Dosing and uses of Prezista (darunavir)
Adult dosage forms and strengths
tablet
- 75mg
- 150mg
- 600mg
- 800mg
oral suspension
- 100mg/mL
HIV Infection
Coadministered with ritonavir and in combination with other antiretroviral agents for HIV infection
Treatment-naive or antiretroviral treatment-experienced (with no darunavir resistance associated substitutions): 800 mg + ritonavir 100 mg PO qDay with food
Treatment-experienced (with at least 1 DRV mutation) or genotyping not obtained: 600 mg + ritonavir 100 mg PO q12hr with food
Pregnant females
- Recommended: 600 mg + ritonavir 100 mg PO q12hr with food
- 800 mg + ritonavir 100 mg PO qDay should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg + ritonavir 100 mg qDay regimen prior to pregnancy, are virologically suppressed (ie, HIV-1 RNA <50 copies/mL), and in whom a change to the twice daily regimen may compromise tolerability or compliance
Dosage modifications
Renal impairment
- Mild-to-moderate (≥ 30 mL/min): No dosage adjustment required
- Severe (≤ 30 mL/min): Data not available, but renal clearance is limited and decreased total body clearance not expected
Hepatic impairment
- Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment required
- Severe (Child-Pugh class C): Not recommended
Dosing Considerations
In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus
Obtain appropriate laboratory testing (eg, serum liver biochemistries) before initiating darunavir
Patients with underlying chronic hepatitis, cirrhosis, or those who have pretreatment liver enzyme should be monitored for elevated transaminases, especially during the first several months
Pediatric dosage forms and strengths
tablet
- 75mg
- 150mg
- 600mg
- 800mg
oral suspension
- 100mg/mL
HIV Infection
Coadministered with ritonavir and in combination with other antiretroviral agents for HIV infection
<3 years: Safety and efficacy not established
Must take with food
Also see Administration
Treatment-naive or antiretroviral treatment-experienced (with no darunavir resistance associated substitutions)
- NOTE: The HIV treatment guidelines differ from the prescribing information and recommend that once-daily darunavir dosing should NOT be used as initial therapy in children <12 yr; a switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance
- Weight 10 kg to <15 kg
- Use oral suspension
- ≥10 kg to <11 kg: 350 mg (3.6 mL)* + ritonavir 64 mg (0.8 mL) PO qDay
- ≥11 kg to <12 kg: 385 mg (4 mL)* + ritonavir 64 mg (0.8 mL) PO qDay
- ≥12 kg to <13 kg: 420 mg (4.2 mL) + ritonavir 80 mg (1 mL) PO qDay
- ≥13 kg to <14 kg: 455 mg (4.6 mL)* + ritonavir 80 mg (1 mL) PO qDay
- ≥14 kg to <15 kg: 490 mg (5 mL)* + ritonavir 96 mg (1.2 ml) PO qDay
- *NOTE: Doses that were rounded up to nearest measurable suspension dose
- Weight ≥15 kg
- ≥15 kg to <30 kg: 600 mg + ritonavir 100 mg PO qDay
- &ge:30 kg to <40 kg: 675 mg + ritonavir 100 mg PO qDay
- ≥40 kg: 800 mg + ritonavir 100 mg PO qDay
Antiretroviral treatment-experienced with at least 1 darunavir resistance associated substitution
- Weight 10 kg to <15 kg
- Use oral suspension
- ≥10 kg to <11 kg: 200 mg (2 mL) + ritonavir 32 mg (0.4 mL) PO BID
- ≥11 kg to <12 kg: 220 mg (2.2 mL) + ritonavir 40 mg (0.4 mL) PO BID
- ≥12 kg to <13 kg: 240 mg (2.4 mL) + ritonavir 32 mg (0.5 mL) PO BID
- ≥13 kg to <14 kg: 260 mg (2.6 mL) + ritonavir 40 mg (0.5 mL) PO BID
- ≥14 kg to <15 kg: 280 mg (2.8 mL) + ritonavir 48 mg (0.6 mL) PO BID
- Weight ≥15 kg
- ≥15 kg to <30 kg: 375 mg + ritonavir 48 mg PO BID
- &ge:30 kg to <40 kg: 450 mg + ritonavir 60 mg PO BID
- ≥40 kg: 600 mg + ritonavir 100 mg PO BID
Dosage modifications
Renal impairment
- Mild-to-moderate: No dosage adjustment required
- Severe: Data not available, but renal clearance is limited and decreased total body clearance not expected
Hepatic impairment
- Mild-to-moderate impairment: No dosage adjustment required
- Severe: Not recommended
Dosing Considerations
In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus
Obtain appropriate laboratory testing (eg, serum liver biochemistries) before initiating darunavir
Patients with underlying chronic hepatitis, cirrhosis, or those who have pretreatment liver enzyme should be monitored for elevated transaminases, especially during the first several months
Prezista (darunavir) adverse (side) effects
>10%
Increased total cholesterol (10-25%)
