Appendix B, Table 5. Characteristics of Protease Inhibitors

Body
Appendix B, Table 5. Characteristics of Protease Inhibitors

Generic Name

(Abbreviations)

Trade Name

Formulations

Dosing Recommendationsa

Elimination/

Metabolic Pathway

Serum Half-Life

Adverse Eventsb

Atazanavir
(ATV)
Reyataz

(ATV/c)
Evotaz

Note: Generic products of ATV are available.

Reyataz:

  • 150-mg, 200-mg, and 300-mg capsules
  • 50-mg oral powder/packet

Generic:

  • 100-mg, 150-mg, 200-mg, and 300-mg capsules

Evotaz:

  • ATV 300-mg/COBI 150-mg tablet

Reyataz

In ARV-Naive Patients:

  • (ATV 300 mg plus RTV 100 mg) PO once daily; or
  • ATV 400 mg PO once daily
  • Take with food.

With TDF or in ARV-Experienced Patients:

  • (ATV 300 mg plus RTV 100 mg) PO once daily
  • Unboosted ATV is not recommended.
  • Take with food.

With EFV in ARV-Naive Patients:

  • (ATV 400 mg plus RTV 100 mg) PO once daily
  • Take with food.

Evotaz:

  • One tablet PO once daily
  • Take with food.
  • The use of ATV/c is not recommended for patients who are taking TDF and who have baseline CrCl <70 mL/min (see Appendix B, Table 11 for the equation for calculating CrCl).

For dosing recommendations for patients who also are receiving H2 antagonists and PPIs, refer to Table 21a.

ATV:

  • CYP3A4 inhibitor and substrate
  • Weak CYP2C8 inhibitor
  • UGT1A1 inhibitor

COBI:

  • CYP3A inhibitor and substrate
  • CYP2D6 inhibitor

Dose adjustment is recommended in patients with hepatic insufficiency (see Appendix B, Table 11).

7 hours

Indirect hyperbilirubinemia

PR interval prolongation. First-degree symptomatic AV block has been reported. Use with caution in patients who have underlying conduction defects or who are on concomitant medications that can cause PR prolongation.

Cholelithiasis

Nephrolithiasis

Renal insufficiency

Serum transaminase elevations

Hyperlipidemia (especially with RTV boosting)

Skin rash

Hyperglycemia

Fat maldistribution

An increase in serum creatinine may occur when ATV is administered with COBI.

Darunavir
(DRV)
Prezista

(DRV/c)
Prezcobix

Prezista:

  • 75-mg, 150-mg, 600-mg, and 800-mg tablets
  • 100-mg/mL oral suspension

Prezcobix:

  • DRV 800-mg/COBI 150-mg tablet

Also available as part of the STR Symtuza (DRV/c/TAF/FTC)

Prezista

In ARV-Naive Patients or ARV-Experienced Patients with No DRV Mutations:

  • (DRV 800 mg plus RTV 100 mg) PO once daily
  • Take with food.

In ARV-Experienced Patients with One or More DRV Resistance Mutations:

  • (DRV 600 mg plus RTV 100 mg) PO twice daily
  • Take with food.

Unboosted DRV is not recommended.

Prezcobix:

  • One tablet PO once daily
  • Take with food.
  • Not recommended for patients with one or more DRV resistance-associated mutations.
  • Coadministering Prezcobix and TDF is not recommended for patients with baseline CrCl <70 mL/min (see Appendix B, Table 11 for the equation for calculating CrCl).

See Appendix B, Table 1 for dosing information for Symtuza.

DRV:

  • CYP3A4 inhibitor and substrate
  • CYP2C9 inducer

COBI:

  • CYP3A inhibitor and substrate
  • CYP2D6 inhibitor

15 hours when combined with RTV

7 hours when combined with COBI

Skin Rash: DRV has a sulfonamide moiety, however incidence and severity of rash are similar in those with or without a sulfonamide allergy; Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythema multiforme have been reported.

