DARUNAVIR (Generic for PREZISTA)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer with food.
-Do NOT administer without ritonavir. Ritonavir coadministration is needed to assure appropriate serum concentrations.
Oral Liquid Formulations
-Shake well before each use.
-Administer using the oral dosing syringe supplied by the manufacturer.
-Rinse measuring device after each administration and before storage.

There have been reports of darunavir-induced hepatitis, including acute hepatitis and cytolytic hepatitis, and hepatotoxicity. In adult clinical trials, hepatitis was reported in 0.5% of patients receiving darunavir with ritonavir. Cases of hepatitis and elevated transaminases of at least moderate intensity (>= Grade 2) have been reported in Phase 2b and Phase 3 trials. Patients with preexisting hepatic disease or dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse events. Prior to and during treatment with darunavir, monitor hepatic function with appropriate laboratory testing. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevated transaminases, especially during the first several months of treatment. Consider interrupting or discontinuing treatment if there is evidence of new or worsening hepatic dysfunction (including clinically significant elevation of hepatic enzymes and/or symptoms). During randomized clinical trials, drug related grade 2 to 4 laboratory abnormalities reported in the darunavir treatment arm included elevated hepatic enzymes. Increased ALT was reported as Grade 3 in 3% of pediatric patients and Grade 4 in 1% of pediatric patients. Increased AST was reported as Grade 3 in 1% of pediatric patients. Grade 2 increases in alkaline phosphatase were noted in <= 1% of adult patients; Grade 3 in < 1% of adult patients. All Grades (2-4) of hyperbilirubinemia were reported in < 1% of adult patients.

Skin reactions and hypersensitivity reactions were reported with darunavir in clinical trials. Severe skin reactions, sometimes accompanied by fever and/or elevated transaminases, have been reported in 0.4% of patients in general. In clinical trials, Stevens-Johnson Syndrome was reported in < 0.1% of adult patients. Rash (unspecified), all grades, regardless of causality, occurred in 10.3% of all patients and 5 to 19% of pediatric patients. If a severe rash develops, discontinue treatment. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. Pruritus, angioedema, urticaria, and hypersensitivity were noted in < 2% of adult patients, and pruritus has been reported in up to 8.3% of pediatric patients. Cases of toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) were noted in post-marketing reports. If signs or symptoms of severe skin reactions occur, discontinue darunavir. These symptoms can include, but are not limited to, severe rash or rash accompanied with fever, general malaise, muscle or joint aches, blisters, oral lesions (oral ulceration), conjunctivitis, hepatitis, and/or eosinophilia.

The most common gastrointestinal adverse events reported in pediatric patients receiving darunavir during clinical trials included diarrhea (11-24%), abdominal pain (5-10%), nausea (4-25%), vomiting (13-33%), anorexia (5%), and decreased appetite (8.3%) Other GI events reported in adults include dyspepsia (up to 2%), flatulence (< 2%), abdominal distension (2%), and acute pancreatitis (< 2%). Elevated pancreatic lipase was reported as Grade 3 in 1% of pediatric patients, while elevated pancreatic amylase (hyperamylasemia) was reported as Grade 3 in 4% of pediatric patients and Grade 4 in 1% of pediatric patients.

In controlled clinical trials with darunavir, headache was reported in 9% of pediatric patients, while abnormal dreams/nightmares was noted in < 2% of adults.

Fatigue was noted in 3% of pediatric patients (6 to < 18 years of age) during darunavir clinical trials. Asthenia (3%), myalgia (< 2%), and osteonecrosis (< 2%) were reported in adults in clinical trials. Rarely, rhabdomyolysis (associated with the coadministration of HMG-CoA reductase inhibitors) have been noted in post-marketing reports.

