Prezista Drug Information
Generic name: DARUNAVIR
Uses of Prezista
PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adult and pediatric patients 3 years of age and older. PREZISTA is a human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV-1 infection in adult and pediatric patients 3 years of age and older. PREZISTA must be co-administered with ritonavir (PREZISTA/ritonavir) and with other antiretroviral agents.
Dosage & Administration of Prezista
Testing Prior to Initiation of PREZISTA/ritonavir
In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus. Refer to Dosage and Administration, and for dosing recommendations. Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with PREZISTA/ritonavir.
Monitoring During Treatment with PREZISTA/ritonavir Patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases should be monitored for elevation in serum liver biochemistries, especially during the first several months of PREZISTA/ritonavir treatment.
Recommended Dosage in Adult Patients PREZISTA must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer PREZISTA with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions. Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg per mL PREZISTA oral suspension.
An 8 mL PREZISTA dose should be taken as two 4 mL administrations with the included oral dosing syringe. Treatment-Experienced Adult Patients The recommended oral dosage for treatment-experienced adult patients is summarized in Table 1. Baseline genotypic testing is recommended for dose selection.
However, when genotypic testing is not feasible, PREZISTA 600 mg taken with ritonavir 100 mg twice daily is recommended. PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance.
Recommended Dosage in Pediatric
Patients (age 3 to less than 18 years) Healthcare professionals should pay special attention to accurate dose selection of PREZISTA, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose. Prescribers should select the appropriate dose of PREZISTA/ritonavir for each individual child based on body weight (kg) and should not exceed the recommended dose for adults. Before prescribing PREZISTA, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets.
If a child is unable to reliably swallow a tablet, the use of PREZISTA oral suspension should be considered. PREZISTA should be taken with ritonavir and with food. The recommendations for the PREZISTA/ritonavir dosage regimens were based on pediatric clinical trial data and population pharmacokinetic modeling and simulation.
Dosing Recommendations for Treatment-Naïve Pediatric Patients or Antiretroviral Treatment-Experienced Pediatric Patients with No Darunavir Resistance Associated Substitutions Pediatric Patients Weighing At Least 10 kg but Less than 15 kg The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is PREZISTA 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table: Table 2: Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutions darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Pediatric Patients Weighing At Least 15 kg Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the following table: Table 3: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutions darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Dosing Recommendations for Treatment-Experienced Pediatric Patients with At Least One Darunavir Resistance Associated Substitutions Pediatric Patients Weighing At Least 10 kg but Less than 15 kg The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is PREZISTA 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table: Table 4: Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitution darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Pediatric Patients Weighing At Least 15 kg Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the following table: Table 5: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitution darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V The use of PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended.
Not Recommended in Patients with Severe Hepatic Impairment
No dosage adjustment is required in patients with mild or moderate hepatic impairment. No data are available regarding the use of PREZISTA/ritonavir when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment.
| Formulation and Recommended Dosing | ||
|---|---|---|
| Baseline Resistance | PREZISTA tablets with ritonavir tablets or capsule | PREZISTA oral suspension (100 mg/mL) with ritonavir oral solution (80 mg/mL) |
| With no darunavir resistance associated substitutions V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V | One 800 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food | 8 mL An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe. PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken once daily with food |
| With at least one darunavir resistance associated substitutions, or with no baseline resistance information | One 600 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken twice daily with food | 6 mL PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken twice daily with food |
| Body weight (kg) | Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) |
|---|---|
| Dose: once daily with food | |
| Greater than or equal to 10 kg to less than 11 kg | PREZISTA 3.6 mL The 350 mg, 385 mg, 455 mg and 490 mg darunavir dose for the specified weight groups were rounded up for suspension dosing convenience to 3.6 mL, 4 mL, 4.6 mL and 5 mL, respectively. (350 mg) with ritonavir 0.8 mL (64 mg) |
| Greater than or equal to 11 kg to less than 12 kg | PREZISTA 4 mL (385 mg) with ritonavir 0.8 mL (64 mg) |
| Greater than or equal to 12 kg to less than 13 kg | PREZISTA 4.2 mL (420 mg) with ritonavir 1 mL (80 mg) |
| Greater than or equal to 13 kg to less than 14 kg | PREZISTA 4.6 mL (455 mg) with ritonavir 1 mL (80 mg) |
| Greater than or equal to 14 kg to less than 15 kg | PREZISTA 5 mL (490 mg) with ritonavir 1.2 mL (96 mg) |
| Body weight (kg) | Formulation: PREZISTA tablet(s) and ritonavir capsules or tablets (100 mg) | Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) |
|---|---|---|
| Dose: once daily with food | Dose: once daily with food | |
| Greater than or equal to 15 kg to less than 30 kg | PREZISTA 600 mg with ritonavir 100 mg | PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg) |
| Greater than or equal to 30 kg to less than 40 kg | PREZISTA 675 mg with ritonavir 100 mg | PREZISTA 6.8 mL The 675 mg dose using darunavir tablets for this weight group is rounded up to 6.8 mL for suspension dosing convenience. The 6.8 mL and 8 mL darunavir dose should be taken as two (3.4 mL or 4 mL respectively) administrations with the included oral dosing syringe. (675 mg) with ritonavir 1.25 mL (100 mg) |
| Greater than or equal to 40 kg | PREZISTA 800 mg with ritonavir 100 mg | PREZISTA 8 mL (800 mg) with ritonavir 1.25 mL (100 mg) |
| Body weight (kg) | Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) |
|---|---|
| Dose: twice daily with food | |
| Greater than or equal to 10 kg to less than 11 kg | PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32 mg) |
| Greater than or equal to 11 kg to less than 12 kg | PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg) |
| Greater than or equal to 12 kg to less than 13 kg | PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg) |
| Greater than or equal to 13 kg to less than 14 kg | PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg) |
| Greater than or equal to 14 kg to less than 15 kg | PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg) |
| Body weight (kg) | Formulation: PREZISTA tablet(s) and ritonavir tablets, capsules (100 mg) or oral solution (80 mg/mL) | Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) |
|---|---|---|
| Dose: twice daily with food | Dose: twice daily with food | |
| Greater than or equal to 15 kg to less than 30 kg | PREZISTA 375 mg with ritonavir 0.6 mL (48 mg) | PREZISTA 3.8 mL (375 mg) The 375 mg and 450 mg dose using darunavir tablets for this weight group is rounded up to 3.8 mL and 4.6 mL for suspension dosing convenience. with ritonavir 0.6 mL (48 mg) |
| Greater than or equal to 30 kg to less than 40 kg | PREZISTA 450 mg with ritonavir 0.75 mL (60 mg) | PREZISTA 4.6 mL (450 mg) with ritonavir 0.75 mL (60 mg) |
| Greater than or equal to 40 kg | PREZISTA 600 mg with ritonavir 100 mg | PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg) |
Side Effects of Prezista
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment Naïve-Adults: TMC114-C211 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The majority of the adverse drug reactions (ADRs) reported during treatment with PREZISTA/ritonavir 800/100 mg once daily were mild in severity.
