Atazanavir

Atazanavir is an oral medication that is used for treating infections caused by the human immunodeficiency virus (HIV). It is in a class of drugs called protease inhibitors that also includes ritonavir (Norvir), nelfinavir (Viracept), indinavir (Crixivan) and saquinavir (Invirase, Fortovase). During infection with HIV, the HIV virus multiplies within the body's cells. Viruses are released from the cells and spread throughout the body where they infect other cells. In this manner, HIV infection is perpetuated among new cells that the body produces continually. During the production of the viruses, new proteins must be made. Some of the proteins are structural proteins, that, is, proteins that form the body of the new viruses. Other proteins are enzymes that manufacture DNA and other components for the new viruses. Protease is the enzyme that forms the new structural proteins and enzymes. Atazanavir blocks the activity of protease and results in the formation of new viruses with defective proteins that are unable to infect the body's cells. As a result, the number of viruses in the body (the viral load) decreases. Nevertheless, atazanavir does not prevent the transmission of HIV among individuals, and it does not cure HIV infections or AIDS. Atazanavir was approved by the FDA in June 2003.

• Angioedema (a severe allergic reaction) may occur. Tell your healthcare provider right away if you have signs or symptoms of angioedema, which include the following:
  • swelling of face, eyes, lips, tongue, larynx and extremities
  • difficulty in swallowing or breathing
  • hoarseness (having difficulty making sounds when trying to speak)
  • Severe rash: Rash may develop in association with other symptoms which could be serious and potentially cause death.
 If you develop a rash with any of the following symptoms stop using atazanavir and call your healthcare provider right away:
    • shortness of breath
    • general ill feeling or "flu-like" symptoms
    • fever
    • muscle or joint aches
    • conjunctivitis (red or inflamed eyes, like "pink eye")
    • blisters
    • mouth sores
    • swelling of your face
• A change in the way your heart beats (heart rhythm change) may occur. Call your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• Diabetes and high blood sugar (hyperglycemia) sometimes happen in patients taking protease inhibitor medicines like atazanavir. Some patients had diabetes before taking protease inhibitors while others did not. Some patients may need changes in their diabetes medicine. If you have liver disease including hepatitis B or C, your liver disease may get worse when you take anti-HIV medicines like atazanavir.
• Kidney stones have been reported in patients taking atazanavir. If you develop signs or symptoms of kidney stones (pain in your side, blood in your urine, pain when you urinate) tell your healthcare provider promptly.
• Some patients with hemophilia have increased bleeding problems with protease inhibitors like atazanavir.
• Changes in body fat. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time.
• Immune reconstitution syndrome. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment, including atazanavir, is started.
• Gallbladder disorders (which may include gallstones and gallbladder inflammation) have been reported in patients taking atazanavir.
• Changes in amylase and lipase.
• Decrease in neutrophils.
• Increase in bilirubin.

Do not take atazanavir if you:

• are taking certain medicines (see Drug Interactions). Serious life-threatening side effects or death may happen. Before you take atazanavir, tell your healthcare provider about all medicines you are taking or planning to take. These include other prescription and nonprescription medicines, vitamins, and herbal supplements.
• are allergic to atazanavir or to any of its ingredients. The active ingredient is atazanavir sulfate. Tell your healthcare provider if you think you have had an allergic reaction to any of these ingredients.
• if you have phenylketonuria. Phenylalanine can be harmful to patients with phenylketonuria (PKU). Atazanavir oral powder contains phenylalanine (a component of aspartame).

Do not give atazanavir to:

• pediatric patients below the age of 3 months. Atazanavir is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus (a bilirubin-induced brain dysfunction).

Atazanavir is an antiviral medicine that prevents human immunodeficiency virus (HIV) from multiplying in your body.

Atazanavir is used with other medications to treat HIV, the virus that can cause acquired immunodeficiency syndrome (AIDS). Atazanavir is not a cure for HIV or AIDS.

Atazanavir is for use in adults and children who are at least 3 months old and weigh at least 11 pounds (5 kilograms).

Atazanavir may also be used for purposes not listed in this medication guide.

Usual Adult Dose for HIV Infection:

THERAPY-NAIVE PATIENTS:
-Recommended dose: Atazanavir 300 mg plus ritonavir 100 mg orally once a day
-If unable to tolerate ritonavir: 400 mg orally once a day
-If used with efavirenz: Atazanavir 400 mg plus ritonavir 100 mg orally once a day

THERAPY-EXPERIENCED PATIENTS:
-Recommended dose: Atazanavir 300 mg plus ritonavir 100 mg orally once a day
-If used with both an H2-receptor antagonist and tenofovir: Atazanavir 400 mg plus ritonavir 100 mg orally once a day

PREGNANCY:
Therapy-naive and Therapy-experienced Patients:
-Recommended dose: Atazanavir 300 mg plus ritonavir 100 mg orally once a day

Therapy-experienced Patients during the Second or Third Trimester:
-If used with either an H2-receptor antagonist or tenofovir: Atazanavir 400 mg plus ritonavir 100 mg orally once a day
-If used with both an H2-receptor antagonist and tenofovir: Not recommended.