Cases of diabetes mellitus of at least a moderate level of intensity (Grade 2) were noted during clinical trials of darunavir. Diabetes mellitus, new onset and exacerbation of pre-existing disease, was reported in up to 2% of adults patients. Elevated glucose concentrations (hyperglycemia) was reported as Grade 2 (glucose 126-250 mg/dL) in 10 to 11% of adults, Grade 3 (glucose 251-500 mg/dL) in 1% of adults, and Grade 4 (> 500 mg/dL) in < 1% of adults. Diabetic ketoacidosis has developed in patients receiving treatment with protease inhibitors (PI). In some cases, initiation or dose adjustments of insulin and oral hypoglycemic agents were required for treatment.

Lipodystrophy has been noted in clinical trials with darunavir. Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement (e.g., gynecomastia), and Cushingoid features have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown and a causal relationship has not been established.

Hyperlipidemia reported with darunavir treatment includes elevated cholesterol, elevated triglycerides, and elevated low density lipoprotein (LDL). Increased total cholesterol (hypercholesterolemia) was reported as Grade 3 in 1% of pediatric patients, while elevated LDL was reported as Grade 3 in 3% of pediatric patients. Elevated triglycerides (hypertriglyceridemia) was reported as Grade 2 in 3 to 10% of adults, Grade 3 in 2-7% of adults, and Grade 4 in 1-3% of adults.

Protease inhibitors have been associated with increased bleeding, including spontaneous hematoma and hemarthrosis, in patients with hemophilia type A and B. Treatment with factor VIII was required to suppress bleeding in some patients. In more than half of the reported cases, protease inhibitor therapy was either continued or re-introduced following treatment discontinuation. A causal relationship with darunavir has not been established.

Cases of crystal nephropathy and crystalluria have been reported during postmarketing use of darunavir. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.

Genotypic or phenotypic testing of HIV strains and/or a detailed medication treatment history should guide the use of darunavir with ritonavir in each individual patient.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered, as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Health care providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Darunavir contains a sulfonamide moiety and should, therefore, be used with caution and appropriate monitoring in patients with a known sulfonamide hypersensitivity.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PJP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Drug-induced hepatitis (including acute hepatitis and cytolytic hepatitis) with darunavir use has been reported; in clinical trials, hepatitis was reported in 0.5% of patients receiving darunavir with ritonavir. Patients with preexisting hepatic disease or dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions. Postmarketing cases of hepatic injury (unspecified), including fatalities, have been reported. The cases have generally occurred in patients with advanced HIV disease receiving multiple concomitant medications, having comorbidities including hepatitis B and HIV coinfection or hepatitis C and HIV coinfection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir has not been established. Prior to and during treatment, monitor hepatic function with appropriate laboratory testing. Consider increased monitoring of AST/ALT concentrations in patients with underlying chronic hepatitis, especially during the first several months of treatment. Consider interrupting or discontinuing treatment if there is evidence of new or worsening hepatic dysfunction (including clinically significant elevation of hepatic enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly). Screening of all patients that present with HIV-infection for hepatitis B virus (HBV) coinfection is recommended to assure appropriate treatment. Start patients who are coinfected with HIV and HBV and require treatment for either infection on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Continue management of HIV with the goal of maximal suppression. Hepatitis C virus (HCV) screening is also recommended in any child whose mother is known to have HCV infection and in all HIV-infected adolescents. Treatment of HCV infection in pediatric patients younger than 3 years is not usually recommended; however, consider treatment for all children 3 years and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, counsel HIV/HCV-coinfected adolescents to avoid alcohol.

Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during treatment with protease inhibitors, including darunavir. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

Protease inhibitors, such as darunavir, should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A casual relationship has not been established.

Consider patient specific factors, such as preexisting hyperlipidemia, when selecting an antiretroviral treatment regimen. Hyperlipidemia is a recognized side effect of protease inhibitor-based regimens. Obtain a random or fasting lipid profile at entry of care, initiation or modification of antiretroviral therapy, every 12 months, and as clinically indicated. Possible interventions for patients who develop hyperlipidemia during treatment with darunavir include dietary modification, use of lipid lowering agents, or switching to a regimen with a more favorable lipid profile. Clinicians should be aware of the potential for drug interactions with certain cholesterol-lowering drugs.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. It should also be noted that varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of darunavir therapy after loss of viral suppression may increase the likelihood of resistance to other protease inhibitors. Darunavir displays a less than 10-fold decreased susceptibility against 90% (n = 3,309) of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir. Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir in cell culture. However, 6 of 9 darunavir-resistant viruses selected in cell culture from protease inhibitor-resistant viruses showed a fold change in EC50 values less than 3 for tipranavir, indicating limited cross-resistance between darunavir and tipranavir. Of viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily, 41% were still susceptible to tipranavir, 10% were susceptible to saquinavir, and less than 2% were susceptible to other protease inhibitors.