The most common clinical ADRs to PREZISTA/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs. ADRs to PREZISTA/ritonavir 800/100 mg once daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 6 and subsequent text below the table. The majority of the ADRs reported during treatment with PREZISTA/ritonavir 600/100 mg twice daily were mild in severity.
The most common clinical ADRs to PREZISTA/ritonavir 600/100 mg twice daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs. ADRs to PREZISTA/ritonavir 600/100 mg twice daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 8 and subsequent text below the table. Table 9: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects Grade 4 data not applicable in Division of AIDS grading scale. (Trial TMC114-C214) Serious ADRs The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b and Phase 3 trials with PREZISTA/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.
Patients Co-Infected with Hepatitis B and/or Hepatitis C Virus In subjects co-infected with hepatitis B or C virus receiving PREZISTA/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/ritonavir who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection. Clinical Trials Experience: Pediatric Patients PREZISTA/ritonavir has been studied in combination with other antiretroviral agents in 3 Phase 2 trials.
The TMC114-C212 and C228 trials evaluated PREZISTA/ritonavir twice daily dosing and the TMC114-C230 trial evaluated PREZISTA/ritonavir once daily dosing. Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults. TMC114-C212 Clinical ADRs to PREZISTA/ritonavir all grades, greater than or equal to or 4 laboratory abnormalities were ALT increased .
TMC114-C228 Clinical ADRs to PREZISTA/ritonavir all grades, greater than or equal to or 4 laboratory abnormalities considered as ADRs in this trial.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of PREZISTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and Nutrition Disorders: Redistribution of body fat Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms Renal and Urinary Disorders: Crystal nephropathy, crystalluria
| System organ class, preferred term, % | PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N=343 | lopinavir/ritonavir 800/200 mg per day + TDF/FTC N=346 |
|---|---|---|
| N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate | ||
| Gastrointestinal Disorders | ||
| Abdominal pain | 6% | 6% |
| Diarrhea | 9% | 16% |
| Nausea | 4% | 4% |
| Vomiting | 2% | 4% |
| General Disorders and Administration Site Conditions | ||
| Fatigue | <1% | 3% |
| Metabolism and Nutrition Disorders | ||
| Anorexia | 2% | <1% |
| Nervous System Disorders | ||
| Headache | 7% | 6% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 6% | 7% |
| Laboratory parameter % | Limit | PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC | lopinavir/ritonavir 800/200 mg per day + TDF/FTC |
|---|---|---|---|
| N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate | |||
| Biochemistry | |||
| Alanine Aminotransferase | |||
| Grade 2 | >2.5 to ≤5.0 × ULN | 9% | 9% |
| Grade 3 | >5.0 to ≤10.0 × ULN | 3% | 3% |
| Grade 4 | >10.0 × ULN | <1% | 3% |
| Aspartate Aminotransferase | |||
| Grade 2 | >2.5 to ≤5.0 × ULN | 7% | 10% |
| Grade 3 | >5.0 to ≤10.0 × ULN | 4% | 2% |
| Grade 4 | >10.0 × ULN | 1% | 3% |
| Alkaline Phosphatase | |||
| Grade 2 | >2.5 to ≤5.0 × ULN | 1% | 1% |
| Grade 3 | >5.0 to ≤10.0 × ULN | 0% | <1% |
| Grade 4 | >10.0 × ULN | 0% | 0% |
| Hyperbilirubinemia | |||
| Grade 2 | >1.5 to ≤2.5 × ULN | <1% | 5% |
| Grade 3 | >2.5 to ≤5.0 × ULN | <1% | <1% |
| Grade 4 | >5.0 × ULN | 0% | 0% |
| Triglycerides | |||
| Grade 2 | 5.65–8.48 mmol/L 500–750 mg/dL | 3% | 10% |