Comments:
-This drug must be used with ritonavir during pregnancy.
-This drug should only be used in pregnant women with HIV-1 strains susceptible to atazanavir.
-No dose adjustment needed for pregnant patients with the above exceptions.
-No dose adjustment needed for postpartum patients; close monitoring for side effects recommended (higher drug exposures possible during first 2 months after delivery).

Use: In combination with other antiretroviral agents, for the treatment of HIV-1 infection

Usual Adult Dose for Nonoccupational Exposure:

US CDC recommendations:
-Recommended dose: 400 mg orally once a day
-If used with tenofovir: Atazanavir 300 mg plus ritonavir 100 mg orally once a day

Duration of therapy: 28 days

Comments:
-Recommended as an alternative regimen for nonoccupational postexposure prophylaxis of HIV infection
-This drug should be used with (lamivudine or emtricitabine) plus (zidovudine or stavudine or abacavir or didanosine) or (tenofovir plus ritonavir [100 mg/day]).
-Prophylaxis should be started as soon as possible, within 72 hours of exposure.
-Not approved by US FDA.

Usual Pediatric Dose for HIV Infection:

ORAL POWDER:
Therapy-naive and Therapy-experienced Patients:
3 months or older:
10 to less than 15 kg: Atazanavir 200 mg plus ritonavir 80 mg orally once a day
15 to less than 25 kg: Atazanavir 250 mg plus ritonavir 80 mg orally once a day

CAPSULES:
Therapy-naive and Therapy-experienced Patients:
6 to less than 18 years:
15 to less than 20 kg: Atazanavir 150 mg plus ritonavir 100 mg orally once a day
20 to less than 40 kg: Atazanavir 200 mg plus ritonavir 100 mg orally once a day
40 or more: Atazanavir 300 mg plus ritonavir 100 mg orally once a day

Therapy-naive Patients Unable to Tolerate Ritonavir:
13 to less than 18 years:
40 kg or more: 400 mg orally once a day

Comments:
-Each packet of the oral powder contains 50 mg of atazanavir.
-The oral powder should be administered after mixing with food or beverage; ritonavir should be administered immediately after that.
-The oral powder is not recommended for patients weighing less than 10 kg or 25 kg or more.
-The capsules and ritonavir should be administered simultaneously with food.
-The capsules must be used with ritonavir in therapy-experienced patients.
-According to the Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, some experts recommend increasing atazanavir to 300 mg at a weight of at least 35 kg to avoid underdosing, especially when tenofovir is coadministered.

Use: In combination with other antiretroviral agents, for the treatment of HIV-1 infection

Binds to the site of HIV-1 protease activity and inhibits cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV. This results in the formation of immature, noninfectious viral particles.

Absorption

Rapid; enhanced with food

Distribution

CSF: Plasma concentration ratio (range): 0.0021 to 0.0226

Metabolism

Hepatic, primarily by cytochrome P450 isoenzyme CYP3A; also undergoes biliary elimination; major biotransformation pathways include mono-oxygenation and deoxygenation; minor pathways for parent drug or metabolites include glucuronidation, N-dealkylation, hydrolysis and oxygenation with dehydrogenation; 2 minor inactive metabolites have been identified

Excretion

Feces (79%, 20% of total dose as unchanged drug); urine (13%, 7% of total dose as unchanged drug)

Time to Peak

Plasma: 2 to 3 hours

Half-Life Elimination

Unboosted therapy: 7 to 8 hours; Boosted therapy (with ritonavir): 9 to 18 hours; 12 hours in patients with hepatic impairment

Protein Binding

86%; binds to both alpha1-acid glycoprotein and albumin (similar affinity)

Treatment of HIV-1 infection: Oral:

Antiretroviral-naive patients: Atazanavir 300 mg once daily plus ritonavir 100 mg or cobicistat 150 mg once daily or atazanavir 400 mg once daily in patients unable to tolerate ritonavir.

Antiretroviral-experienced patients: Atazanavir 300 mg once daily plus ritonavir 100 mg or cobicistat 150 mg once daily. Note: Atazanavir without ritonavir is not recommended in antiretroviral-experienced patients with prior virologic failure.

Pregnant patients, antiretroviral naive or experienced: Atazanavir 300 mg once daily plus ritonavir 100 mg once daily. Postpartum dosage adjustment not needed. Observe patient for adverse events, especially within 2 months after delivery.

Dose adjustments required for concomitant therapy in pregnancy: Dose adjustments required during the second and third trimester with concomitant tenofovir disoproxil fumarate or H2 antagonist use (use is not recommended if both tenofovir disoproxil fumarate and an H2 antagonist are used): Atazanavir 400 mg plus ritonavir 100 mg. Note: Product labeling recommends this dose adjustment in treatment-experienced pregnant patients, while some experts recommend this adjustment in all pregnant women during the second and third trimester (HHS [perinatal] 2016).

