Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 01 September 2017

Indication(s)

1 INDICATIONS AND USAGE 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 [see Use in Specific Populations (8.4) and Clinical Studies (14)] . 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. ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS 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). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed in Table 6 . Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications. 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). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed in Table 6 [see Drug Interactions (7.3)] . Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications. Table 6: Drugs That Are Contraindicated With PREZISTA/ritonavir Drug class Drugs within class that are contraindicated with PREZISTA/ritonavir Clinical comment Alpha 1-adrenoreceptor antagonist alfuzosin Potential for serious and/or life-threatening reactions such as hypotension. Antianginal ranolazine Potential for serious and/or life-threatening reactions. Antiarrhythmic dronedarone Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Anti-gout colchicine Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment. Antimycobacterial rifampin Rifampin is a potent inducer of CYP450 metabolism. PREZISTA/ritonavir should not be used in combination with rifampin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. Antipsychotics lurasidone Potential for serious and/or life-threatening reactions. pimozide Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Ergot derivatives dihydroergotamine, ergotamine, methylergonovine Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agent cisapride Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Sedative/hypnotics Orally administered midazolam, triazolam Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZISTA/ritonavir may cause large increases in the concentrations of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Herbal product St. John's wort ( Hypericum perforatum) Patients taking PREZISTA/ritonavir should not use products containing St. John's wort because co-administration may result in reduced plasma concentrations of darunavir. This may result in loss of therapeutic effect and development of resistance. Hepatitis C direct-acting antiviral elbasvir/grazoprevir Potential for the increased risk of alanine transaminase (ALT) elevations. HMG-CoA reductase inhibitors lovastatin, simvastatin Potential for serious reactions such as myopathy including rhabdomyolysis. For dosing recommendation regarding atorvastatin, pravastatin and rosuvastatin, see Table 11: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction. PDE-5 inhibitor sildenafil for treatment of pulmonary arterial hypertension A safe and effective dose for the treatment of pulmonary arterial hypertension has not been established with PREZISTA/ritonavir. There is an increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). 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). ( 4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of labeling: Hepatotoxicity [see Warnings and Precautions (5.2)] Severe Skin Reactions [see Warnings and Precautions (5.3)] Diabetes Mellitus/Hyperglycemia [see Warnings and Precautions (5.6)] Fat Redistribution [see Warnings and Precautions (5.7)] Immune Reconstitution Syndrome [see Warnings and Precautions (5.8)] Hemophilia [see Warnings and Precautions (5.9)] Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions. The most common clinical adverse drug reactions to PREZISTA/ritonavir (incidence greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain and vomiting. ( 6) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 total mean exposure for subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively. 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 7 and subsequent text below the table. Table 7: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once Daily Excluding laboratory abnormalities reported as ADRs. of at Least Moderate Intensity (≥Grade 2) Occurring in ≥2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Trial TMC114-C211) 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% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving PREZISTA/ritonavir 800/100 mg once daily are listed below by body system: Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence General Disorders and Administration Site Conditions: asthenia Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity) Immune System Disorders: (drug) hypersensitivity, immune reconstitution syndrome Metabolism and Nutrition Disorders: diabetes mellitus Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticaria Laboratory Abnormalities Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with PREZISTA/ritonavir 800/100 mg once daily are presented in Table 8. Table 8: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects Grade 4 data not applicable in Division of AIDS grading scale. (Trial TMC114-C211) 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% Treatment-Experienced Adults: TMC114-C214 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively. 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 9 and subsequent text below the table. Table 9: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 600/100 mg Twice Daily Excluding laboratory abnormalities reported as ADRs of at Least Moderate Intensity (≥Grade 2) Occurring in ≥2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects (Trial TMC114-C214) 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% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving PREZISTA/ritonavir 600/100 mg twice daily are listed below by body system: Gastrointestinal Disorders: acute pancreatitis, flatulence Musculoskeletal and Connective Tissue Disorders: myalgia Psychiatric Disorders: abnormal dreams Skin and Subcutaneous Tissue Disorders: pruritus, urticaria Laboratory Abnormalities Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with PREZISTA/ritonavir 600/100 mg twice daily are presented in Table 10. Table 10: 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) 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% 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 [see Warnings and Precautions (5.2)] . 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. TMC114-C212, in which 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 20 kg were included, TMC114-C228, in which 21 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 6 years of age and weighing at least 10 kg were included, and TMC114-C230 in which 12 antiretroviral treatment-naïve HIV-1 infected pediatric patients aged from 12 to less than 18 years and weighing at least 40 kg were included. The TMC114-C212 and C228 trials evaluated PREZISTA/ritonavir twice daily dosing and the TMC114-C230 trial evaluated PREZISTA/ritonavir once daily dosing [see Use in Specific Populations (8.4) and Clinical Studies (14.4)] . 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 3%), were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%), and fatigue (3%). Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%). TMC114-C228 Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 5%), were diarrhea (24%), vomiting (19%), rash (19%), abdominal pain (5%), and anorexia (5%). There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this trial. TMC114-C230 Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), were vomiting (33%), nausea (25%), diarrhea (16.7%), abdominal pain (8.3%), decreased appetite (8.3%), pruritus (8.3%), and rash (8.3%). There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this trial. 6.2 Postmarketing Experience The following events have been identified during post approval use of PREZISTA. Because these events 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. Redistribution of body fat has been reported. Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) has been reported. In addition, toxic epidermal necrolysis, acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely [see Warnings and Precautions (5.3)] .

