Atazanavir and cobicistat

Atazanavir and cobicistat
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2]

Disclaimer

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Overview

Atazanavir and cobicistat is a combination of a human immunodeficiency virus protease inhibitor and a CYP3A inhibitor that is FDA approved for the treatment of HIV-1 infection in combination with other antiretroviral agents. Common adverse reactions include abnormal bilirubin levels, jaundice, and scleral icterus.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

EVOTAZ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults.

Limitations of Use: Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions.

Dosing Information

• EVOTAZ 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 Impairment
  • EVOTAZ 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 Impairment
  • EVOTAZ is not recommended in patients with any degree of hepatic impairment.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Atazanavir and cobicistat in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Atazanavir and cobicistat in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Atazanavir and cobicistat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Atazanavir and cobicistat in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Atazanavir and cobicistat in pediatric patients.

Contraindications

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 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 1).
• When coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ (see Table 1).

Table 1 displays drugs that are contraindicated with EVOTAZ.

This image is provided by the National Library of Medicine

Warnings

• Cardiac Conduction Abnormalities
  • Atazanavir 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 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 weeks 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 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%) 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 Cholelithiasis
  • Cases 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.
• Hepatotoxicity
  • Patients 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 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.
• 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 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/Hyperglycemia
  • New-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 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.

Adverse Reactions

Clinical Trials Experience

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

• atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (N=344) or
• atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (N=348)

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.

This image is provided by the National Library of Medicine

Less Common Adverse Reactions: 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 Abnormalities: The 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.

This image is provided by the National Library of Medicine

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 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 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.

This image is provided by the National Library of Medicine

Postmarketing Experience

There is limited information regarding Atazanavir and cobicistat Postmarketing Experience in the drug label.

Drug Interactions

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 H2-receptor antagonists are administered with EVOTAZ.

Established and Other Potentially Significant Drug Interactions:

• Drug interaction trials were not conducted for EVOTAZ. Drug interaction trials were conducted with cobicistat in combination with desipramine, digoxin, or efavirenz.
• 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.

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Atazanavir and cobicistat in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atazanavir and cobicistat in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Atazanavir and cobicistat during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Atazanavir and cobicistat in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Atazanavir and cobicistat in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Atazanavir and cobicistat in geriatric settings.

Gender

There is no FDA guidance on the use of Atazanavir and cobicistat with respect to specific gender populations.

Race

There is no FDA guidance on the use of Atazanavir and cobicistat with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Atazanavir and cobicistat in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Atazanavir and cobicistat in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Atazanavir and cobicistat in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Atazanavir and cobicistat in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Atazanavir and cobicistat Administration in the drug label.

Monitoring

There is limited information regarding Atazanavir and cobicistat Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Atazanavir and cobicistat and IV administrations.

Overdosage

There is limited information regarding Atazanavir and cobicistat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Atazanavir and cobicistat Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Atazanavir and cobicistat Mechanism of Action in the drug label.

Structure

There is limited information regarding Atazanavir and cobicistat Structure in the drug label.

Pharmacodynamics

There is limited information regarding Atazanavir and cobicistat Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Atazanavir and cobicistat Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Atazanavir and cobicistat Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Atazanavir and cobicistat Clinical Studies in the drug label.

How Supplied

There is limited information regarding Atazanavir and cobicistat How Supplied in the drug label.

Storage

There is limited information regarding Atazanavir and cobicistat Storage in the drug label.

Images

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Patient Counseling Information

There is limited information regarding Atazanavir and cobicistat Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Atazanavir and cobicistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Atazanavir and cobicistat Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Atazanavir and cobicistat Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.