Dosage adjustments for concomitant therapy:

Coadministration with efavirenz:

Antiretroviral-naive patients: Atazanavir 400 mg plus ritonavir 100 mg given with efavirenz 600 mg (all once daily but administered at different times; atazanavir and ritonavir with food and efavirenz on an empty stomach).

Antiretroviral-experienced patients: Concurrent use not recommended due to decreased atazanavir exposure.

Coadministration with didanosine buffered or enteric-coated formulations: Administer atazanavir 2 hours before or 1 hour after didanosine buffered or enteric coated formulations

Coadministration with H2 antagonists:

Antiretroviral-naive patients: Atazanavir 300 mg plus ritonavir 100 mg given simultaneously with, or at least 10 hours after an H2 antagonist equivalent dose of ≤80 mg famotidine/day

Patients unable to tolerate ritonavir: Atazanavir 400 mg once daily given at least 2 hours before or at least 10 hours after an H2 antagonist equivalent daily dose of ≤40 mg famotidine (single dose ≤20 mg)

Antiretroviral-experienced patients: Atazanavir 300 mg plus ritonavir 100 mg given simultaneously with, or at least 10 hours after an H2 antagonist equivalent dose of ≤40 mg famotidine/day

Antiretroviral-experienced pregnant patients in the second or third trimester: Atazanavir 400 mg plus ritonavir 100 mg simultaneously with, or at least 10 hours after an H2 antagonist. Note: Use not recommended if tenofovir and an H2 antagonist are used.

Coadministration with proton pump inhibitors:

Antiretroviral-naive patients: Atazanavir 300 mg plus ritonavir 100 mg given 12 hours after a proton pump inhibitor equivalent dose of ≤20 mg omeprazole/day

Antiretroviral-experienced patients: Concurrent use not recommended. (Note: One study noted adequate serum concentrations when atazanavir 400 mg plus ritonavir 100 mg was given at the same time or 12 hours after omeprazole 20 mg.)

Coadministration with tenofovir disoproxil fumarate:

Antiretroviral-naive patients: Atazanavir 300 mg plus ritonavir 100 mg given with tenofovir disoproxil fumarate 300 mg (all as a single daily dose)

Antiretroviral-experienced patients: Atazanavir 300 mg plus ritonavir 100 mg given with tenofovir disoproxil fumarate 300 mg (all as a single daily dose); if H2 antagonist coadministered (not to exceed equivalent daily dose of ≤40 mg famotidine), increase atazanavir to 400 mg (plus ritonavir 100 mg) once daily

Antiretroviral-experienced pregnant patients in the second or third trimester: Atazanavir 400 mg plus ritonavir 100 mg. Note: Use not recommended if tenofovir disoproxil fumarate and an H2 antagonist are used

Refer to adult dosing.

Treatment of HIV-1 infection: Infants ≥3 months, Children and Adolescents <18 years: Oral: Note: Ritonavir-boosted atazanavir dosing regimen is preferred.

Ritonavir-unboosted regimen:

Antiretroviral-naive patients:

Children 6 years to <13 years: Dose not established; use not recommended

Adolescents <40 kg who are not able to tolerate ritonavir: No dosage recommendations provided in the manufacturer’s labeling.

Adolescents ≥40 kg who are not able to tolerate ritonavir: Atazanavir 400 mg once daily (without ritonavir). Note: Ritonavir boosted atazanavir dosing regimen is preferred; data indicate that higher atazanavir dosing (ie, higher on a mg/kg or mg/m2 basis than predicted by adult dosing guidelines) may be needed when atazanavir is used without ritonavir boosting in children and adolescents (HHS [pediatric], 2016).

Ritonavir-boosted regimen:

Antiretroviral-naive and experienced patients:

Oral powder: Infants ≥3 months and Children and Adolescents weighing ≥5 kg:

5 to <15 kg: Atazanavir 200 mg (4 packets) plus ritonavir 80 mg once daily. In antiretroviral-naïve patients weighing 5 to <10 kg unable to tolerate this dose, may use atazanavir 150 mg (3 packets) plus ritonavir 80 mg once daily with close HIV viral load monitoring.

15 to <25 kg: Atazanavir 250 mg (5 packets) plus ritonavir 80 mg once daily

≥25 kg, patient cannot swallow capsules: Atazanavir 300 mg (6 packets) plus ritonavir 100 mg once daily

Oral capsules: Children ≥6 years and Adolescents <18 years: Note: Some experts recommend switching to the capsule formulation for any child ≥15 kg (regardless of age) who can swallow a capsule whole (HHS [pediatric] 2016).

15 to <35 kg: Atazanavir 200 mg once daily plus ritonavir 100 mg once daily

≥35 kg: Atazanavir 300 mg once daily plus ritonavir 100 mg once daily

Dosage adjustment for concomitant therapy: Antiretroviral-experienced or antiretroviral-naive patients: Coadministration with H2 antagonists, proton pump inhibitors, or other antiretroviral agents (eg, efavirenz, tenofovir disoproxil fumarate, didanosine):

Infants ≥3 months, Children and Adolescents: Refer to adult dosing for recommendations regarding the timing and maximum doses of concomitant proton pump inhibitors, H2 antagonists, and other antiretroviral agents.