| Grade 3 | 8.49–13.56 mmol/L 751–1200 mg/dL | 2% | 5% |
| Grade 4 | >13.56 mmol/L >1200 mg/dL | 1% | 1% |
| Total Cholesterol | |||
| Grade 2 | 6.20–7.77 mmol/L 240–300 mg/dL | 23% | 27% |
| Grade 3 | >7.77 mmol/L >300 mg/dL | 1% | 5% |
| Low-Density Lipoprotein Cholesterol | |||
| Grade 2 | 4.13–4.90 mmol/L 160–190 mg/dL | 14% | 12% |
| Grade 3 | ≥4.91 mmol/L ≥191 mg/dL | 9% | 6% |
| Elevated Glucose Levels | |||
| Grade 2 | 6.95–13.88 mmol/L 126–250 mg/dL | 11% | 10% |
| Grade 3 | 13.89–27.75 mmol/L 251–500 mg/dL | 1% | <1% |
| Grade 4 | >27.75 mmol/L >500 mg/dL | 0% | 0% |
| Pancreatic Lipase | |||
| Grade 2 | >1.5 to ≤3.0 × ULN | 3% | 2% |
| Grade 3 | >3.0 to ≤5.0 × ULN | <1% | 1% |
| Grade 4 | >5.0 × ULN | 0% | <1% |
| Pancreatic Amylase | |||
| Grade 2 | >1.5 to ≤2.0 × ULN | 5% | 2% |
| Grade 3 | >2.0 to ≤5.0 × ULN | 5% | 4% |
| Grade 4 | >5.0 × ULN | 0% | <1% |
| System organ class, preferred term, % | PREZISTA/ritonavir 600/100 mg twice daily + OBR N=298 | lopinavir/ritonavir 400/100 mg twice daily + OBR N=297 |
|---|---|---|
| N=total number of subjects per treatment group; OBR=optimized background regimen | ||
| Gastrointestinal Disorders | ||
| Abdominal distension | 2% | <1% |
| Abdominal pain | 6% | 3% |
| Diarrhea | 14% | 20% |
| Dyspepsia | 2% | 1% |
| Nausea | 7% | 6% |
| Vomiting | 5% | 3% |
| General Disorders and Administration Site Conditions | ||
| Asthenia | 3% | 1% |
| Fatigue | 2% | 1% |
| Metabolism and Nutrition Disorders | ||
| Anorexia | 2% | 2% |
| Diabetes mellitus | 2% | <1% |
| Nervous System Disorders | ||
| Headache | 3% | 3% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 7% | 3% |
| Laboratory parameter, % | Limit | PREZISTA/ritonavir 600/100 mg twice daily + OBR | lopinavir/ritonavir 400/100 mg twice daily + OBR |
|---|---|---|---|
| N=total number of subjects per treatment group; OBR=optimized background regimen | |||
| Biochemistry | |||
| Alanine Aminotransferase | |||
| Grade 2 | >2.5 to ≤5.0 × ULN | 7% | 5% |
| Grade 3 | >5.0 to ≤10.0 × ULN | 2% | 2% |
| Grade 4 | >10.0 × ULN | 1% | 2% |
| Aspartate Aminotransferase | |||
| Grade 2 | >2.5 to ≤5.0 × ULN | 6% | 6% |
| Grade 3 | >5.0 to ≤10.0 × ULN | 2% | 2% |
| Grade 4 | >10.0 × ULN | <1% | 2% |
| Alkaline Phosphatase | |||
| Grade 2 | >2.5 to ≤5.0 × ULN | <1% | 0% |
| Grade 3 | >5.0 to ≤10.0 × ULN | <1% | <1% |
| Grade 4 | >10.0 × ULN | 0% | 0% |
| Hyperbilirubinemia | |||
| Grade 2 | >1.5 to ≤2.5 × ULN | <1% | 2% |
| Grade 3 | >2.5 to ≤5.0 × ULN | <1% | <1% |
| Grade 4 | >5.0 × ULN | <1% | 0% |
| Triglycerides | |||
| Grade 2 | 5.65–8.48 mmol/L 500–750 mg/dL | 10% | 11% |
| Grade 3 | 8.49–13.56 mmol/L 751–1200 mg/dL | 7% | 10% |
| Grade 4 | >13.56 mmol/L >1200 mg/dL | 3% | 6% |
| Total Cholesterol | |||
| Grade 2 | 6.20–7.77 mmol/L 240–300 mg/dL | 25% | 23% |
| Grade 3 | >7.77 mmol/L >300 mg/dL | 10% | 14% |
| Low-Density Lipoprotein Cholesterol | |||
| Grade 2 | 4.13–4.90 mmol/L 160–190 mg/dL | 14% | 14% |
| Grade 3 | ≥4.91 mmol/L ≥191 mg/dL | 8% | 9% |
| Elevated Glucose Levels | |||
| Grade 2 | 6.95–13.88 mmol/L 126–250 mg/dL | 10% | 11% |
| Grade 3 | 13.89–27.75 mmol/L 251–500 mg/dL | 1% | <1% |
| Grade 4 | >27.75 mmol/L >500 mg/dL | <1% | 0% |
| Pancreatic Lipase | |||
| Grade 2 | >1.5 to ≤3.0 × ULN | 3% | 4% |
| Grade 3 | >3.0 to ≤5.0 × ULN | 2% | <1% |
| Grade 4 | >5.0 × ULN | <1% | 0% |
| Pancreatic Amylase | |||
| Grade 2 | >1.5 to ≤2.0 × ULN | 6% | 7% |
| Grade 3 | >2.0 to ≤5.0 × ULN | 7% | 3% |
| Grade 4 | >5.0 × ULN | 0% | 0% |
Warnings & Cautions for Prezista
Importance of Co-administration with Ritonavir PREZISTA must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir. Please refer to ritonavir prescribing information for additional information on precautionary measures.
