Darunavir (Prezista) is an antiretroviral medicine that is used in combination with other antiretroviral medicines (ritonavir and cobicistat) for the treatment and prevention of HIV-1 infection.

Darunavir (Prezista) Uses:

• HIV-1 infection:

  • Used in the treatment of HIV-1 infection, co-administered with ritonavir and other antiretroviral agents, in adults and pediatric patients 3 years and older

• Off Label Use of Darunavir in Adults:

  • Used in HIV-1 nonoccupational postexposure prophylaxis

Darunavir (Prezista) Dose in Adults

Darunavir (Prezista) Dose in the Treatment of HIV-1 infection: Oral:

• Treatment-naive:

  • 800 mg once in a day; coadministration with ritonavir 100 mg or cobicistat 150 mg once in a day (HHS [adult] 2016) is required.

• Treatment-experienced:

Note: Genotypic testing is recommended in therapy experienced patients.

• • With no darunavir resistance-associated substitutions:
    • 800 mg once in a day; coadministration with ritonavir 100 mg or cobicistat 150 mg once in a day is required
  • With ≥1 darunavir resistance-associated substitution:
    • 600 mg twice a day;
    • coadministration with ritonavir 100 mg twice daily is required
  • If genotypic testing is not possible:
    • 600 mg twice in a day, coadministered with ritonavir 100 mg twice a day.

• Pregnant patients:

  • 600 mg twice in a day, coadministered with ritonavir 100 mg twice in a day.
  • Product labeling notes 800 mg once in a day coadministered with ritonavir 100 mg once in a day should only be considered in patients already on a stable once-daily regimen prior to pregnancy who are virologically suppressed (HIV-1 RNA less than 50 copies/mL), and in whom a change to twice-daily dosing may compromise tolerability or compliance.
  • However, current guidelines do not recommend once-daily dosing during pregnancy.

Darunavir (Prezista) for HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label):

• Oral: 800 mg plus ritonavir 100 mg once in a day (in combination with other antiretroviral agents);
• initiate therapy within 72 hours of exposure and continue for 28 days.

Darunavir (Prezista) Dose in Children

Darunavir (Prezista) Dose in the treatment of HIV-1 infection:

Note:

• Genotypic testing for viral resistance is recommended in therapy experienced patients; coadministration with ritonavir is required;
• use in combination with other antiretroviral agents.

Note: Darunavir resistance-associated viral mutations include: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V.

• Infants and Children <3 years of age or weighing <10 kg:

  • Avoid to use; seizures and death associated with immaturity of the blood-brain barrier and immature hepatic metabolic pathways were observed in juvenile rats.

• Treatment-naïve patients or treatment-experienced patients, without darunavir resistance-associated mutation:

  • Children ≥3 years weighing ≥10 kg and Adolescents:

    • AIDS info recommendations (HHS [pediatric] 2016): Oral:

      • Weight-directed dosing:

        • Body weight 10 to 15 kg:
          • Darunavir 20 mg per kg twice in a day plus ritonavir 3 mg per kg twice in a day.

      • Fixed-dosing: Tablets, Oral solution (darunavir: 100 mg/mL):

Note: Darunavir oral solution dose volume for some weight ranges are rounded for convenience.

• Twice-daily regimen:

  • Children 3 to <12 years weighing ≥10 kg:

    • 10 kg to <11 kg: Darunavir 200 mg (2 mL) plus ritonavir 32 mg twice in a day.
    • 11 kg to <12 kg: Darunavir 220 mg (2.2 mL) plus ritonavir 32 mg twice in a day.
    • 12 kg to <13 kg: Darunavir 240 mg (2.4 mL) plus ritonavir 40 mg twice in a day.
    • 13 kg to <14 kg: Darunavir 260 mg (2.6 mL) plus ritonavir 40 mg twice in a day.
    • 14 kg to <15 kg: Darunavir 280 mg (2.8 mL) plus ritonavir 48 mg twice in a day.
    • 15 kg to <30 kg: Darunavir 375 mg (tablets or 3.8 mL) plus ritonavir 48 mg twice in a day.
    • 30 kg to <40 kg: Darunavir 450 mg (tablets or 4.6 mL) plus ritonavir 100 mg twice in a day.
    • ≥40 kg: Darunavir 600 mg (tablet or 6 mL) plus ritonavir 100 mg twice in a day.

• Once-daily regimen:

  • Children ≥12 years and Adolescents weighing ≥30 kg:
    • 30 kg to <40 kg: Darunavir 675 mg plus ritonavir 100 mg once in a day.
    • ≥40 kg: Darunavir 800 mg (tablet or combination of tablets) plus ritonavir 100 mg once in a day.