Capsules: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Oral powder: Store below 30°C (86°F). Store oral powder in the original packet and do not open until ready to use. Once the oral powder is mixed with food or beverage, it may be kept at 20°C to 30°C (68°F to 86°F) for up to 1 hour prior to administration.

Abacavir: Protease Inhibitors may decrease the serum concentration of Abacavir. Monitor therapy

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Alfuzosin: Protease Inhibitors may increase the serum concentration of Alfuzosin. Avoid combination

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Consider therapy modification

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

ALPRAZolam: Protease Inhibitors may increase the serum concentration of ALPRAZolam. Management: Seek alternatives to alprazolam in patients treated with HIV protease inhibitors. Concurrent use of alprazolam with indinavir is contraindicated. All patients receiving such a combination should be monitored closely for excessive response to alprazolam. Consider therapy modification

Amiodarone: Atazanavir may increase the serum concentration of Amiodarone. Monitor therapy

AmLODIPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Antacids: May decrease the absorption of Atazanavir. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Astemizole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Protease Inhibitors may increase the serum concentration of AtorvaSTATin. Management: See full monograph for recommended dose limits. Avoid atorvastatin with tipranavir/ritonavir. Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

Belinostat: Atazanavir may increase the serum concentration of Belinostat. Avoid combination

Benperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Boceprevir: May decrease the serum concentration of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Boceprevir. Management: Some combinations are not recommended. See full drug interaction monograph for details. Consider therapy modification

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy

Bosentan: May decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Bosentan. Management: Concurrent use of atazanavir (without ritonavir) and bosentan is not recommended. Bosentan dose adjustments are required when used together with atazanavir/ritonavir. Consider therapy modification

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brigatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Buprenorphine: May decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Buprenorphine. Management: Avoid this combination in patients un-boosted atazanavir due to possible decreased atazanavir concentrations. This combination is not contraindicated in patients also receiving ritonavir, but monitoring for buprenorphine toxicity is recommended. Avoid combination

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Protease Inhibitors may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated. Consider therapy modification

Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: May increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine. Consider therapy modification

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cisapride: Protease Inhibitors may increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias. Avoid combination

Clarithromycin: Protease Inhibitors may diminish the therapeutic effect of Clarithromycin. Specifically, certain protease inhibitors may decrease formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness vs. H. influenzae and other non-MAC infections. Protease Inhibitors may increase the serum concentration of Clarithromycin. Clarithromycin dose adjustment in renally impaired patients may be needed. Clarithromycin may increase the serum concentration of Protease Inhibitors. Management: Avoid clarithromycin adult doses greater than 1000 mg/day when used with a protease inhibitor. Further dose reductions may be needed in patients with impaired renal function. Consider alternative antimicrobial for any non-MAC infection. Consider therapy modification

CloZAPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Contraceptives (Estrogens): Protease Inhibitors may decrease the serum concentration of Contraceptives (Estrogens). Management: Use oral contraceptives containing at least 35mcg ethinyl estradiol with atazanavir/ritonavir, or no more than 30mcg in patients receiving atazanavir alone. Use of an alternative, non-hormonal contraceptive is recommended with other protease inhibitors. Consider therapy modification

Contraceptives (Progestins): Atazanavir may increase the serum concentration of Contraceptives (Progestins). However, atazanavir may lead to decreased ethinyl estradiol concentrations and decreased effectiveness of oral contraceptive products. Management: Consider an alternative or additional method of contraception, particularly with combined estrogen/progestin products. Depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

Cyclophosphamide: Protease Inhibitors may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Monitor therapy

CycloSPORINE (Systemic): Protease Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Protease Inhibitors. Consider therapy modification

CycloSPORINE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); AmLODIPine; Buprenorphine; Gefitinib; HYDROcodone; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Dapsone (Systemic): May enhance the adverse/toxic effect of Atazanavir. Specifically, the risk of hyperbilirubinemia may be increased. Monitor therapy

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deflazacort: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Delamanid: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Delamanid. Management: Increase electrocardiogram (ECG) monitoring frequency if delamanid is combined with strong CYP3A4 inhibitors because the risk for QTc interval prolongation may be increased. Continue frequent ECG assessments throughout the full delamanid treatment period. Consider therapy modification

Delavirdine: Protease Inhibitors may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Protease Inhibitors. Consider therapy modification

Dexamethasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dexamethasone (Ophthalmic). Monitor therapy

Didanosine: May decrease the serum concentration of Atazanavir. Specifically, the buffered formulation of didanosine may decrease atazanavir absorption. Atazanavir may decrease the serum concentration of Didanosine. Reported with enteric coated didanosine capsules. Management: To avoid therapeutic failure of atazanavir the drug should be administered 2 hours before or 1 hour after didanosine. This recommendation applies to both buffered didanosine products and enteric coated didanosine products. Consider therapy modification