Hepatotoxicity
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.
Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/ritonavir therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/ritonavir treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/ritonavir should prompt consideration of interruption or discontinuation of treatment.
Severe Skin Reactions During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported.
Discontinue PREZISTA/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/ritonavir.
Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/ritonavir was 0.5%. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/ritonavir + raltegravir compared to subjects receiving PREZISTA/ritonavir without raltegravir or raltegravir without PREZISTA/ritonavir.
However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
Sulfa Allergy
Darunavir contains a sulfonamide moiety. PREZISTA should be used with caution in patients with a known sulfonamide allergy. In clinical studies with PREZISTA/ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.
Risk of Serious Adverse
Reactions due to Drug Interactions Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZISTA/ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir. Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s). Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance from lower exposures of PREZISTA/ritonavir.
See Table 10 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREZISTA/ritonavir therapy; review concomitant medications during PREZISTA/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs.
Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred.
In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.
Fat Redistribution 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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZISTA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.
Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued.
A causal relationship between PI therapy and these episodes has not been established.
Not Recommended in Pediatric Patients Below 3 Years of Age PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age.
Drug Interactions with Prezista
Potential for PREZISTA/ritonavir to Affect Other Drugs
PREZISTA co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events. PREZISTA co-administered with ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 10 ).
Potential for Other Drugs to Affect Darunavir Darunavir and ritonavir are metabolized by CYP3A. In vitro data indicate that darunavir may be a P-gp substrate. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir.
Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A, or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 10 ).
Established and Other Potentially Significant Drug Interactions Table 10 provides dosing recommendations as a result of drug interactions with PREZISTA/ritonavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. The table includes examples of potentially significant interactions but is not all inclusive, and therefore the label of each drug that is co-administered with PREZISTA/ritonavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co-administration.
Table 10: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction (see Contraindications for a list of examples of contraindicated drugs) Other HIV protease inhibitors, except atazanavir Effective alternative (non-hormonal) contraceptive method or a barrier method of contraception is recommended.
Drugs without Clinically Significant Interactions with PREZISTA No dosage adjustments are recommended when PREZISTA/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, or rilpivirine.
| Concomitant Drug Class Drug Name Examples | Effect on Concentration of Darunavir Or Concomitant Drug | Clinical Comment |
|---|---|---|
| HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
| didanosine | ↔ darunavir ↔ didanosine | Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
| HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs) | ||
| indinavir | ↑ darunavir ↑ indinavir | The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) | ||
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir | Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir | Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
| Other HIV protease inhibitors, except atazanavir [see Drug Interactions (7.4) ] | As co-administration with PREZISTA/ritonavir has not been studied, co-administration is not recommended. | |
| HIV-1-Antiviral Agents: CCR5 co-receptor antagonists | ||
| maraviroc | ↑ maraviroc | When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
| Other Agents | ||
| Alpha 1-adrenoreceptor antagonist: | ||
| alfuzosin | ↑ alfuzosin | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. |
| Antibacterial: clarithromycin | ↔ darunavir ↑ clarithromycin | No dose adjustment of the combination is required for patients with normal renal function. For co-administration of clarithromycin and PREZISTA/ritonavir in patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of <30 mL/min, the dose of clarithromycin should be reduced by 75%. |
| Anticoagulants: Direct Oral Anticoagulants (DOACs) | ||
| apixaban | ↑ apixaban | Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with PREZISTA/ritonavir depend on the apixaban dose. Refer to apixaban dosing instructions for co-administration with P-gp and strong CYP3A inhibitors in apixaban prescribing information. |
| rivaroxaban | ↑ rivaroxaban | Co-administration of PREZISTA/ritonavir and rivaroxaban is not recommended because it may lead to an increased bleeding risk. |
| dabigatran etexilate edoxaban | ↑ dabigatran ↑ edoxaban | Refer to the dabigatran etexilate or edoxaban prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the co-administered P-gp inhibitors on the concentration of dabigatran or edoxaban. Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with PREZISTA/ritonavir. |
| Other Anticoagulants | ||
| warfarin | ↓ warfarin ↔ darunavir | Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
| Anticonvulsants: carbamazepine | ↔ darunavir ↑ carbamazepine | The dose of either PREZISTA/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with PREZISTA/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
| clonazepam | ↑ clonazepam | Clinical monitoring of anticonvulsants that are metabolized by CYP3A is recommended. |
| phenobarbital, phenytoin | ↔ darunavir ↓ phenytoin ↓ phenobarbital | Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
| Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): | ||
| paroxetine, sertraline | ↓ paroxetine ↓ sertraline | If either sertraline or paroxetine is initiated in patients receiving PREZISTA/ritonavir, dose titrating the SSRI based on a clinical assessment of antidepressant response is recommended. Monitor for antidepressant response in patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir. |
| Tricyclic Antidepressants (TCAs): | ||
| amitriptyline, desipramine, imipramine, nortriptyline | ↑ amitriptyline ↑ desipramine ↑ imipramine ↑ nortriptyline | Use a lower dose of the tricyclic antidepressants and trazodone due to potential increased adverse events such as nausea, dizziness, hypotension and syncope. |
| Other: trazodone | ↑ trazodone | |
| Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole | ↑ darunavir ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole | Monitor for increased PREZISTA/ritonavir and/or antifungal adverse events with concomitant use of these antifungals. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg with monitoring for increased antifungal adverse events. |
| voriconazole | ↓ voriconazole | Voriconazole is not recommended for patients receiving PREZISTA/ritonavir unless an assessment comparing predicted benefit to risk ratio justifies the use of voriconazole. |
| Anti-gout: colchicine | ↑ colchicine | Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. For patients without renal or hepatic impairment: Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimalarial: artemether/lumefantrine | ↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir | The combination of PREZISTA/ritonavir and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation. |
| Antimycobacterials: | ||
| rifampin | ↓ darunavir | Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| rifabutin (The reference regimen for rifabutin was 300 mg once daily.) | ↑ darunavir ↑ rifabutin ↑ 25- O -desacetylrifabutin | Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| rifapentine | ↓ darunavir | Co-administration of PREZISTA/ritonavir with rifapentine is not recommended. |
| Antineoplastics: dasatinib, nilotinib | ↑ antineoplastics | A decrease in the dosage or an adjustment of the dosing interval of dasatinib and nilotinib may be necessary for patients. Please refer to the dasatinib and nilotinib prescribing information for dosing instructions. |
| vinblastine, vincristine | For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when PREZISTA/ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. | |
| Antipsychotics: | ||
| lurasidone | ↑ lurasidone | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. |
| pimozide | ↑ pimozide | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| quetiapine | ↑ quetiapine | Initiation of PREZISTA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking PREZISTA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| e.g. perphenazine, risperidone, thioridazine | ↑ antipsychotics | A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with PREZISTA/ritonavir. |
| β-Blockers: e.g. carvedilol, metoprolol, timolol | ↑ beta-blockers | Clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir and a lower dose of the beta blocker should be considered. |
| Calcium Channel Blockers: amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil | ↑ calcium channel blockers | Clinical monitoring of patients is recommended. |
| Cardiac Disorders: | ||
| ranolazine, ivabradine | ↑ ranolazine ↑ ivabradine | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. |
| dronedarone | ↑ dronedarone | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Other antiarrhythmics e.g. amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine | ↑ antiarrhythmics | Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
| Corticosteroids: | ||
| dexamethasone (systemic) | ↓ darunavir | Co-administration of PREZISTA/ritonavir with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to darunavir. Consider alternative corticosteroids. |
| Corticosteroids primarily metabolized by CYP3A: e.g. betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone | ↑ corticosteroids | Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use. |
| Endothelin receptor antagonist: | ||
| bosentan | ↑ bosentan | Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| Ergot derivatives: | ||
| e.g. dihydroergotamine, ergotamine, methylergonovine | ↑ ergot derivatives | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Hepatitis C virus (HCV): | ||
| Direct-Acting Antivirals: elbasvir/grazoprevir | ↑ elbasvir/grazoprevir | Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. |
| glecaprevir/pibrentasvir | ↑ glecaprevir ↑ pibrentasvir | Co-administration of PREZISTA/ritonavir with glecaprevir/pibrentasvir is not recommended. |
| Herbal product: | ||
| St. John's wort ( Hypericum perforatum ) | ↓ darunavir | Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. |
| Hormonal contraceptives: | Effective alternative (non-hormonal) contraceptive method or a barrier method of contraception is recommended [see Use in Specific Populations (8.3) ]. | |
| ethinyl estradiol, norethindrone, drospirenone | ↓ ethinyl estradiol ↓ norethindrone drospirenone: effects unknown | For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. No data are available to make recommendations on co-administration with other hormonal contraceptives. |
| Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus | ↑ immunosuppressants | Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
| Immunosuppressant/neoplastic: everolimus | Co-administration of everolimus and PREZISTA/ritonavir is not recommended. | |
| irinotecan | Discontinue PREZISTA/ritonavir at least 1 week prior to starting irinotecan therapy. Do not administer PREZISTA/ritonavir with irinotecan unless there are no therapeutic alternatives. | |
| Inhaled beta agonist: | ||
| salmeterol | ↑ salmeterol | Co-administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Lipid Modifying Agents: | ||
| HMG-CoA reductase inhibitors: | ||
| lovastatin, simvastatin | ↑ lovastatin ↑ simvastatin | Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. |
| atorvastatin, pravastatin, rosuvastatin | ↑ HMG-CoA reductase inhibitors | Co-administration of PREZISTA/ritonavir with HMG-Co A reductase inhibitors may lead to adverse events such as myopathy. Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for adverse events. Do not exceed atorvastatin 20 mg/day. |
| Other lipid modifying agents: | ||
| lomitapide | ↑ lomitapide | Co-administration is contraindicated due to potential for markedly increased transaminases. |
| Narcotic analgesics metabolized by CYP3A: | ||
| e.g. fentanyl, oxycodone | ↑ fentanyl ↑ oxycodone | Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. |
| tramadol | ↑ tramadol | A dose decrease may be needed for tramadol with concomitant use. |
| Narcotic analgesics/treatment of opioid dependence: buprenorphine, buprenorphine/naloxone | ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) | No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are co-administered. |
| methadone | ↓ methadone | No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. |
| Opioid Antagonist | ||
| naloxegol | ↑ naloxegol | Co-administration of PREZISTA/ritonavir and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms. |
| PDE-5 inhibitors: e.g. avanafil, sildenafil, tadalafil, vardenafil | ↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) | Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. Co-administration of PREZISTA/ritonavir and avanafil is not recommended. |
| Platelet aggregation inhibitor: ticagrelor | ↑ ticagrelor | Co-administration of PREZISTA/ritonavir and ticagrelor is not recommended. |
| clopidogrel | ↓ clopidogrel active metabolite | Co-administration of PREZISTA/ritonavir and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. |
| prasugrel | ↔ prasugrel active metabolite | No dose adjustment is needed when prasugrel is co-administered with PREZISTA/ritonavir. |
| Proton pump inhibitor: omeprazole | ↓ omeprazole ↔ darunavir | When omeprazole is co-administered with PREZISTA/ritonavir, monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. |
| Sedatives/hypnotics: | ||
| orally administered midazolam, triazolam | ↑ midazolam ↑ triazolam | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZISTA may cause large increases in the concentrations of these benzodiazepines. |
| metabolized by CYP3A e.g. buspirone, diazepam, estazolam, zolpidem | ↑ sedatives/hypnotics | Titration is recommended when co-administering PREZISTA/ritonavir with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for adverse events. |
| parenterally administered midazolam | Co-administration of parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. | |
| Urinary antispasmodics | ||
| fesoterodine | ↑ fesoterodine | When fesoterodine is co-administered with PREZISTA/ritonavir, do not exceed a fesoterodine dose of 4 mg once daily. |
| solifenacin | ↑ solifenacin | When solifenacin is co-administered with PREZISTA/ritonavir, do not exceed a solifenacin dose of 5 mg once daily. |
Pregnancy Safety for Prezista
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREZISTA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage.