Patients receiving darunavir may be at increase risk of developing serious rash. Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir plus raltegravir. According to the manufacturer, 10.3% of patients developed a rash; most occurred within the first 4 weeks of treatment, were mild/moderate in severity, and resolved with continued treatment. However, more severe rashes have also been reported. During the clinical development program (n = 3063), 0.4% of patients reported a severe skin reaction. Further, cases of Stevens-Johnson Syndrome (< 0.1%), toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have also been rarely reported. Discontinue treatment immediately in any patient who develops signs of severe skin reactions, such as severe rash or rash accompanied with fever, fatigue, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, or eosinophilia.

Darunavir should not be used in neonates, infants, or children younger than 3 years of age due to toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1,000 mg/kg).

Description: Darunavir is an anti-retroviral protease inhibitor. It was granted accelerated approval by the FDA based on evidence from two randomized, controlled studies comparing the safety and efficacy of a darunavir (boosted with ritonavir) treatment regimen with other ritonavir-boosted protease inhibitor (PI) treatment regimens. Darunavir treated patients experienced higher rates of reduction of their HIV viral load than patients on other ritonavir-boosted PI combinations. Darunavir should be used in combination with an individualized antiretroviral regimen and must be administered with low dose ritonavir and food in order to attain appropriate concentrations. Hepatotoxicity and severe skin reactions have been reported. Darunavir is FDA-approved in pediatric patients as young as 3 years.

NOTE: Administration of darunavir without a pharmacokinetic enhancer (i.e., cobicistat or low dose ritonavir) is NOT recommended. Coadministration of a pharmacokinetic enhancer is required to assure appropriate serum concentrations. Darunavir; cobicistat is available as a combination product for use in adolescents.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Darunavir boosted with ritonavir, in combination with a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option, is recommended as an alternative initial regimen for treatment-naive children 3 years and older weighing 10 kg or more.
-Darunavir boosted with ritonavir or cobicistat, in combination with a 2-NRTI backbone option, is a preferred initial regimen for treatment-naive adolescents in certain clinical situations. Darunavir boosted with ritonavir plus lamivudine/emtricitabine (without HBV coinfection) or raltegravir (if HIV RNA is less than 100,000 copies/mL, CD4 is greater than 200 cells/mm3, and without HBV coinfection) is also a regimen that may be used in patients unable to take abacavir or tenofovir.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
-Treatment-naive patients or treatment-experienced patients with no darunavir resistance associated substitutions:
Oral dosage:
Neonates, Infants, and Children 1 to 2 years: Not recommended. The FDA-approved labeling states that darunavir should not be used due to toxicity and mortality observed in juvenile rats.
Children 3 years and older weighing 10 kg: 350 mg PO once daily with ritonavir 64 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children 3 years and older weighing 11 kg: 385 mg PO once daily with ritonavir 64 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children 3 years and older weighing 12 kg: 420 mg PO once daily with ritonavir 80 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children 3 years and older weighing 13 kg: 455 mg PO once daily with ritonavir 80 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children 3 years and older weighing 14 kg: 490 mg PO once daily with ritonavir 96 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children 3 years and older weighing 15 to 29 kg: 600 mg PO once daily with ritonavir 100 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children and Adolescents weighing 30 to 39 kg: 675 mg PO once daily with ritonavir 100 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
Children and Adolescents weighing 40 kg or more: 800 mg PO once daily with ritonavir 100 mg PO once daily is the FDA-approved dosage. However, the HIV treatment guidelines recommend that once-daily darunavir dosing should NOT be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. 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.
-Treatment-experienced patients with at least one darunavir resistance associated substitution:
NOTE: Twice-daily dosing is also recommended as initial therapy in treatment-naive patients younger than 12 years by the HIV guidelines.
Oral dosage:
Neonates, Infants, and Children 1 to 2 years: Not recommended. The FDA-approved labeling states that darunavir should not be used due to toxicity and mortality observed in juvenile rats.
Children 3 years and older weighing 10 kg: 200 mg PO twice daily with ritonavir 32 mg PO twice daily.
Children 3 years and older weighing 11 kg: 220 mg PO twice daily with ritonavir 32 mg PO twice daily.
Children 3 years and older weighing 12 kg: 240 mg PO twice daily with ritonavir 40 mg PO twice daily.
Children 3 years and older weighing 13 kg: 260 mg PO twice daily with ritonavir 40 mg PO twice daily.
Children 3 years and older weighing 14 kg: 280 mg PO twice daily with ritonavir 48 mg PO twice daily.
Children 3 years and older weighing 15 to 29 kg: 375 mg PO twice daily with ritonavir 48 mg PO twice daily.
Children and Adolescents weighing 30 to 39 kg: 450 mg PO twice daily with ritonavir 100 mg PO twice daily is recommended by HIV guidelines; 450 mg PO twice daily with ritonavir 60 mg PO twice daily is the FDA-approved dosage.
Children and Adolescents weighing 40 kg or more: 600 mg PO twice daily with ritonavir 100 mg PO twice daily.