Disulfiram: Atazanavir may diminish the therapeutic effect of Disulfiram. Monitor therapy

DOCEtaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities. Consider therapy modification

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Efavirenz: May decrease the serum concentration of Atazanavir. Management: When used with efavirenz, the adult atazanavir dose should be 400 mg daily, boosted with ritonavir 100 mg daily or cobicistat 150 mg daily, for treatment-naive patients only; treatment-experienced patients should not use atazanavir with efavirenz. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Eluxadoline: Atazanavir may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with atazanavir and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Elvitegravir: Atazanavir may increase the serum concentration of Elvitegravir. Specifically, atazanavir/ritonavir may increase the concentration of elvitegravir. Management: When elvitegravir is combined with atazanavir/ritonavir, the dose of elvitegravir should be reduced to 85 mg once daily and the dose of atazanavir/ritonavir should be 300 mg/100 mg once daily. Avoid the use of atazanavir/cobicistat and elvitegravir. Consider therapy modification

Enfuvirtide: Protease Inhibitors may increase the serum concentration of Enfuvirtide. Enfuvirtide may increase the serum concentration of Protease Inhibitors. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Ergot Derivatives: Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Nicergoline. Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Estazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. Monitor therapy

Eszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Consider therapy modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Etravirine: Atazanavir may increase the serum concentration of Etravirine. Etravirine may decrease the serum concentration of Atazanavir. Management: The combination of etravirine and atazanavir should be avoided unless atazanavir is boosted with ritonavir. The use of cobicistat instead of ritonavir has not been evaluated and is not recommended. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

Evogliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin. Monitor therapy

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Avoid combination

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fluvastatin: Atazanavir may increase the serum concentration of Fluvastatin. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Garlic: May decrease the serum concentration of Protease Inhibitors. Management: Concurrent use of garlic supplements with protease inhibitors is not recommended. If this combination is used, monitor closely for altered serum concentrations/effects of protease inhibitors, and particularly for signs/symptoms of therapeutic failure. Consider therapy modification

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

Glecaprevir and Pibrentasvir: Atazanavir may increase the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

Grazoprevir: Atazanavir may increase the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

H2-Antagonists: May decrease the serum concentration of Atazanavir. Management: Specific dose limitations and administration guidelines exist; consult full interaction monograph or atazanavir prescribing information. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone. Monitor therapy

HydrOXYzine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HydrOXYzine. Management: This combination is specifically contraindicated in some non-U.S. labeling. Consider therapy modification

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Consider therapy modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Indinavir: May enhance the adverse/toxic effect of Atazanavir. Atazanavir may enhance the adverse/toxic effect of Indinavir. Avoid combination

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

LamoTRIgine: Atazanavir may decrease the serum concentration of LamoTRIgine. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lovastatin: Protease Inhibitors may increase the serum concentration of Lovastatin. Avoid combination

Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination

Lurasidone: Atazanavir may increase the serum concentration of Lurasidone. Management: Atazanavir labeling recommends reducing the lurasidone dose as directed by the lurasidone labeling for moderate CYP3A4 inhibitors when used together with lurasidone. Consider therapy modification

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

Manidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required. Consider therapy modification

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

Meperidine: Protease Inhibitors may enhance the adverse/toxic effect of Meperidine. Protease Inhibitors may decrease the serum concentration of Meperidine. Concentrations of the toxic Normeperidine metabolite may be increased. Consider therapy modification

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification

Midazolam: Protease Inhibitors may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use. Avoid combination

Midostaurin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Consider therapy modification

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 600 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May decrease the serum concentration of Atazanavir. Monitor therapy

Minoxidil (Systemic): Atazanavir may increase the serum concentration of Minoxidil (Systemic). Monitor therapy

Mirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Naldemedine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Nefazodone: Protease Inhibitors may increase the serum concentration of Nefazodone. Management: Consider alternatives to, or reduced doses of, nefazodone in patients treated with HIV protease inhibitors. Monitor patients receiving these combinations closely for toxic effects of nefazodone. Consider therapy modification

Neratinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nevirapine: Atazanavir may increase the serum concentration of Nevirapine. Nevirapine may decrease the serum concentration of Atazanavir. Avoid combination

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Ombitasvir, Paritaprevir, and Ritonavir: Atazanavir may increase the serum concentration of Ombitasvir, Paritaprevir, and Ritonavir. Specifically, the paritaprevir component may increase significantly. Avoid combination

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: Atazanavir may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the paritaprevir component may increase significantly. Management: These agents can be combined if the atazanavir dose is 300 mg daily, atazanavir is administered in the morning at the same time as the ombitasvir/paritaprevir/ritonavir/dasabuvir combination product, and atazanavir is given without additional ritonavir. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