Available limited data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP ). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.
The background risk of major birth defects and miscarriage for the indicated population is unknown. Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose.
Clinical Considerations The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food. PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance. Data Human Data PREZISTA/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women during the second and third trimesters, and postpartum.
Eighteen subjects were enrolled in each BID and QD treatment arms. The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6–12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen.
Virologic response was preserved. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure). PREZISTA/ritonavir was well tolerated during pregnancy and postpartum.
There were no new clinically relevant safety findings compared with the known safety profile of PREZISTA/ritonavir in HIV-1-infected adults. Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine.
Based on prospective reports to the APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was with first trimester exposure to darunavir-containing regimens and with second/third trimester exposure to darunavir-containing regimens. Animal Data Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone).
Pediatric Use of Prezista
The safety, pharmacokinetic profile, and virologic and immunologic responses of PREZISTA/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults. Refer to Dosage and Administration for twice-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg.
In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of PREZISTA/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects). Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although a PREZISTA/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted PREZISTA exposures for the dosing recommendations in this age group.
Juvenile Animal Data In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.
Contraindications for Prezista
Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below. Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.
Alpha 1-adrenoreceptor antagonist: alfuzosin Anti-gout: colchicine, in patients with renal and/or hepatic impairment Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Cardiac Disorders: dronedarone, ivabradine, ranolazine Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine Herbal product: St.
Overdosage Information for Prezista
Human experience of acute overdose with PREZISTA/ritonavir is limited. No specific antidote is available for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
Clinical Studies of Prezista
Description of Adult Clinical Trials
The evidence of efficacy of PREZISTA/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.
Treatment-Naïve Adult Subjects TMC114-C211 TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC). HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL.
Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in trial TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier. Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 19 ).
Table 19 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in trial TMC114-C211. In the 192 week analysis, statistical superiority of the PREZISTA/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.
Treatment-Experienced Adult Subjects TMC114-C229 TMC114-C229 is a randomized, open-label trial comparing PREZISTA/ritonavir 800/100 mg once daily to PREZISTA/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.
HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier. Table 21 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm in trial TMC114-C229.
No imbalances between the 2 arms were noted. Table 21: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C229 Median number of resistance-associated Johnson VA, Brun-Vézinet F, Clotet B, et al. Top HIV Med outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from trial TMC114-C229 are shown in Table 22.
TMC114-C214 TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs). Analyses included 595 subjects in trial TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.
Table 23 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in trial TMC114-C214. Table 23: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C214 Median number of resistance-associated Johnson VA, Brun-Vezinet F, Clotet B, et al. TMC114-C213 and TMC114-C202 TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to PREZISTA/ritonavir received the recommended dose of 600/100 mg twice daily.
HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide. The virologic response rate was evaluated in subjects receiving PREZISTA/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR.
Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve.
Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log 10 versus baseline. In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the comparator PI arm (see Table 25 ). Table 25 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of trials TMC114-C213 and TMC114-C202.
Table 25: Demographic and Baseline Characteristics of Subjects in the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis) Median number of resistance-associated Johnson VA, Brun-Vezinet F, Clotet B, et al. Table 26: Outcomes of Randomized Treatment Through Week 96 of the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis) In the pooled trials TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. TMC114-C212 Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received PREZISTA tablets with either ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.
Eighty patients were randomized and received at least one dose of PREZISTA/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.
Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ≥100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI. Seventy-seven pediatric subjects (96%) completed the 24-week period.
Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation. The mean increase in CD4+ cell count from baseline was 117 cells/mm 3.
TMC114-C228 Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received PREZISTA oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of PREZISTA/ritonavir. Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL.
Twenty subjects (95%) completed the 48 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir. The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%.
The mean increase in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 187 × 10 6 cells/L. TMC114-C230 Treatment-naïve pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of PREZISTA/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.