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Testing: In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with PREZISTA/ritonavir to assess drug susceptibility of the HIV-1 virus ( 2.1, 12.4) Monitor serum liver chemistry tests before and during therapy with PREZISTA/ritonavir. ( 2.1, 2.2, 5.2) Treatment-naïve adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet) taken with ritonavir 100 mg once daily and with food. ( 2.3) Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. ( 2.3) Pregnant patients: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. ( 2.4) Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of PREZISTA and ritonavir is based on body weight and should not exceed the adult dose. PREZISTA should be taken with ritonavir and with food. ( 2.5) PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment. ( 2.6) 2.1 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 [see Microbiology (12.4)]. Refer to Dosage and Administration (2.3), (2.4) and (2.5) for dosing recommendations. Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with PREZISTA/ritonavir [see Warnings and Precautions (5.2)] . 2.2 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 [see Warnings and Precautions (5.2)] . 2.3 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. Treatment-Naïve Adult Patients The recommended oral dose of PREZISTA is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet or capsule or 1.25 mL of a 80 mg per mL ritonavir oral solution) once daily and with food. 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. Table 1: Recommended PREZISTA/ritonavir Dosage in Treatment-Experienced Adult Patients 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 2.4 Recommended Dosage During Pregnancy 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. 2.5 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. The recommended dose of PREZISTA/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose. 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 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. 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 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) 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 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) 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 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) 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 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) The use of PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended [see Warnings and Precautions (5.10) and Use in Specific Populations (8.4)] . 2.6 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Total darunavir exposures were generally lower during pregnancy compared to postpartum period. The reduction in darunavir exposures during pregnancy were greater for once daily dosing compared to the twice daily dosing regimen. ( 8.1, 12.3) Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2) Pediatrics: Not recommended for patients less than 3 years of age. ( 8.4) 8.1 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 Available limited data from the APR show no difference in rate of overall birth defects for darunavir (2.7%) 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 ) [see Data] . The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. 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 [see Data] . 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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] . 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 34 pregnant women during the second and third trimesters, and postpartum. 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). Virologic response was preserved throughout the trial period in both arms. No mother to child transmission occurred in the infants born to the 29 subjects who stayed on the antiretroviral treatment through delivery. 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 [see Clinical Pharmacology (12.3)] . Based on prospective reports to the APR of 615 live births following exposure to darunavir-containing regimens during pregnancy (including 385 exposed in the first trimester and 230 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir containing regimens and 1.7% (95% CI: 0.5% to 4.4%) 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). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is present in the milk of lactating rats [see Data] . Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving PREZISTA [see Use in Specific Populations (8.4)] . Data Animal Data Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir. 8.3 Females and Males of Reproductive Potential Contraception Use of PREZISTA may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients using combined hormonal contraceptives or the progestin only pill to use an effective alternative contraceptive method or add a barrier method of contraception [see Drug Interactions (7.3)] . 8.4 Pediatric Use PREZISTA/ritonavir is not recommended in pediatric patients below 3 years of age because 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 [see Warnings and Precautions (5.10) , Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)] . 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. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age) [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.4)] . Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.1)] . Refer to Dosage and Administration (2.5) 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) [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.4)] . Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.1)] . 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 [see Clinical Pharmacology (12.3)] . Please see Dosage and Administration (2.5) for once-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg. 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. 8.5 Geriatric Use Clinical studies of PREZISTA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)] . 8.6 Hepatic Impairment No dosage adjustment of PREZISTA/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of PREZISTA/ritonavir in subjects with severe hepatic impairment. Therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)] . 8.7 Renal Impairment Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)] .

Interactions

7 DRUG INTERACTIONS Co-administration of PREZISTA/ritonavir with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of darunavir. The potential drug-drug interactions must be considered prior to and during therapy. ( 4, 5.5, 7, 12.3) 7.1 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 (see Table 11). 7.2 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 11). 7.3 Established and Other Potentially Significant Drug Interactions Table 11 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 [see Contraindications (4) and Clinical Pharmacology (12.3)] . Table 11: 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 (4) for a complete list of contraindicated drugs) [see Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 16 and 17] Concomitant Drug Class Drug Name 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 coadministration with PREZISTA/ritonavir has not been studied, coadministration 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 Antiarrhythmics: For contraindicated antiarrhythmics, [see Contraindications (4)] . 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. 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: apixaban ↑ anticoagulant Concomitant use of apixaban and PREZISTA/ritonavir is not recommended. dabigatran etexilate The combination of PREZISTA/ritonavir and dabigatran etexilate is not recommended in specific renal impairment groups, depending on the indication. