Dosing: Adult

Treatment of HIV infection: Oral:

Therapy-naive: 800 mg once daily; coadministration with ritonavir 100 mg once daily is required. Note: Recommended (with ritonavir) as a first-line therapy with tenofovir/emtricitabine in antiretroviral naïve patients (DHHS, 2011).

Therapy-experienced: Note: If genotypic testing is not possible, 600 mg twice daily, coadministered with ritonavir 100 mg twice daily, is recommended.

With no resistance-associated substitutions: 800 mg once daily; coadministration with ritonavir 100 mg once daily is required

With ≥1 resistance-associated substitution: 600 mg twice daily; coadministration with ritonavir 100 mg twice daily is required

Dosage adjustments for concomitant therapy: Oral:

Coadministration with bosentan:

Coadministration of bosentan in patients currently receiving darunavir/ritonavir: For patients receiving ritonavir for at least 10 days, begin with bosentan 62.5 mg once daily or every other day based on tolerability

Coadministration of darunavir/ritonavir in patients currently receiving bosentan: Discontinue bosentan 36 hours prior to the initiation of ritonavir. After at least 10 days of ritonavir, resume bosentan 62.5 mg once daily or every other day based on tolerability.

Coadministration with colchicine:

Familial Mediterranean fever (FMF): Maximum colchicine dose: 0.6 mg/day (0.3 mg twice daily)

Gout prophylaxis:

If original colchicine dose is 0.6 mg twice daily, adjust dose to 0.3 mg once daily

If original colchicine dose is 0.6 mg once daily, adjust dose to 0.3 mg every other day

Gout flare treatment: Initial: Colchicine 0.6 mg, followed in 1 hour by a single dose of 0.3 mg; do not repeat for at least 3 days

Coadministration with phosphodiesterase-5 enzyme (PDE-5) inhibitor:

Pulmonary arterial hypertension: Darunavir/ritonavir coadministered with tadalafil:

Patient receiving darunavir with ritonavir for at least 1 week: Initiate tadalafil at 20 mg once daily; increase to 40 mg once daily based on individual tolerability

Patient receiving tadalafil when initiating darunavir/ritonavir: Discontinue tadalafil at least 24 hours prior to starting darunavir/ritonavir. After at least 1 week following the initiation of ritonavir, resume tadalafil at 20 mg once daily; increase to 40 mg once daily based on individual tolerability.

Erectile dysfunction: Darunavir/ritonavir coadministered with:

Sildenafil (Viagra®): Maximum sildenafil dose: 25 mg in a 48-hour period

Tadalafil (Cialis®): Maximum tadalafil dose: 10 mg in a 72-hour period

Vardenafil: Maximum vardenafil dose: 2.5 mg in a 72-hour period

Dosing: Pediatric

Treatment of HIV infection: Oral: Note: Do not use once-daily dosing in pediatric patients; maximum dose: 600 mg darunavir/100 mg ritonavir twice daily.

Children ≥6 years:

≥20 kg to <30 kg: 375 mg twice daily; coadministration with ritonavir 50 mg twice daily is required

≥30 kg to <40 kg: 450 mg twice daily; coadministration with ritonavir 60 mg twice daily is required

≥40 kg: 600 mg twice daily; coadministration with ritonavir 100 mg twice daily is required

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No adjustment required for mild-to-moderate impairment. No data available for use in severe renal failure or end-stage renal disease.

Dosing: Hepatic Impairment

No adjustment for mild-to-moderate impairment (Child-Pugh classes A and B). Not recommended for patients with severe impairment (contraindicated in Canadian labeling).

Dosing: Adjustment for Toxicity

Severe rash: Discontinue treatment.

New or worsening liver dysfunction: Consider interrupting or discontinuing treatment.

Dosage Forms: U.S.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral:

Prezista®: 75 mg, 150 mg, 400 mg, 600 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:

Prezista®: 300 mg, 400 mg, 600 mg

Generic Equivalent Available: U.S.

No

Administration

Coadministration with ritonavir and food is required (bioavailability is increased).

Use

Treatment of HIV-1 infections in combination with ritonavir and other antiretroviral agents

Adverse Reactions Significant

As a class, protease inhibitors potentially cause dyslipidemias which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause increased abdominal girth, buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia. Frequency of adverse events is reported for darunavir/ritonavir. See also Ritonavir monograph.