PACLitaxel (Conventional): Atazanavir may increase the serum concentration of PACLitaxel (Conventional). Management: Use of paclitaxel or other narrow therapeutic index CYP2C8 substrates with atazanavir without concurrent ritonavir is not recommended. If paclitaxel is used with ritonavir-boosted atazanavir, no significant interaction is expected. Avoid combination

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Protease Inhibitors may increase the serum concentration of Pimozide. Avoid combination

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pitavastatin: Atazanavir may increase the serum concentration of Pitavastatin. Monitor therapy

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Posaconazole: May increase the serum concentration of Atazanavir. Monitor therapy

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Monitor therapy

Propafenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Monitor therapy

Protease Inhibitors: May increase the serum concentration of other Protease Inhibitors. Management: Atazanavir--indinavir combination contraindicated. Tipranavir/ritonavir or atazanavir/ritonavir not recommended with other protease inhibitors (PI). Darunavir/cobicistat not recommended with PI that require boosting.Other combos may require dose changes. Consider therapy modification

Proton Pump Inhibitors: May decrease the serum concentration of Atazanavir. Management: See full drug interaction monograph for details. Consider therapy modification

QUEtiapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce the quetiapine dose to one sixth of the regular dose following strong CYP3A4 inhibitor initiation. In patients receiving strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and up-titrate as needed. Consider therapy modification

QuiNIDine: Atazanavir may increase the serum concentration of QuiNIDine. Monitor therapy

Radotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib. Avoid combination

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: Atazanavir may increase the serum concentration of Repaglinide. Management: Use of repaglinide or other narrow therapeutic index CYP2C8 substrates with atazanavir without concurrent ritonavir is not recommended. If repaglinide is used with ritonavir-boosted atazanavir, no significant interaction is expected. Avoid combination

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Ribociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ribociclib. Management: Avoid use of ribociclib with strong CYP3A4 inhibitors when possible; if combined use cannot be avoided, reduce ribociclib dose to 400 mg once daily. Consider therapy modification

Rifabutin: Atazanavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Atazanavir may increase the serum concentration of Rifabutin. Management: Reduce rifabutin doses. Atazanavir US labeling recommends a decrease of at least 75%, to 150 mg every other day or 3 times per week for adults. Clinical guidelines recommend 150 mg/day or 300 mg 3 times per week with atazanavir/ritonavir. Consider therapy modification

RifAMPin: May decrease the serum concentration of Atazanavir. Avoid combination

Rilpivirine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rilpivirine. Monitor therapy

Riociguat: Protease Inhibitors may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day (for adults). Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy

Rosiglitazone: Atazanavir may increase the serum concentration of Rosiglitazone. Monitor therapy

Rosuvastatin: Protease Inhibitors may increase the serum concentration of Rosuvastatin. Management: Start at the lowest rosuvastatin dose and monitor for toxicity. See full drug interaction monograph for details. Consider therapy modification

Rupatadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine. Avoid combination

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

Sildenafil: Protease Inhibitors may increase the serum concentration of Sildenafil. Management: Erectile dysfunction: sildenafil max = 25 mg/48 hrs with ritonavir, atazanavir, or darunavir; starting dose = 25 mg with other protease inhibitors (adult doses). Contraindicated if sildenafil being used for pulmonary arterial hypertension. Consider therapy modification

Sildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours. Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simeprevir: Protease Inhibitors may increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors. Avoid combination

Simvastatin: Protease Inhibitors may increase the serum concentration of Simvastatin. Avoid combination

Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

St John's Wort: May decrease the serum concentration of Atazanavir. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

SUFentanil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil. Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression). Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Protease Inhibitors may decrease the metabolism of Tacrolimus (Systemic). Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tacrolimus (Systemic). Management: Monitor clinical tacrolimus response closely and frequently monitor tacrolimus serum concentrations with concurrent use of any strong CYP3A4 inhibitor. Tacrolimus dose reductions and/or prolongation of the dosing interval will likely be required. Consider therapy modification

Tacrolimus (Topical): Protease Inhibitors may decrease the metabolism of Tacrolimus (Topical). Monitor therapy

Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Telaprevir: Atazanavir may decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Atazanavir. Monitor therapy

Temsirolimus: Protease Inhibitors may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism. Consider therapy modification

Temsirolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Temsirolimus. Consider therapy modification

Tenofovir Disoproxil Fumarate: May decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Must use ritonavir-boosting in adults; give combo (atazanavir/ritonavir 300mg/100mg and tenofovir 300mg) as a single daily dose with food. Pediatric patients, pregnant patients, and users of H2-blockers require other dose changes. Consider therapy modification

Terfenadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Theophylline Derivatives: Protease Inhibitors may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

Tipranavir: May decrease the serum concentration of Protease Inhibitors. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Consider therapy modification

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

TraZODone: Atazanavir may increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with atazanavir. Consider therapy modification

Triazolam: Protease Inhibitors may increase the serum concentration of Triazolam. Avoid combination

Tricyclic Antidepressants: Protease Inhibitors may increase the serum concentration of Tricyclic Antidepressants. Monitor therapy