All subjects completed the 48 week treatment period. The mean increase in CD4+ cell count from baseline was 221 × 10 6 cells/L.
| PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N=343 | lopinavir/ritonavir 800/200 mg per day + TDF/FTC N=346 | |
|---|---|---|
| FTC=emtricitabine; TDF=tenofovir disoproxil fumarate | ||
| Demographic characteristics | ||
| Median age (years) (range, years) | 34 (18–70) | 33 (19–68) |
| Sex | ||
| Male | 70% | 70% |
| Female | 30% | 30% |
| Race | ||
| White | 40% | 45% |
| Black | 23% | 21% |
| Hispanic | 23% | 22% |
| Asian | 13% | 11% |
| Baseline characteristics | ||
| Mean baseline plasma HIV-1 RNA (log 10 copies/mL) | 4.86 | 4.84 |
| Median baseline CD4+ cell count (cells/mm 3 ) (range, cells/mm 3 ) | 228 (4–750) | 218 (2–714) |
| Percentage of patients with baseline viral load ≥100,000 copies/mL | 34% | 35% |
| Percentage of patients with baseline CD4+ cell count <200 cells/mm 3 | 41% | 43% |
| PREZISTA/ritonavir 800/100 mg once daily + TDF/FTC N=343 | lopinavir/ritonavir 800/200 mg per day + TDF/FTC N=346 | |
|---|---|---|
| N = total number of subjects with data; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate | ||
| Virologic success HIV-1 RNA <50 copies/mL | 70% 95% CI: 1.9; 16.1 | 61% |
| Virologic failure Includes patients who discontinued prior to Week 192 for lack or loss of efficacy and patients who are ≥50 copies in the 192-week window and patients who had a change in their background regimen that was not permitted by the protocol. | 12% | 15% |
| No virologic data at Week 192 window Window 186–198 Weeks. | ||
| Reasons | ||
| Discontinued trial due to adverse event or death Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. | 5% | 13% |
| Discontinued trial for other reasons Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL. | 13% | 12% |
| Missing data during window but on trial | <1% | 0% |
| PREZISTA/ritonavir 800/100 mg once daily + OBR N=294 | PREZISTA/ritonavir 600/100 mg twice daily + OBR N=296 | |
|---|---|---|
| OBR=optimized background regimen | ||
| Demographic characteristics | ||
| Median age (years) (range, years) | 40 (18–70) | 40 (18–77) |
| Sex | ||
| Male | 61% | 67% |
| Female | 39% | 33% |
| Race | ||
| White | 35% | 37% |
| Black | 28% | 24% |
| Hispanic | 16% | 20% |
| Asian | 16% | 14% |
| Baseline characteristics | ||
| Mean baseline plasma HIV-1 RNA (log 10 copies/mL) | 4.19 | 4.13 |
| Median baseline CD4+ cell count (cells/mm 3 ) (range, cells/mm 3 ) | 219 (24–1306) | 236 (44–864) |
| Percentage of patients with baseline viral load ≥100,000 copies/mL | 13% | 11% |
| Percentage of patients with baseline CD4+ cell count <200 cells/mm 3 | 43% | 39% |
| Median darunavir fold change (range) Based on phenotype (Antivirogram ®). | 0.50 (0.1–1.8) | 0.50 (0.1–1.9) |
| Median number of resistance-associated Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: December 2008. Top HIV Med 2008; 16(5): 138–145.: | ||
| PI mutations | 3 | 4 |
| NNRTI mutations | 2 | 1 |
| NRTI mutations | 1 | 1 |
| Percentage of subjects susceptible to all available PIs at baseline | 88% | 86% |
| Percentage of subjects with number of baseline primary protease inhibitor mutations: | ||
| 0 | 84% | 84% |
| 1 | 8% | 9% |
| 2 | 5% | 4% |
| ≥3 | 3% | 2% |
| Median number of ARVs previously used Only counting ARVs, excluding low-dose ritonavir.: | ||
| NRTIs | 3 | 3 |
| NNRTIs | 1 | 1 |
| PIs (excluding low-dose ritonavir) | 1 | 1 |
| PREZISTA/ritonavir 800/100 mg once daily + OBR N=294 | PREZISTA/ritonavir 600/100 mg twice daily + OBR N=296 | |
|---|---|---|
| N = total number of subjects with data; OBR=optimized background regimen | ||
| Virologic success HIV-1 RNA <50 copies/mL | 69% | 69% |
| Virologic failure Includes patients who discontinued prior to Week 48 for lack or loss of efficacy, patients who are ≥50 copies in the 48-week window, patients who had a change in their background regimen that was not permitted in the protocol (provided the switch occurred before the earliest onset of an AE leading to permanent stop of trial medication) and patients who discontinued for reasons other than AEs/death and lack or loss of efficacy (provided their last available viral load was detectable (HIV RNA ≥50 copies/mL). | 26% | 23% |
| No virologic data at Week 48 window Window 42–54 Weeks | ||
| Reasons | ||
| Discontinued trial due to adverse event or death Patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. | 3% | 4% |
| Discontinued trial for other reasons Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL. | 2% | 3% |
| Missing data during window but on trial | 0% | <1% |
| PREZISTA/ritonavir 600/100 mg twice daily + OBR N=298 | lopinavir/ritonavir 400/100 mg twice daily + OBR N=297 | |
|---|---|---|
| OBR=optimized background regimen | ||
| Demographic characteristics | ||