  • Manufacturer's labeling: Oral:

Note:

• Although FDA approved, the Pediatric AIDS info guidelines do not recommend once-daily dosing in children less than 12 years.
• Alternate weight-directed and fixed-dosing regimens with twice-daily dosing are recommended for children 3 to <12 years of age (see above AIDS info recommendations);
• once-daily dosing is only recommended in patients ≥12 years of age and ≥30 kg without resistant-associated mutations.
• If once-daily dosing is used in children less than 12 years of age, therapeutic drug monitoring with measurement of plasma concentrations and close monitoring of viral load should be performed.

  • Weight-directed dosing:

    • Bodyweight 10 to <15 kg:
      • Darunavir 35 mg/kg (maximum dose 800 mg per dose) once daily plus ritonavir 7 mg per kg (maximum dose: 100 mg per dose) once in a day.

  • Fixed-dosing: Oral solution (darunavir: 100 mg/mL):

Note: Darunavir dose volume for some weight ranges are rounded for convenience.

• 10 kg to <11 kg: Darunavir 350 mg (3.6 mL) plus ritonavir 64 mg once in a day.
• 11 kg to <12 kg: Darunavir 385 mg (4 mL) plus ritonavir 64 mg once in a day.
• 12 kg to <13 kg: Darunavir 420 mg (4.2 mL) plus ritonavir 80 mg once in a day.
• 13 kg to <14 kg: Darunavir 455 mg (4.6 mL) plus ritonavir 80 mg once in a day.
• 14 kg to <15 kg: Darunavir 490 mg (5 mL) plus ritonavir 96 mg once in a day.

  • Fixed-dosing: Tablets or Oral solution (darunavir: 100 mg/mL):

Note: Darunavir oral solution dose volume for some weight ranges are rounded for convenience.

• 15 kg to <30 kg: Darunavir 600 mg (tablet or 6 mL) plus ritonavir 100 mg once in a day.
• 30 kg to <40 kg: Darunavir 675 mg (tablet or 6.8 mL) plus ritonavir 100 mg once in a day.
• ≥40 kg: Darunavir 800 mg (tablet or 8 mL) plus ritonavir 100 mg once in a day.

• Treatment-experienced patients, with at least one darunavir resistance-associated mutation:

  • Children ≥3 years of age weighing ≥10 kg and Adolescents:

    • Weight-directed dosing:

      • Bodyweight 10 kg to <15 kg: Darunavir 20 mg/kg twice daily plus ritonavir 3 mg per kg twice in a day.

    • Fixed-dosing: Oral solution:

      • 10 kg to <11 kg: Darunavir 200 mg plus ritonavir 32 mg twice in a day.
      • 11 kg to <12 kg: Darunavir 220 mg plus ritonavir 32 mg twice in a day.
      • 12 kg to <13 kg: Darunavir 240 mg plus ritonavir 40 mg twice in a day.
      • 13 kg to <14 kg: Darunavir 260 mg plus ritonavir 40 mg twice in a day.
      • 14 kg to <15 kg: Darunavir 280 mg plus ritonavir 48 mg twice in a day.

  • Fixed-dosing: Tablets or oral solution (darunavir: 100 mg/mL):

Note: Darunavir oral solution dose volume for some weight ranges are rounded for convenience.

• 15 kg to <30 kg:
  • Darunavir 375 mg (tablets or 3.8 mL) plus ritonavir 48 mg twice daily;
  • Note: If weight ≥20 kg, the ritonavir 100 mg tablet may be substituted for the liquid formulation to enhance palatability.
• 30 kg to <40 kg:
  • Darunavir 450 mg (tablets or 4.6 mL) plus ritonavir 60 mg twice daily;
  • Note: The ritonavir 100 mg tablet may be substituted for the liquid formulation to enhance palatability.
• ≥40 kg: Darunavir 600 mg plus ritonavir 100 mg twice in a day.

Darunavir (Prezista) Dose in the HIV-1 nonoccupational postexposure prophylaxis (nPEP):

Note: Initiate therapy within 72 hours of exposure and continue for 28 days in combination with other antiretroviral agents; Oral:

• Children ≥3 years weighing ≥10 kg:

  • 10 to <11 kg: 200 mg plus ritonavir 32 mg twice in a day.
  • 11 to <12 kg: 220 mg plus ritonavir 32 mg twice in a day.
  • 12 to <13 kg: 240 mg plus ritonavir 40 mg twice in a day.
  • 13 to <14 kg: 260 mg plus ritonavir 40 mg twice in a day.
  • 14 to <15 kg: 280 mg plus ritonavir 48 mg twice in a day.
  • 15 to <30 kg: 375 mg plus ritonavir 48 mg twice in a day.
  • 30 to <40 kg: 450 mg plus ritonavir 100 mg twice in a day.
  • ≥40 kg: 600 mg plus ritonavir 100 mg twice in a day.