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Valbenazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors. Consider therapy modification

Valproate Products: Protease Inhibitors may decrease the serum concentration of Valproate Products. Monitor therapy

Vardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. See full drug interaction monograph for details. Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Voriconazole: Atazanavir may decrease the serum concentration of Voriconazole. Atazanavir may increase the serum concentration of Voriconazole. Voriconazole may decrease the serum concentration of Atazanavir. Management: Voriconazole should not be used in a patient who is being treated with ritonavir-boosted atazanavir unless the benefits of the combination outweigh the potential risks. Extra monitoring for both loss of effectiveness and toxicity is warranted. Avoid combination

Voxilaprevir: Atazanavir may increase the serum concentration of Voxilaprevir. Avoid combination

Warfarin: Atazanavir may increase the serum concentration of Warfarin. Monitor therapy

Zidovudine: Protease Inhibitors may decrease the serum concentration of Zidovudine. Monitor therapy

Zolpidem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification

Applies to atazanavir: oral capsule, oral powder

Along with its needed effects, atazanavir may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking atazanavir:

• Abdominal or stomach discomfort, fullness, or pain
• bloating
• blood in the urine
• blurred vision
• chest pain or discomfort
• chills
• clay-colored stools
• constipation
• dark-colored urine
• decreased appetite
• diarrhea
• dizziness or lightheadedness
• dry mouth
• fainting
• fast heartbeat
• fast, shallow breathing
• fever
• flushed, dry skin
• fruit-like breath odor
• gaseous abdominal or stomach pain
• general feeling of discomfort
• headache
• hives, itching, or skin rash
• increased hunger
• increased thirst
• increased urination
• indigestion
• irregular heartbeat
• loss of appetite
• loss of consciousness
• muscle pain or cramping
• nausea
• pain in the groin or genitals
• pain in the stomach, side, or abdomen, possibly radiating to the back
• recurrent fever
• severe nausea or vomiting
• sharp back pain just below the ribs
• sleepiness
• slow or irregular heartbeat
• stomachache
• sweating
• swelling
• tightness in the chest
• trouble with breathing
• unexplained weight loss
• unpleasant breath odor
• unusual tiredness or weakness
• vomiting
• vomiting of blood
• yellow eyes or skin

Some side effects of atazanavir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• cough, increased
• discouragement
• extra body fat
• feeling sad or empty
• irritability
• loss of interest or pleasure
• trouble concentrating
• trouble sleeping

• Burning, numbness, tingling, or painful sensations
• difficulty with moving
• muscle stiffness
• pain
• pain in the joints
• unsteadiness or awkwardness
• weakness in the arms, hands, legs, or feet

• Hair loss or thinning of the hair
• rash with flat lesions or small raised lesions on the skin

US CDC recommendations:
-Recommended dose: 400 mg orally once a day
-If used with tenofovir: Atazanavir 300 mg plus ritonavir 100 mg orally once a day

Duration of therapy: 28 days

Comments:
-Recommended as an alternative regimen for nonoccupational postexposure prophylaxis of HIV infection
-This drug should be used with (lamivudine or emtricitabine) plus (zidovudine or stavudine or abacavir or didanosine) or (tenofovir plus ritonavir [100 mg/day]).
-Prophylaxis should be started as soon as possible, within 72 hours of exposure.
-Not approved by US FDA.

This drug is not recommended for use in patients younger than 3 months due to risk of kernicterus.

Consult WARNINGS section for additional precautions.

Animal studies have failed to reveal evidence of teratogenicity at maternal doses producing systemic drug exposure levels 0.7 (rabbits) or 1.2 (rats) times those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). This drug has been evaluated in a limited number of women during pregnancy and postpartum. Available data suggest risk of major birth defects overall (compared to background rate) is not increased by this drug; however, human studies cannot rule out the possibility of harm. Hyperbilirubinemia has been reported frequently during drug therapy and it is not known whether maternal use would lead to neonatal kernicterus. Hyperlactatemia and lactic acidosis syndrome (in some cases fatal) have been reported in pregnant women using this drug in combination with nucleoside analogs. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com As of January 2010, the APR has received prospective reports of 635 pregnancies (425, 160, and 50 first, second, and third trimester exposures, respectively). Birth defects occurred in 9 of 393 live births with first trimester exposure and 5 of 212 live births with second or third trimester exposure. The background rate of birth defects among pregnant women in the US reference population is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR. In one clinical study, atazanavir plus ritonavir was given with lamivudine and zidovudine to 41 HIV-infected pregnant women during the second or third trimester. Less than 50 copies/mL HIV RNA was achieved at time of delivery by 38 of the 39 patients completing the study. Hyperbilirubinemia (total bilirubin at least 2.6 times the upper limit of normal) was reported in 6 of 20 women on atazanavir 300 mg plus ritonavir 100 mg and 13 of 21 women on atazanavir 400 mg plus ritonavir 100 mg. Lactic acidosis was not reported during this study. Drug levels in fetal umbilical cord blood were about 12% to 19% of maternal levels. All 40 infants (83% Black/African American) born to 40 HIV-infected pregnant women were negative for HIV-1 DNA at delivery and/or during the first 6 months postpartum. Antiretroviral prophylactic therapy containing zidovudine was administered to all 40 infants. During this study, the neonates did not develop severe hyperbilirubinemia (total bilirubin greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy. Bilirubin levels of at least 4 mg/dL were reported within the first day of life in 10 of 36 infants (6 were at least 38 weeks gestation and 4 were less than 38 weeks gestation). Three of the 38 infants who had glucose samples collected the first day of life had values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. The manufacturer recommends that all infants, including newborns exposed to this drug in utero, be monitored for severe hyperbilirubinemia during the first few days of life. AU TGA pregnancy category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage. US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk. AU TGA pregnancy category: B2 US FDA pregnancy category: B Comments: -This drug should not be administered without ritonavir during pregnancy and postpartum. -This drug should only be used in pregnant women with HIV-1 strains susceptible to atazanavir.