For human immunodeficiency virus (HIV) prophylaxis* after nonoccupational exposure, including sexual assault:
NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
Oral dosage:
Children 3 years and older weighing 10 kg: 200 mg PO twice daily boosted with ritonavir 32 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 11 kg: 220 mg PO twice daily boosted with ritonavir 32 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 12 kg: 240 mg PO twice daily boosted with ritonavir 40 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 13 kg: 260 mg PO twice daily boosted with ritonavir 40 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 14 kg: 280 mg PO twice daily boosted with ritonavir 48 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 15 to 29 kg: 375 mg PO twice daily boosted with ritonavir 48 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 30 to 39 kg: 450 mg PO twice daily boosted with ritonavir 100 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 40 kg or more: 600 mg PO twice daily boosted with ritonavir 100 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Adolescents: 800 mg PO once daily boosted with ritonavir 100 mg PO once daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine (patients with renal dysfunction [CrCl 59 mL/minute or less]) for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in adolescents. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 2,200 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs


Maximum Dosage Limits:
-Neonates
Not recommended.
-Infants
Not recommended.
-Children
younger than 3 years: Not recommended.
3 to 12 years weighing less than 10 kg: Not recommended.
3 to 12 years weighing 10 to 10.9 kg: 400 mg/day PO.
3 to 12 years weighing 11 to 11.9 kg: 440 mg/day PO.
3 to 12 years weighing 12 to 12.9 kg: 480 mg/day PO.
3 to 12 years weighing 13 to 13.9 kg: 520 mg/day PO.
3 to 12 years weighing 14 to 14.9 kg: 560 mg/day PO.
3 to 12 years weighing 15 to 29 kg: 750 mg/day PO.
3 to 12 years weighing 30 to 39 kg: 900 mg/day PO.
3 to 12 years weighing 40 kg or more: 1200 mg/day PO.
-Adolescents
weighing 30 to 39 kg: 900 mg/day PO.
weighing 40 kg or more: 1200 mg/day PO.

Patients with Hepatic Impairment Dosing
Dosage adjustments are not necessary for patients with mild or moderate hepatic impairment. Darunavir is not recommended for use in adult patients with severe hepatic impairment; no pharmacokinetic or safety data are available. There are no recommendations in pediatric patients.

Patients with Renal Impairment Dosing
No dose adjustment is required in patients with mild or moderate renal impairment. Specific guidelines for dosage adjustments in severe renal impairment are not available; however a decrease in clearance is not expected because renal clearance of darunavir is limited.