• Adolescents:

  • 800 mg plus ritonavir 100 mg twice in a day.

Darunavir (Prezista) Pregnancy Risk Category: C

• Darunavir has a low level of transfer across the human placenta.
• Maternal antiretroviral therapy (ART) may increase the risk of preterm delivery, although available information is conflicting possibly due to the variability of maternal factors (disease severity; gestational age at initiation of therapy).
• No increased risk of overall birth defects has been observed following first-trimester exposure according to data collected by the antiretroviral pregnancy registry.
• An increased risk of stillbirth, low birth weight, and small for gestational age infants have been observed in some but not all studies.
• Hyperglycemia, new onset of diabetes mellitus, or diabetic ketoacidosis have been reported with PIs; it is not clear if pregnancy increases this risk.
• The Health and Human Services (HHS) Perinatal HIV Guidelines consider darunavir (when combined with low-dose ritonavir boosting) a preferred protease inhibitor for HIV-infected pregnant females who are antiretroviral-naive (initial therapy), who have had ART therapy in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), and who are not yet pregnant but are trying to conceive.
• Because there is a clear benefit to appropriate treatment, maternal ART should not be withheld due to concerns for adverse neonatal outcomes.
• Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.
• In addition, females who become pregnant while taking darunavir may continue if viral suppression is effective and the regimen is well tolerated.
• Serum concentrations are decreased during pregnancy; therefore, ritonavir-boosted twice-daily dosing should be used.
• According to product labeling, once-daily dosing of darunavir should only be considered in women who are already pregnant, and virologically stable on a once-daily dose, and in whom changing to a twice-daily regimen would compromise tolerability or compliance.
• However, the current HHS perinatal guidelines do not recommend once-daily dosing during pregnancy.
• Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-2584263 or http://www.APRegistry.com).
• In general, ART is recommended for all pregnant females with HIV to keep the viral load below the limit of detection and reduce the risk of perinatal transmission.
• Monitoring during pregnancy is more frequent than in nonpregnant adults. ART should be continued postpartum for all females living with HIV and can be modified after delivery.

Darunavir use during breastfeeding:

• It is not known if darunavir is present in breast milk.
• Maternal or infant antiretroviral therapy does not completely eliminate the risk of postnatal HIV transmission.
• In addition, a multiclass-resistant virus has been detected in breastfeeding infants despite maternal therapy.
• Therefore, in the US, where a formula is affordable, safe, accessible, and sustainable, and the risk of infant mortality due to diarrhea and respiratory infections is low, females with HIV infection should completely avoid breastfeeding to decrease the potential transmission of HIV.

Darunavir (Prezista) Dose in Kidney Disease:

Manufacturer's labeling doesn't provide any dosage adjustments; however, the need for dosage adjustment is unlikely as renal clearance of darunavir is limited.

Darunavir (Prezista) Dose in Liver disease:

• Mild to moderate impairment (Child-Pugh class A or B):

  • No dosage adjustments required.

• Severe impairment (Child-Pugh class C):

  • Use not recommended.

The frequency of adverse events is reported for darunavir/ritonavir in both treatment-naive and experienced patients. Frequency, type, and severity of adverse events in pediatric patients are comparable to adult patients unless otherwise noted. See also Ritonavir monograph.

Common Side Effects of Darunavir (Prezista):

• Dermatologic:

  • Skin rash

• Endocrine & metabolic:

  • Increased serum cholesterol
  • Increased LDL cholesterol
  • Increased serum glucose

• Gastrointestinal:

  • Vomiting
  • Nausea
  • Diarrhea

Less Common Side Effects of Darunavir (Prezista):

• Central Nervous System:

  • Headache
  • Fatigue
  • Abnormal Dreams

• Dermatologic:

  • Pruritus
  • Stevens-Johnson Syndrome
  • Urticaria

• Endocrine & Metabolic:

  • Increased Serum Triglycerides
  • Increased Amylase
  • Diabetes Mellitus

• Gastrointestinal:

  • Abdominal Pain
  • Decreased Appetite
  • Anorexia
  • Increased Serum Lipase
  • Abdominal Distention
  • Dyspepsia
  • Flatulence
  • Acute Pancreatitis

• Hepatic:

  • Increased Serum ALT
  • Increased Serum AST
  • Hepatitis
  • Increased Serum Alkaline Phosphatase

• Hypersensitivity:

  • Angioedema
  • Hypersensitivity Reaction

• Immunologic:

  • Immune Reconstitution Syndrome

• Neuromuscular & Skeletal:

  • Weakness
  • Myalgia
  • Osteonecrosis

Contraindication to Darunavir (Prezista):

• Co-administration with drugs that are highly dependent on CYP3A for clearance and drugs for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index), examples include:
  • dronedarone, alfuzosin, colchicine (in patients with renal and/or hepatic impairment),
  • ranolazine,
  • ergot derivatives (ergotamine, methylergonovine, dihydroergotamine, and ergonovine),
  • cisapride,
  • triazolam,
  • lurasidone,
  • pimozide,
  • oral midazolam,
  • St. John's wort,
  • elbasvir/grazoprevir,
  • simvastatin,
  • rifampin,
  • lomitapide,
  • lovastatin,
  • sildenafil (for the treatment of pulmonary hypertension).
• Must be coadministered with ritonavir; refer to individual monograph for ritonavir for additional contraindication information.

Canadian labeling: Additional contraindications:

• Hypersensitivity to darunavir or any component of the formulation;
• coadministration with:
  • apixaban,
  • astemizole
  • amiodarone,
  • bepridil,
  • lidocaine (systemic),
  • quinidine,
  • rivaroxaban,
  • terfenadine;
  • severe (Child-Pugh class C) hepatic impairment

Warnings and Precautions

• Fat redistribution:

  • May cause redistribution/accumulation of fat (eg, central obesity, buffalo hump, peripheral wasting, facial wasting, breast enlargement, cushingoid appearance).

• Hepatotoxicity:

  • Infrequent cases of drug-induced hepatitis (including acute and cytolytic) have been reported.
  • Monitor patients closely; consider interrupting or discontinuing therapy if signs/symptoms of liver impairment occur.
  • 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.

• Hypersensitivity reactions:

  • Protease inhibitors have been associated with a variety of hypersensitivity events (some severe), including rash, anaphylaxis (rare),  Stevens-Johnson syndrome (rare), angioedema, bronchospasm, erythema multiforme, acute generalized exanthematous pustulosis, toxic epidermal necrolysis, and/or drug rash with eosinophilia and systemic symptoms (DRESS).
  • Discontinue treatment if severe skin reactions develop.
  • Severe skin reactions may be accompanied by fever, arthralgias, hepatitis, oral lesions, blisters malaise, fatigue, conjunctivitis, and/or eosinophilia.
  • A 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 during initial HIV treatment or activation of autoimmune disorders (eg, polymyositis, Graves disease,  Guillain-Barré syndrome) later in therapy;
  • further evaluation and treatment may be required.

• Sulfonamide allergy:

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

• Diabetes:

  • The initiation or dose adjustments of antidiabetic agents may be required.
  • 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 (PI) therapy has been reported.
  • In more than half the cases, PI therapy was continued or reintroduced if it had been discontinued.
  • In some patients, additional factor VIII was administered.

• Hepatic impairment:

  • Use is not recommended in severe impairment.
  • May exacerbate preexisting hepatic dysfunction;
  • use with caution in patients with underlying hepatic disease, such as hepatitis B or C or cirrhosis.

Darunavir: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Viral load,
• CD4,
• baseline genotypic and/or phenotypic testing in treatment-experienced patients (if possible);
• serum glucose;
• transaminase levels prior to and during therapy (increase monitoring in patients at risk for liver impairment),
• cholesterol,
• triglycerides

How to administer Darunavir (Prezista)?

• Coadministration with ritonavir and food is required (bioavailability is increased).
• Shake suspension prior to each dose; use provided oral dosing syringe to measure the dose.

Mechanism of action of Darunavir (Prezista):

• 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, non-infectious viral particles.
• All kinetic parameters derived in the presence of ritonavir coadministration; pharmacokinetic data in pediatric patients (6 to 18 years) reported being similar to adult data.

Absorption:

• Increased ~40% with food

Protein binding:

• ~95%; primarily to alpha acid glycoprotein (AAG)

Metabolism:

• Hepatic, via CYP3A to minimally active metabolites

Bioavailability:

• Absolute oral: 82% (darunavir 600 mg single dose with ritonavir twice daily); bioavailability is increased 30% to 40% with food

Half-life elimination:

• ~15 hours

Time to peak,

• plasma: 2.5 to 4 hours

Excretion:

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

International Brand Names of Darunavir:

• Prezista
• Durart

Darunavir Brand Names in Pakistan:

There is no brand available in Pakistan.