Substance Name

Atazanavir

CAS Registry Number

198904-31-3

Drug Class

Antiinfective Agents

Anti-HIV Agents

Antiviral Agents

Anti-Retroviral Agents

HIV Protease Inhibitors

Atazanavir Capsules:

Potential for Atazanavir to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of Atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir is a weak inhibitor of CYP2C8. Use of Atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When Atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3)].

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when Atazanavir is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

Potential for Other Drugs to Affect Atazanavir

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease Atazanavir plasma concentrations and reduce atazanavir’s therapeutic effect.

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 Atazanavir [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6)].

Established and Other Potentially Significant Drug Interactions

Table 16 provides dosing recommendations in adults as a result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Drugs with No Observed Interactions with Atazanavir

No clinically significant drug interactions were observed when Atazanavir was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3)].

Human experience of acute overdose with Atazanavir is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of Atazanavir in an HIV-infected patient (73 times the 400-mg recommended dose) 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 [see Warnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.2)].

Treatment of overdosage with Atazanavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed Atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with atazanavir. Since Atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

Mechanism of Action

Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12.4)].

Pharmacodynamics

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of Atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. 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 [see Warnings and Precautions (5.1)].

Electrocardiographic effects of Atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of Atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the Atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)].

Pharmacokinetics

The pharmacokinetics of Atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients after administration of Atazanavir 400 mg once daily and after administration of Atazanavir 300 mg with ritonavir 100 mg once daily (see Table 17).

Figure 1 displays the mean plasma concentrations of Atazanavir at steady state after Atazanavir 400 mg once daily (as two 200-mg capsules) with a light meal and after Atazanavir 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.

Figure 1:  Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Patients

Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.

Administration of Atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of Atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of Atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of Atazanavir with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.

Coadministration of a single 300-mg dose of Atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of Atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of Atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of Atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with Atazanavir 400 mg once daily with a light meal for 12 weeks, Atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for Atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

Atazanavir is extensively metabolized in humans. The major biotransformation pathways of Atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for Atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of Atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that Atazanavir is metabolized by CYP3A.

Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of Atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Renal Impairment

In healthy subjects, the renal elimination of unchanged Atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean Atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When Atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7)].

Hepatic Impairment

Atazanavir has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of Atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of Atazanavir are expected. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of Atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of Atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)].

Pediatrics

The pharmacokinetic parameters for Atazanavir at steady state in pediatric patients taking the Atazanavir (REYATAZ) powder formulation are summarized in Table 18 by weight ranges [see Dosage and Administration (2.5)].

The pharmacokinetic parameters for Atazanavir at steady state in pediatric patients taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)].

Pregnancy

The pharmacokinetic data from HIV-infected pregnant women receiving Atazanavir capsules with ritonavir are presented in Table 20.

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min−1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM).

Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, Atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

Clinically significant interactions are not expected between Atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between Atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between Atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).

Drug interaction studies were performed with Atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of Atazanavir on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on Atazanavir exposures (see Table 22 for effect of Atazanavir on didanosine EC or diltiazem exposures). Atazanavir did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).

Microbiology

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted Atazanavir vs. Unboosted Atazanavir: Study AI424-089 compared Atazanavir 300 mg once daily with ritonavir 100 mg vs. Atazanavir 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.

Clinical Studies of Treatment-Naive Patients Receiving Atazanavir 300 mg with Ritonavir 100 mg: In Phase III Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Patients Receiving Atazanavir 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on Atazanavir 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.

Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent ATV/RTV resistance-associated amino acid substitution M36I in the protease was detected in the virus of one subject among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one subject each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to ATV, RTV, or ATV/RTV was not seen with these viruses. In AI424-451, ATV/RTV resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two subjects. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to RTV (RTV phenotypic fold-change of 3.5, with a RTV cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold-change of <1.8, with an ATV cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one subject each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from nine subjects in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1).

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.

Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 24.

Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to patients with 1–2 PI substitutions, including one of these substitutions.

The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for atazanavir.

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Atazanavir
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