| Median age (years) (range, years) | 40 (18–68) | 41 (22–76) |
| Sex | ||
| Male | 77% | 81% |
| Female | 23% | 19% |
| Race | ||
| White | 54% | 57% |
| Black | 18% | 17% |
| Hispanic | 15% | 15% |
| Asian | 9% | 9% |
| Baseline characteristics | ||
| Mean baseline plasma HIV-1 RNA (log 10 copies/mL) | 4.33 | 4.28 |
| Median baseline CD4+ cell count (cells/mm 3 ) (range, cells/mm 3 ) | 235 (3–831) | 230 (2–1096) |
| Percentage of patients with baseline viral load ≥100,000 copies/mL | 19% | 17% |
| Percentage of patients with baseline CD4+ cell count <200 cells/mm 3 | 40% | 40% |
| Median darunavir fold change (range) | 0.60 (0.10–37.40) | 0.60 (0.1–43.8) |
| Median lopinavir fold change (range) | 0.70 (0.40–74.40) | 0.80 (0.30–74.50) |
| Median number of resistance-associated Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125–130.: | ||
| PI mutations | 4 | 4 |
| NNRTI mutations | 1 | 1 |
| NRTI mutations | 2 | 2 |
| Percentage of subjects with number of baseline primary protease inhibitor mutations: | ||
| ≤1 | 78% | 80% |
| 2 | 8% | 9% |
| ≥3 | 13% | 11% |
| Median number of ARVs previously used Only counting ARVs, excluding low-dose ritonavir.: | ||
| NRTIs | 4 | 4 |
| NNRTIs | 1 | 1 |
| PIs (excluding low-dose ritonavir) | 1 | 1 |
| Percentage of subjects resistant Based on phenotype (Antivirogram ®). to all available Commercially available PIs at the time of trial enrollment. PIs at baseline, excluding darunavir | 2% | 3% |
| PREZISTA/ritonavir 600/100 mg twice daily + OBR N=298 | lopinavir/ritonavir 400/100 mg twice daily + OBR N=297 | |
|---|---|---|
| N = total number of subjects with data; OBR=optimized background regimen | ||
| Virologic success HIV-1 RNA <50 copies/mL | 58% | 52% |
| Virologic failure Includes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are ≥50 copies in the 96-week window and patients who had a change in their OBR that was not permitted by the protocol. | 26% | 33% |
| No virologic data at Week 96 window Window 90–102 Weeks. | ||
| Reasons | ||
| Discontinued trial due to adverse event or death Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. | 7% | 8% |
| Discontinued trial for other reasons Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL. | 8% | 7% |
| Missing data during window but on trial | 1% | <1% |
| PREZISTA/ritonavir 600/100 mg twice daily + OBR | Comparator PI(s) + OBR | |
|---|---|---|
| N=131 | N=124 | |
| OBR=optimized background regimen | ||
| Demographic characteristics | ||
| Median age (years) (range, years) | 43 (27–73) | 44 (25–65) |
| Sex | ||
| Male | 89% | 88% |
| Female | 11% | 12% |
| Race | ||
| White | 81% | 73% |
| Black | 10% | 15% |
| Hispanic | 7% | 8% |
| Baseline characteristics | ||
| Mean baseline plasma HIV-1 RNA (log 10 copies/mL) | 4.61 | 4.49 |
| Median baseline CD4+ cell count (cells/mm 3 ) (range, cells/mm 3 ) | 153 (3–776) | 163 (3–1274) |
| Percentage of patients with baseline viral load >100,000 copies/mL | 24% | 29% |
| Percentage of patients with baseline CD4+ cell count <200 cells/mm 3 | 67% | 58% |
| Median darunavir fold change | 4.3 | 3.3 |
| Median number of resistance-associated Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125–130.: | ||
| PI mutations | 12 | 12 |
| NNRTI mutations | 1 | 1 |
| NRTI mutations | 5 | 5 |
| Percentage of subjects with number of baseline primary protease inhibitor mutations: | ||
| ≤1 | 8% | 9% |
| 2 | 22% | 21% |
| ≥3 | 70% | 70% |
| Median number of ARVs previously used Based on phenotype (Antivirogram ®).: | ||
| NRTIs | 6 | 6 |
| NNRTIs | 1 | 1 |
| PIs (excluding low-dose ritonavir) | 5 | 5 |
| Percentage of subjects resistant to all available Commercially available PIs at the time of trial enrollment. PIs at baseline, excluding tipranavir and darunavir | 63% | 61% |
| Percentage of subjects with prior use of enfuvirtide | 20% | 17% |
| Randomized trials TMC114-C213 and TMC114-C202 | ||
|---|---|---|
| PREZISTA/ritonavir 600/100 mg twice daily + OBR | Comparator PI(s) + OBR | |
| N=131 | N=124 | |
| OBR=optimized background regimen | ||
| Virologic responders confirmed at least 1 log 10 HIV-1 RNA below baseline through Week 96 (<50 copies/mL at Week 96) | 57% (39%) | 10% (9%) |
| Virologic failures | 29% | 80% |
| Lack of initial response Subjects who did not achieve at least a confirmed 0.5 log 10 HIV-1 RNA drop from baseline at Week 12. | 8% | 53% |
| Rebounder Subjects with an initial response (confirmed 1 log 10 drop in viral load), but without a confirmed 1 log 10 drop in viral load at Week 96. | 17% | 19% |
| Never suppressed Subjects who never reached a confirmed 1 log 10 drop in viral load before Week 96. | 4% | 8% |
| Death or discontinuation due to adverse events | 9% | 3% |
| Discontinuation due to other reasons | 5% | 7% |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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