Observed or Predicted Interactions with the Components of EVOTAZ Based on known metabolic profiles, clinically significant drug interactions are not expected between EVOTAZ and acetaminophen, atenolol, dapsone, fluconazole, trimethoprim/sulfamethoxazole, or azithromycin.
| Concomitant Drug Class: Specific Drugs | Effect b on Concentration | Clinical Comment | |
|---|---|---|---|
| a For magnitude of interactions see Clinical Pharmacology (12.3; Table 7). b ↑ = Increase, ↓ = Decrease, ↔ = No change. | |||
| 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 [see Warnings and Precautions (5.4) ]. | |
| HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | |||
| nevirapine | ↓ atazanavir ↑ nevirapine | Coadministration of EVOTAZ with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions [see Contraindications (4) ]. | |
| efavirenz | ↓ atazanavir ↓ cobicistat ↔ efavirenz | Coadministration of EVOTAZ with efavirenz is not recommended because it may result in a loss of therapeutic effect and development of resistance to 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 | |||
| indinavir | Coadministration with indinavir is contraindicated [see Contraindications (4) ]. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. | ||
| 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 [see Warnings and Precautions (5.9) ]. | |
| Hepatitis C Antiviral Agents | |||
| sofosbuvir/velpatasvir/ voxilaprevir | ↑ voxilaprevir | Coadministration with EVOTAZ is not recommended. | |
| Other Agents | |||
| Alpha 1-adrenoreceptor antagonist: alfuzosin | ↑ alfuzosin | Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension [see Contraindications (4) ]. | |
| Antacids and buffered medications (please also see H 2 -receptor antagonists and proton-pump inhibitors below) | ↓ atazanavir | With concomitant use, administer a minimum of 2 hours apart. | |
| Antianginal: ranolazine | ↑ ranolazine | Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. | |
| Antiarrhythmics: dronedarone | ↑ dronedarone | Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. | |
| amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone digoxin | ↑ other antiarrhythmics ↑ digoxin | Clinical monitoring is recommended upon coadministration with antiarrhythmics. When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations. | |
| Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin | ↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin | Consider alternative antibiotics. | |
| Anticancer Agents: irinotecan | ↑ irinotecan | Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity [see Contraindications (4) ]. | |
| (e.g., dasatinib, nilotinib, vinblastine, vincristine) | ↑ other 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. | |
| Anticoagulants: Direct-acting oral anticoagulants (DOACs) apixaban | ↑ apixaban | Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with EVOTAZ depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in apixaban prescribing information. | |
| rivaroxaban | ↑ rivaroxaban | Coadministration of EVOTAZ and rivaroxaban is not recommended because it may lead to increased bleeding risk. | |
| betrixaban dabigatran etexilate edoxaban | ↑ betrixaban ↑ dabigatran ↑ edoxaban | Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as EVOTAZ depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information. | |
| warfarin | warfarin: effect unknown | Monitor the International Normalized Ratio (INR) when EVOTAZ is coadministered with warfarin. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine) | ↓ atazanavir ↓ cobicistat ↓ atazanavir ↓ cobicistat | Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4) ]. 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 | Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. 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 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. | |
| rifampin | ↓ atazanavir ↓ cobicistat | Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4) ]. | |
| Antineoplastics: apalutamide | ↓ atazanavir ↓cobicistat | Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors. [see Contraindications (4) ]. Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide. | |
| ivosidenib | ↓ atazanavir ↓ cobicistat ↑ ivosidenib | Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4) ]. Mechanism: The mechanism of interaction is CYP3A4 induction by ivosidenib. | |
| encorafenib | ↓ atazanavir ↓ cobicistat ↑ encorafenib | Coadministration with encorafenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4) ]. Mechanism: The mechanism of interaction is CYP3A4 induction by encorafenib. | |
| Antiplatelets: ticagrelor | ↑ ticagrelor | Coadministration with ticagrelor is not recommended due to the potential increase of the antiplatelet activity of ticagrelor. | |
| clopidogrel | ↓ clopidogrel active metabolite | Coadministration with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel. | |
| prasugrel | ↔ prasugrel active metabolite | No dose adjustment is needed when prasugrel is coadministered with atazanavir and/or cobicistat. | |
| Antipsychotics: lurasidone | ↑ lurasidone | Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. | |
| pimozide | ↑ pimozide | Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. | |
| quetiapine | ↑ quetiapine | 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-agonist (inhaled): 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. | |
| 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: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone | ↓ atazanavir ↓ cobicistat ↑ corticosteroids | Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. | |
| Kinase inhibitors: fostamatinib | ↑ R406 active metabolite of fostamatinib | Coadministration with fostamatinib may increase the plasma concentration of R406, the active metabolite of fostamatinib. Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. | |
| 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. | |
| Gonadotropin releasing hormone antagonist Receptor (GnRH): elagolix | ↓ atazanavir ↓ cobicistat ↑ elagolix | Coadministration of EVOTAZ with elagolix may result in decreased plasma concentrations of atazanavir and/or cobicistat. Concomitant use of elagolix 200 mg twice daily with EVOTAZ for more than 1 month is not recommended due to the potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily with EVOTAZ to 6 months. In addition, monitor virologic responses due to the potential reduction in atazanavir/cobicistat exposure. | |
| Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine | ↑ ergot derivatives | Coadministration of EVOTAZ with ergot derivatives is contraindicated due to the 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 [see Contraindications (4) ]. | |
| Hepatitis C Direct-Acting Antivirals: elbasvir/grazoprevir | ↑ grazoprevir | Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [see Contraindications (4) ]. | |
| glecaprevir/pibrentasvir | ↑ glecaprevir ↑ pibrentasvir | Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations [see Contraindications (4 )]. | |
| Herbal Products: St. John’s wort ( Hypericum perforatum) | ↓ atazanavir ↓ cobicistat | Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4) ]. | |
| H 2 ‑Receptor antagonists (H 2 RA ): (e.g., famotidine) | ↓ atazanavir | Coadministration of EVOTAZ with tenofovir DF and an H 2 RA 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 H 2 RA. The dose of the H 2 RA 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. | |
| Lipid-modifying agents: Other lipid-modifying agents: lomitapide | ↑ lomitapide | Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity [see Contraindications (4) ]. | |
| HMG-CoA reductase inhibitors: lovastatin simvastatin | ↑lovastatin ↑simvastatin | Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) ]. | |
| Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin | ↑ HMG-CoA reductase inhibitors | 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: drospirenone/ethinyl estradiol | ↑ drospirenone | Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia [see Contraindications (4) ]. | |
| (e.g., progestin/estrogen) | progestin and estrogen: effects unknown | 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. | |
| 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. 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. | |
| fentanyl | ↑ fentanyl | 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 | Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope) [see Contraindications (4) ]. Tadalafil: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ: Initiation of tadalafil in patients taking EVOTAZ: | |
| o For patients receiving EVOTAZ for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. | |||
| Initiation of EVOTAZ in patients taking tadalafil: | |||
| o Avoid the use of tadalafil when starting EVOTAZ. Stop tadalafil at least 24 hours before starting EVOTAZ. At least one week after starting EVOTAZ, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. | |||
| Patients switching from atazanavir coadministered with ritonavir to EVOTAZ: | |||
| o Maintain tadalafil dose. | |||
| Use of PDE-5 inhibitors for erectile dysfunction: Avanafil: Not recommended because a safe and effective dose of avanafil has not been established. 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: Benzodiazepines midazolam (oral) triazolam | ↑ midazolam ↑ triazolam | Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4 [see Contraindications (4) ]. | |
| Other Benzodiazepines: clorazepate diazepam estazolam flurazepam parenterally administered midazolam | ↑ 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. | |
| Other Sedatives/Hypnotics: buspirone, zolpidem | With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended. | ||
Pregnancy Safety for Evotaz
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals 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 Summary EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals; use of an alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ.
Pharmacokinetic data from studies conducted in pregnant individuals receiving cobicistat showed substantially lower exposures during the second and third trimesters, and consequently also for the coadministered antiretroviral agent. Consult the full prescribing information for cobicistat for additional information. Pharmacokinetic data from the evaluation of atazanavir and cobicistat in a limited number of pregnant individuals showed a similar trend in lower exposures of the antiretroviral component, atazanavir.
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Atazanavir use during pregnancy has been evaluated in a limited number of individuals. Available data from the APR show no increase 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) (see Data).
The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15−20%. 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 (see Data).
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 (see Data). Clinical Considerations EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals. Maternal Adverse Reactions Atazanavir Reports of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant individuals 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 individuals. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy. Fetal/Neonatal Adverse Reactions Atazanavir Infants exposed to atazanavir in utero may develop severe hyperbilirubinemia during the first few days of life.
Data Human Data Atazanavir The APR has received prospective reports of live births following exposure to atazanavir-containing regimens during pregnancy, including 1361 exposures in the first trimester and 737 exposures in second/third trimester. Birth defects occurred in live births in with first trimester exposure to atazanavir-containing regimens and with second/third trimester exposure to atazanavir-containing regimens. There was no increase in the overall rate of birth defects for atazanavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
Cobicistat The APR has received prospective reports of live births following exposure to cobicistat-containing regimens during pregnancy, including 347 exposures in the first trimester and 79 exposures in the second/third trimester. Among pregnant individuals in the U.S. reference population, the background rate of birth defects is 2.7%. Methodological limitations of the APR include the use of MACDP as the external comparator group.
Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. 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 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 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 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. 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.
Pediatric Use of Evotaz
Pediatric Use The safety and effectiveness of EVOTAZ for the treatment of HIV-1 in pediatric participants weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric participants with HIV-1 aged 12 years and older. The safety in these participants through 48 weeks was similar to that in antiretroviral treatment-naive adults.
Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.
Contraindications for Evotaz
- The concomitant use of EVOTAZ and the following drugs in Table 1, are contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect. EVOTAZ is contraindicated:
- In patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.
- When coadministered with drugs that strongly induce CYP3A4, which may lead to lower exposure of EVOTAZ resulting in potential loss of efficacy and development of possible resistance (Table 5).
- When coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 5). For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5. Coadministration is contraindicated with, but not limited to, the following drugs: Table 1: Drugs Contraindicated with EVOTAZ Drug Class Drugs within class that are contraindicated with EVOTAZ a Refer to Table 5 for sildenafil when administered for erectile dysfunction. b Refer to Table 5 for parenterally administered midazolam. Alpha 1-adrenoreceptor antagonist alfuzosin Antianginal ranolazine Antiarrhythmics dronedarone Anticonvulsants carbamazepine, phenobarbital, phenytoin Antigout colchicine (when used in patients with hepatic and/or renal impairment) Antimycobacterials rifampin Antineoplastics apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics lurasidone, pimozide Ergot Derivatives dihydroergotamine, ergotamine, methylergonovine Hepatitis C Direct-Acting Antivirals elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum ) Hormonal Contraceptives drospirenone/ethinyl estradiol Lipid-modifying Agents lomitapide, lovastatin, simvastatin Non-nucleoside Reverse Transcriptase Inhibitor nevirapine Phosphodiesterase-5 (PDE-5) Inhibitor sildenafil a when administered for the treatment of pulmonary arterial hypertension Protease Inhibitors indinavir Sedative/hypnotics triazolam, orally administered midazolam b
- EVOTAZ is contraindicated with drugs that are strong inducers of CYP3A4 due to the potential for loss of therapeutic effect and development of possible resistance.
- EVOTAZ is contraindicated with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect.
Overdosage Information for Evotaz
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 a patient with HIV-1 (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.
Clinical Studies of Evotaz
Clinical Trial Results in Treatment-Naive Adult Participants with HIV-1 Study GS-US-216-0114 The safety and efficacy of atazanavir coadministered with cobicistat were evaluated in a randomized, double-blind, active-controlled trial (Study GS-US-216-0114 ) in treatment-naive participants with HIV-1 infection with baseline estimated creatinine clearance above 70 mL/min (N=692). All participants 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 baseline plasma HIV-1 RNA was 4.8 log 10 copies/mL (range: 3.2-6.4). Forty percent (40%) of patients had baseline viral loads >100,000 copies/mL. Virologic outcomes in Study GS-US-216-0114 through Week 144 are presented in Table 10.
Table 10: Virologic Outcomes of Randomized Treatment of Study GS-US-216-0114 in Treatment-Naive Adults with HIV-1 at Week 144 a
Clinical Trial Results in Virologically Suppressed Pediatric Participants with HIV-1 Infection– Study GS-US-216-0128 Study GS-US-216-0128 (NCT02016924) was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of atazanavir coadministered with cobicistat in pediatric participants ages 12 years and older with HIV-1 who were virologically suppressed and had a baseline estimated creatinine clearance ≥90 mL/min/1.73 m 2. Participants were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir administered with ritonavir, combined with 2 nucleotide reverse transcriptase inhibitors (NRTIs). They were switched from ritonavir to cobicistat 150 mg once daily and continued atazanavir (N=14) and 2 NRTIs.
| 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 participants who had ≥50 copies/mL in the Week 48 window; participants who discontinued early due to lack or loss of efficacy; participants 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 participants 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 GS-US-216-0114. d Includes participants 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 <50 copies/mL | 72% | 74% |
| Treatment Difference | −2.1% (95% CI = −8.7%, 4.5%) | |
| HIV-1 RNA ≥50 copies/mL b | 8% | 5% |
| No Virologic Data at Week 48 Window | 20% | 21% |
| Discontinued Study Drug Due to AE or Death c | 11% | 11% |
| Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mL d | 8% | 10% |
| Missing Data During Window, but on Study Drug | <1% | <1% |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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