Intermittent hemodialysis
Darunavir is not expected to be significantly removed by hemodialysis.

Peritoneal dialysis
Darunavir is not expected to be significantly removed by peritoneal dialysis.


*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Darunavir inhibits HIV protease, an enzyme involved in the replication of HIV. It binds to the active site of HIV protease and inhibits the virus-specific processing of the viral gag-pol polyproteins in HIV infected cells, thus preventing formation of mature virions. During the later stages of the HIV growth cycle, the gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, and in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages).

Pharmacokinetics: Darunavir is administered orally. It is approximately 95% bound to plasma proteins, specifically alpha-1-acid glycoprotein (AAG). The primary route of metabolism is oxidative via CYP3A to inactive metabolites. In order to achieve effective plasma concentrations, it is coadministered (boosted) with a pharmacokinetic enhancer (i.e., ritonavir or cobicistat). These pharmacokinetic enhancers inhibit CYP3A metabolism, thereby increasing darunavir concentrations (e.g., approximately 14-fold with ritonavir). In healthy volunteers, approximately 80% of a single dose (400 mg, with ritonavir 100 mg) is excreted in the feces and approximately 14% is recovered in the urine. Unchanged darunavir accounted for approximately 41% and 8% of the administered dose in feces and urine, respectively. The terminal elimination half-life in adults is approximately 15 hours when administered with ritonavir and approximately 7 hours when administered with cobicistat.

Affected cytochrome P450 isoenzymes: CYP3A4, CYP2D6, P-gp
Darunavir is an inhibitor of CYP3A4. When administered as approved by the FDA boosted with either ritonavir or cobicistat, further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Coadministration with CYP3A inducers may decrease darunavir plasma concentrations; coadministration with CYP3A inhibitors may increase darunavir plasma concentrations. Darunavir plus ritonavir is also an inhibitor of CYP2D6. In vivo data suggest that darunavir is a P-glycoprotein (P-gp) inhibitor. In vitro data also indicate that darunavir may be a P-gp substrate.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, a single 600 mg dose of darunavir alone exhibits an absolute bioavailability of 37%. Coadministration with ritonavir increases bioavailability to 82%. When administered with food and ritonavir, darunavir Cmax and AUC is approximately 40% higher relative to the fasting state; exposure was similar within the ranges of meals studied (240 Kcal with 12 grams fat to 928 Kcal with 56 grams fat). Administer with food.


-Special Populations
Pediatrics
Children >= 3 years and Adolescents
The pharmacokinetics of darunavir (with ritonavir) have been evaluated in 93 antiretroviral treatment-experienced HIV-1-infected pediatric patients (aged 3 to < 18 years and weighing at least 10 kg), and 12 antiretroviral treatment-naive HIV-1-infected pediatric patients (aged 12 to < 18 and weighing at least 40 kg). For both pediatric groups, darunavir exposures were comparable to the exposures achieved by treatment-experience and treatment-naive adults, respectively. Although not studied, population pharmacokinetic modeling and simulation predict antiretroviral treatment-naive pediatric patients aged 3 to < 12 years treated with the recommended dosing regimen will also achieve darunavir exposures similar to those observed in treatment-naive adults.

Hepatic Impairment
Darunavir is primarily metabolized by the liver. Steady-state pharmacokinetic parameters were similar after multiple dose administration (darunavir 600 mg, with ritonavir 100 mg, twice daily) to subjects with normal hepatic function (n = 16), mild hepatic impairment (Child-Pugh Class A, n = 8), and moderate hepatic impairment (Child-Pugh Class B, n = 8). Darunavir was not studied in patients with severe hepatic impairment; use in this patient population is not recommended.

Renal Impairment
Darunavir pharmacokinetic parameters are not significantly affected in HIV infected subjects with moderate renal impairment (CrCl 30-60 mL/min, n = 20). There are no pharmacokinetic data available in HIV infected patients with severe renal impairment or end stage renal disease. As darunavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.