>10%:

Endocrine & metabolic: Hypercholesterolemia (grade 2: 16% to 25%; grade 3: 1% to 10%), LDL increased (grade 2: 14%; grade 3: 5% to 8%)

Gastrointestinal: Vomiting (children 13%; adults 2% to 5%), diarrhea (8% to 14%)

2% to 10%:

Central nervous system: Headache (children 9%; adults 3% to 6%), fatigue (children 3%; adults ≤2%)

Dermatologic: Rash (5% to 10%)

Endocrine & metabolic: Hyperglycemia (grade 2: 7% to 10%; grade 3: ≤1%; grade 4: <1%), triglycerides increased (grade 2: 3% to 10%; grade 3: 1% to 7%; grade 4: ≤3%), diabetes mellitus (2%)

Gastrointestinal: Abdominal pain (children 10%; adults 5% to 6%), nausea (3% to 7%), amylase increased (grade 2: 5% to 6%; grade 3: 3% to 7%), lipase increased (grade 2: 2% to 3%; grade 3: ≤2%; grade 4: <1%), abdominal distention (2%), anorexia (2%), dyspepsia (2%)

Hepatic: ALT increased (grade 2: 7%, grade 3: 2% to 3%; grade 4: ≤1%), AST increased (grade 2: 6%; grade 3: 2% to 4%; grade 4: <1%), alkaline phosphatase (grade 2: ≤2%; grade 3: <1%)

Neuromuscular & skeletal: Weakness (≤3%)

<2% (Limited to important or life-threatening): Acute renal failure, acute respiratory distress syndrome, allergic dermatitis, alopecia, anemia, angioedema, appetite decreased, arthralgia, bile duct obstruction, bradycardia, cerebrovascular accident, dermatitis medicamentosa, dyspnea, erythema multiforme, extremity pain, facial edema, fat redistribution (eg, buffalo hump, increased abdominal girth, breast engorgement, facial atrophy), fever, folliculitis, gynecomastia, hematuria, hepatic cirrhosis, hepatic failure, hepatic neoplasm (malignant), hepatitis (acute and cytolytic), hepatotoxicity, hiccups, hyperbilirubinemia, hyperhidrosis, hyperkalemia, hyperlipidemia, hypersensitivity, hypertension, hyperthermia, hypoesthesia, immune reconstitution syndrome, infection (including clostridium, cryptosporidiosis, cytomegalovirus encephalitis, hepatitis B, esophageal candidiasis), jaundice, large B-cell neoplasm (diffuse), lipoatrophy, lymphoma, maculopapular rash, metabolic acidosis, MI, myalgia, myocarditis, myositis, nephrolithiasis, neuromyopathy, night sweats, nightmare, obesity, osteonecrosis, osteopenia, osteoporosis, pancreatitis, pancytopenia, paresthesia, peripheral edema, peripheral neuropathy, pharyngeal lesion, pneumothorax, polydipsia, polyuria, progressive multifocal leukoencephalopathy, pruritus, rectal hemorrhage, renal insufficiency, renal tubular necrosis, rhabdomyolysis (coadministration with HMG-CoA reductase inhibitors), respiratory failure, rigors, seizure, sepsis, skin inflammation, somnolence, Stevens-Johnson syndrome, suicide (completed), tachycardia, toxic skin eruption, toxic epidermal necrolysis, transient ischemic attack, urticaria, vertigo, xerostomia

Contraindications

Coadministration with medications highly dependent upon CYP3A4 for clearance and for which increased levels are associated with serious and/or life-threatening events (includes alfuzosin, cisapride, ergot alkaloids [eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine], lovastatin, midazolam [oral], pimozide, rifampin, sildenafil (when used for pulmonary artery hypertension [eg, Revatio®]), simvastatin, St John's wort, triazolam

Canadian labeling: Additional contraindications: Hypersensitivity to darunavir or any component of the formulation; coadministration with amiodarone, lidocaine (systemic), quinidine; severe (Child-Pugh class C) hepatic impairment

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hepatotoxicity: Infrequent cases of drug-induced hepatitis (including acute and cytolytic) have been reported. Liver injury has been reported with use (including some fatalities), though generally in patients on multiple medications, with advanced HIV disease, hepatitis B/C coinfection, and/or immune reconstitution syndrome. Monitor patients closely; consider interrupting or discontinuing therapy if signs/symptoms of liver impairment occur.

• Hypersensitivity reactions: Protease inhibitors have been associated with a variety of hypersensitivity events (some severe), including rash, anaphylaxis (rare), angioedema, bronchospasm, erythema multiforme, Stevens-Johnson syndrome (rare), and/or toxic epidermal necrolysis. Discontinue treatment if severe skin reactions develop. Severe skin reactions may be accompanied by fever, malaise, fatigue, arthralgias, hepatitis, oral lesions, blisters, conjunctivitis, and/or eosinophilia. Mild-to-moderate rash may occur early in treatment and resolve with continued therapy.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection; further evaluation and treatment may be required.

• Increased cholesterol: Increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.

• Pancreatitis: Pancreatitis has been observed during therapy; use caution in patients at risk for pancreatitis including those with elevated triglycerides, advanced HIV disease, or history of pancreatitis.

• Sulfonamide allergy: Use with caution in patients with sulfonamide allergy (contains sulfa moiety).

Disease-related concerns:

• Diabetes: Changes in glucose tolerance, hyperglycemia, exacerbation of diabetes, DKA, and new-onset diabetes mellitus have been reported in patients receiving protease inhibitors.

• Hemophilia A or B: Use with caution in patients with hemophilia A or B; increased bleeding during protease inhibitor therapy has been reported.

• Hepatic impairment: May exacerbate pre-existing hepatic dysfunction; use with caution in patients with underlying hepatic disease, such as hepatitis B or C or cirrhosis. Use is not recommended in severe impairment. Use in severe impairment is contraindicated in the Canadian labeling.

Concurrent drug therapy issues:

• Colchicine: Do not coadminister in patients with renal or hepatic impairment.

• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.

• Ritonavir: Coadministration with ritonavir is required (DHHS, 2011). Treatment history and resistance data should guide use of darunavir with ritonavir.

• Salmeterol: Concomitant use not recommended due to increased risk of cardiovascular adverse events, including QTc prolongation.

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Inhibits P-glycoprotein

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program )

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

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

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

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. Risk D: Consider therapy modification

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

ALPRAZolam: Protease Inhibitors may increase the serum concentration of ALPRAZolam. Management: Concurrent use of alprazolam with indinavir is contraindicated. All patients receiving such a combination should be monitored closely for excessive response to alprazolam. Risk C: Monitor therapy

Amiodarone: Protease Inhibitors may decrease the metabolism of Amiodarone. Risk X: Avoid combination

Antifungal Agents (Azole Derivatives, Systemic): Protease Inhibitors may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Protease Inhibitors. Management: Limit indinavir adult dose to 600 mg every 8 hours with itraconazole or ketoconazole. With ritonavir, limit ketoconazole adult dose to 200 mg/day. Limit fluconazole, itraconazole, and ketoconazole to 200 mg (adult dose) with tipranavir/ritonavir. Risk D: Consider therapy modification

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

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

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

Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification

Calcium Channel Blockers (Dihydropyridine): Protease Inhibitors may decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Exceptions: Clevidipine. Risk D: Consider therapy modification

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 this combination is used, monitor for evidence of toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Use of ritonavir with bepridil is contraindicated. Risk D: Consider therapy modification

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

CarBAMazepine: Darunavir may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

Ciclesonide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ciclesonide. Specifically, concentrations of the active des-ciclesonide metabolite may be increased. Risk C: Monitor therapy

Cisapride: Protease Inhibitors may decrease the metabolism of Cisapride. The resultant increase in serum cisapride concentrations may result in QTc prolongation and malignant cardiac arrhythmias. Risk X: 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. Clarithromycin may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Clarithromycin. Clarithromycin dose adjustment in renally impaired patients may be needed. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

Contraceptives (Estrogens): May diminish the therapeutic effect of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Contraceptives (Estrogens). Management: Use of an alternative, non-hormone-based contraceptive is recommended. Risk D: Consider therapy modification

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Monitor for signs and symptoms of adrenal suppression if inhaled budesonide or mometasone are coadministered with a strong CYP3A4 inhibitor. Avoid combining inhaled fluticasone with any strong CYP3A4 inhibitor. Exceptions: Beclomethasone; Beclomethasone (Oral Inhalation); Flunisolide; Flunisolide (Oral Inhalation); Triamcinolone; Triamcinolone (Systemic). Risk C: Monitor therapy

CycloSPORINE: May increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification

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

CYP2D6 Substrates: Darunavir may increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

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

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

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dabigatran Etexilate: P-Glycoprotein Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. According to Canadian labeling, dabigatran dose for prevention of venous thromboembolism post hip or knee replacement should be reduced to 150 mg/day in patients receiving amiodarone, verapamil, or quinidine. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