Increased triglycerides (3-10%)
1-10%
Diarrhea (9%)
Headache (7%)
Rash (6%)
Abdominal pain (6%)
Nausea (4%)
Vomiting (2%)
Anorexia (2%)
<1%
Fatigue
Frequency not defined
Gastrointestinal disorders: Acute pancreatitis, dyspepsia, flatulence
General disorders and administration site Conditions: Asthenia
Hepatobiliary disorders: Acute hepatitis (eg, cytolytic hepatitis, hepatotoxicity)
Immune dystem disorders: Hypersensitivity, immune reconstitution syndrome
Metabolism and nutrition disorders: Diabetes mellitus
Musculoskeletal and connective tissue disorders: Myalgia, osteonecrosis
Psychiatric disorders: Abnormal dreams
Skin and subcutaneous tissue disorders: Angioedema, pruritus, Stevens-Johnson Syndrome, urticaria
Postmarketing Reports
Body fat redistribution
Rhabdomyolysis (associated with statin coadministration)
Toxic epidermal necrolysis and acute generalized exanthematous pustulosis
Warnings
Contraindications
Hypersensitivity
Concomitant CYP3A4 substrates that are toxic in excess
Concurrent strong CYP3A4 inducers (eg, St John's wort, rifampin)
Drugs that are contraindicated with darunavir (when coadministered 'boosted' with ritonavir) include alpha1-adrenoreptor agonists (eg, alfuzosin), antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, quinidine), rifampin, colchicine, dronedarone, ranolaxine, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, lovastatin, simvastatin, lurasidone, pimozide, sildenafil (when used for PAH), midazolam, and triazolam
Cautions
Must be taken with ritonavir and food, since dose is based on the fact that darunavir is metabolized by CYP3A4 and ritonavir is a potent CYP3A4 inhibitor
Severe skin reactions, accompanied by fever and/or elevations of transaminases reported (0.4%); Stevens-Johnson Syndrome (<0.1%), toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis also reported
Caution with elderly patients
Caution with hepatic impairment (not recommended if severe)
Contains a sulfa moiety; monitor patients with a known sulfonamide allergy
Increase in total cholesterol and triglycerides reported; screen before therapy and throughout treatment
Pancreatitis reported; use caution in patients at risk for pancreatitis (those with elevated triglycerids, history of pancreatitis, or advanced HIV disease
Risk of immune reconstitution syndrome
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy
Patients may develop new onset diabetes mellitus or hyperglycemia; initiation or dose adjustments of insulin or oral hypoglycemic agents may be required
Patients with hemophilia may develop increased bleeding events
Not for use in patients < 3 years of age; toxicity may occur
Hepatoxicity
- Risk of hepatotoxicity including drug induced hepatitis: acute hepatitis, cytolytic hepatitis
- Especially with preexisting liver dysfunction (chronic hepatitis B or C)
- Interrupt or discontinue treatment if new/worsening liver dysfunction develops
Pregnancy and lactation
Pregnancy category: C
Antiretroviral Pregnancy Registry has been established:1-800-258-4263.
Lactation
Not known whether distributed into milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed.
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Prezista (darunavir)
Mechanism of action
Protease Inhibitor; inhibits cleavage of Gag-Pol polyprotein precursors, which in turn causes the formation of immature, noninfectious viral particles.
Pharmacokinetics
Bioavailability: with ritonavir: 82%; without ritonavir: 37%
Peak Plasma Time: 2.5-4 hr
Protein Bound: 95%
Metabolism: CYP3A4
Half-life, elimination: 15 hr
Excretion: Urine (14%) feces (80%)
Pharmacogenomics
Genotyping is recommended to determine if darunavir resistance mutations are present in treatment experienced patients
Increase dose if 1 of the following resistance associated substitutions is present: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V
Genetic testing laboratories
- The following companies provide genetic testing for antiretrovirals
- Monogram Biosciences (https://www.monogrambio.com/200HIVProducts.aspx)
- Virco (https://www.vircolab.com/)
Administration
Oral Administration
Swallow tablet whole; do not chew, crush, or split
Must take with food; food increases the area under the curve (AUC) and maximum plasma concentration (Cmax) by 30%
Assess ability to swallow; use oral suspension for adults or children who cannot swallow the tablet whole