Hepatotoxicity

Diarrhea, nausea

Headache

Hyperlipidemia

Serum transaminase elevation

Hyperglycemia

Fat maldistribution

An increase in serum creatinine may occur when DRV is administered with COBI.

Lopinavir/
Ritonavir

(LPV/r)
Kaletra

Note: LPV is only available as a component of an FDC tablet that also contains RTV.

Kaletra:

  • LPV/r 200-mg/50-mg tablets
  • LPV/r 100-mg/25-mg tablets
  • LPV/r 400-mg/100-mg per 5 mL of oral solution. Oral solution contains 42% alcohol.

Kaletra:

  • LPV/r 400 mg/100 mg PO twice daily, or
  • LPV/r 800 mg/200 mg PO once daily. However, once-daily dosing is not recommended for patients with three or more LPV-associated mutations, pregnant women, or patients receiving EFV, NVP, carbamazepine, phenytoin, or phenobarbital.

With EFV or NVP in PI-Naive or PI‑Experienced Patients:

  • LPV/r 500-mg/125-mg tablets PO twice daily (use a combination of two LPV/r 200-mg/50-mg tablets plus one LPV/r 100-mg/25-mg tablet to make a total dose of LPV/r 500 mg/125 mg), or
  • LPV/r 533 mg/133 mg oral solution twice daily

Food Restrictions

Tablet:

  • Take without regard to meals.

Oral Solution:

  • Take with food.

CYP3A4 inhibitor and substrate

5–6 hours

GI intolerance, nausea, vomiting, diarrhea

Pancreatitis

Asthenia

Hyperlipidemia (especially hypertriglyceridemia)

Serum transaminase elevation

Hyperglycemia

Insulin resistance/diabetes mellitus

Fat maldistribution

Possible increase in the frequency of bleeding episodes in patients with hemophilia

PR interval prolongation

QT interval prolongation and Torsades de Pointes have been reported; however, causality could not be established.

Ritonavir
(RTV)
Norvir

Note: Generic is available.

Although RTV was initially developed as a PI for HIV treatment, RTV is currently used at a lower dose of 100 mg to 200 mg once or twice daily as a PK enhancer to increase the concentrations of other PIs.

Norvir:

  • 100-mg tablet
  • 100-mg soft gel capsule
  • 80-mg/mL oral solution. Oral solution contains 43% alcohol.
  • 100 mg single packet oral powder

Also available as part of the FDC tablet Kaletra (LPV/r)

As a PK Booster (or Enhancer) for Other PIs:

  • RTV 100–400 mg PO per day in one or two divided doses (refer to other PIs for specific dosing recommendations).

Food Restrictions

Tablet:

  • Take with food.

Capsule and Oral Solution:

To improve tolerability, take with food if possible.

CYP3A4 > 2D6 substrate

Potent CYP3A4 and 2D6 inhibitor

Inducer of UGT1A1 and CYPs 1A2, 2C8, 2C9, and 2C19

3–5 hours

GI intolerance, nausea, vomiting, diarrhea

Paresthesia (circumoral and extremities)

Hyperlipidemia (especially hypertriglyceridemia)

Hepatitis

Asthenia

Taste perversion

Hyperglycemia

Fat maldistribution

Possible increase in the frequency of bleeding episodes in patients with hemophilia

a For dose adjustments in patients with hepatic insufficiency, see Appendix B, Table 11.

b Also see Table 20.

Key: ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; AV = atrioventricular; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DRV = darunavir; DRV/c = darunavir/cobicistat; EFV = efavirenz; FDC = fixed-dose combination; FTC = emtricitabine; GI = gastrointestinal; H2 = histamine H2 receptor; LPV = lopinavir; LPV/r = lopinavir/ritonavir; NVP = nevirapine; PI = protease inhibitor; PK = pharmacokinetic; PO = orally; PPI = proton pump inhibitor; RTV = ritonavir; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; UGT1 = uridine diphosphate glucuronyl transferase 1 family