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

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

Didanosine: Darunavir may decrease the serum concentration of Didanosine. More specifically, this interaction is likely due to the effects of food (with which darunavir/ritonavir are taken) on didanosine, which is supposed to be given on an empty stomach. Management: Didanosine should be administered 1 hour prior to or 2 hours after administration of darunavir/ritonavir (which must be taken with food). Risk D: Consider therapy modification

Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Risk C: Monitor therapy

Digoxin: Protease Inhibitors may increase the serum concentration of Digoxin. Increased serum concentrations of digoxin may increase risk of AV nodal blockade. Risk C: Monitor therapy

Divalproex: Protease Inhibitors may decrease the serum concentration of Divalproex. Risk C: Monitor therapy

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

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

Efavirenz: May increase the metabolism of Protease Inhibitors. This specifically includes amprenavir, indinavir, and saquinavir. Efavirenz may increase the serum concentration of Protease Inhibitors. This specifically includes nelfinavir and ritonavir. Risk D: Consider therapy modification

Efavirenz: Darunavir may increase the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of Darunavir. Risk C: Monitor therapy

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

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

Eplerenone: Protease Inhibitors may decrease the metabolism of Eplerenone. Risk C: Monitor therapy

Ergot Derivatives: Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Cabergoline. Risk X: Avoid combination

Etravirine: May increase the serum concentration of Protease Inhibitors. This effect is anticipated with nelfinavir. Protease Inhibitors may decrease the serum concentration of Etravirine. This effect is anticipated with darunavir, saquinavir, and lopinavir (with low-dose ritonavir). Management: Low-dose ritonavir boosting must be used when any protease inhibitor is used with etravirine. Avoid use of etravirine in combination with atazanavir, fosamprenavir, full-dose ritonavir (600 mg twice daily), or tipranavir. Risk C: Monitor therapy

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

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients extra closely for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate. Risk D: 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. Risk D: Consider therapy modification

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

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Risk X: Avoid combination

Fosphenytoin: May decrease the serum concentration of Darunavir. Risk X: Avoid combination

Fusidic Acid: May decrease the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of Fusidic Acid. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Risk C: Monitor therapy

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

HMG-CoA Reductase Inhibitors: Protease Inhibitors may increase the serum concentration of HMG-CoA Reductase Inhibitors. Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations. Management: Lovastatin and simvastatin are contraindicated with protease inhibitors; also, avoid rosuvastatin with indinavir. Use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs of toxicity if these agents are used concomitantly. Exceptions: Fluvastatin. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

Lidocaine: Darunavir may increase the serum concentration of Lidocaine. Risk C: Monitor therapy

Lidocaine (Systemic): Darunavir may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

Lidocaine (Topical): Darunavir may increase the serum concentration of Lidocaine (Topical). Risk C: Monitor therapy

Lopinavir: May decrease the serum concentration of Darunavir. Darunavir may increase the serum concentration of lopinavir Risk X: Avoid combination

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

Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Risk C: Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Risk X: Avoid combination

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. Risk D: 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. Risk D: Consider therapy modification

Methadone: Protease Inhibitors may decrease the serum concentration of Methadone. Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose titration and/or adjustments in patients receiving strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors) and monitor for increased steroid related adverse effects. Risk D: 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. Risk X: Avoid combination

Nefazodone: Protease Inhibitors may increase the serum concentration of Nefazodone. Risk C: Monitor therapy

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

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

Norethindrone: Darunavir may decrease the serum concentration of Norethindrone. Risk D: Consider therapy modification

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

PARoxetine: Darunavir may decrease the serum concentration of PARoxetine. Risk C: Monitor therapy

Pazopanib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pazopanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required. Risk D: Consider therapy modification

P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

PHENobarbital: May decrease the serum concentration of Darunavir. Risk X: Avoid combination

Phenytoin: May decrease the serum concentration of Darunavir. Risk X: Avoid combination

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

Pimozide: Protease Inhibitors may decrease the metabolism of Pimozide. Risk X: Avoid combination

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Risk C: 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. Other combos may require dose changes. Risk D: Consider therapy modification

QuiNIDine: Protease Inhibitors may decrease the metabolism of QuiNIDine. Risk X: Avoid combination

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

Rifabutin: Darunavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Darunavir may increase the serum concentration of Rifabutin. Rifabutin may increase the serum concentration of Darunavir. Risk D: Consider therapy modification

Rifampin: May decrease the serum concentration of Darunavir. Risk X: Avoid combination

Rivaroxaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. Risk X: Avoid combination

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Risk X: Avoid combination

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

Saquinavir: May decrease the serum concentration of Darunavir. Risk X: Avoid combination

Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Limit saxagliptin adult dose to 2.5 mg/day and monitor for increased saxagliptin levels/effects (e.g., hypoglycemia) when used with a strong CYP3A4 inhibitor. Monitor for decreased saxagliptin levels/effects if discontinuing CYP3A4 inhibitor. Risk D: Consider therapy modification

Sertraline: Darunavir may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

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

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

Sirolimus: Protease Inhibitors may increase the serum concentration of Sirolimus. Risk C: Monitor therapy

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

St Johns Wort: May increase the metabolism of Protease Inhibitors. Risk X: Avoid combination

Tacrolimus: Protease Inhibitors may decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification

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

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

Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Erectile dysfunction: tadalafil max = 2.5 mg/day (daily use) or 10 mg/72 hrs (as needed use) (adult doses). Avoid use of tadalafil with a strong CYP3A4 inhibitor for treatment of pulmonary arterial hypertension. Risk D: Consider therapy modification

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

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. Risk D: Consider therapy modification

Tenofovir: May decrease the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Tenofovir. Risk C: Monitor therapy

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

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

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

Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

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

TraZODone: Protease Inhibitors may increase the serum concentration of TraZODone. Risk D: Consider therapy modification

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

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

Valproic Acid: Protease Inhibitors may decrease the serum concentration of Valproic Acid. Risk C: Monitor therapy

Vardenafil: Protease Inhibitors may increase the serum concentration of Vardenafil. Management: Limit vardenafil adult dose to max of 2.5 mg/72 hrs with ritonavir, atazanavir, or darunavir; limit to max adult dose of 2.5 mg/24 hrs with other protease inhibitors. Risk D: 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. Risk D: Consider therapy modification

Voriconazole: Darunavir may decrease the serum concentration of Voriconazole. Risk X: Avoid combination

Warfarin: Darunavir may decrease the serum concentration of Warfarin. Risk C: Monitor therapy

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

Ethanol/Nutrition/Herb Interactions

Food: Bioavailability is increased when administered with food.

Herb/nutraceutical: St John’s wort may decrease the plasma levels of darunavir; concomitant use is contraindicated.

Pregnancy Risk Factor

C (show table)

Pregnancy Implications

It is not known if darunavir crosses the human placenta. Teratogenic effects have not been observed in animal reproduction studies. However, there are no adequate and well-controlled studies in pregnant women. Pregnancy and protease inhibitors are both associated with an increased risk of hyperglycemia. Glucose levels should be closely monitored. The Perinatal HIV Guidelines Working Group notes there is insufficient data to recommend use during pregnancy; however, if used, darunavir must be given with low-dose ritonavir boosting. Healthcare providers are encouraged to enroll pregnant women exposed to antiretroviral medications in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Healthcare providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation.

Women receiving estrogen (as hormonal contraception or replacement therapy) have an increased incidence of rash. Alternative forms of contraception may be needed.

Lactation

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

In infants born to mothers who are HIV positive, HAART while breast-feeding may decrease postnatal infection. However, maternal or infant antiretroviral therapy does not completely eliminate the risk of postnatal HIV transmission. In addition, multiclass-resistant virus has been detected in breast-feeding infants despite maternal therapy.

In the United States where formula is accessible, affordable, safe, and sustainable, complete avoidance of breast-feeding by HIV-infected women is recommended to decrease potential transmission of HIV.

Dietary Considerations

Absorption increased with food. Take with meals.

Pricing: U.S. (www.drugstore.com)

Tablets (Prezista)

400 mg (60): $1060.01

600 mg (60): $1100.02

Monitoring Parameters

Viral load, CD4, serum glucose; transaminase levels prior to and during therapy (increase monitoring in patients at risk for liver impairment), cholesterol, triglycerides

Canadian Brand Names

Prezista®

International Brand Names

Prezista (AR, BB, BE, BM, BS, BZ, CH, CN, CO, CZ, DE, DK, DO, EE, FR, GB, GY, IE, IL, JM, KP, MY, NL, NZ, SE, SG, SR, TH, TT, UY)

Mechanism of Action

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.

Pharmacodynamics/Kinetics

All kinetic parameters derived in the presence of ritonavir coadministration.

Absorption: Increased 30% with food

Protein binding: ~95%; primarily to alpha1 acid glycoprotein (AAG)

Metabolism: Hepatic, via CYP3A4 to minimally-active metabolites

Bioavailability: 82%

Half-life elimination: ~15 hours

Time to peak, plasma: 2.5-4 hours

Excretion: Feces (~80%, 41% as unchanged drug); urine (~14%, 8% as unchanged drug)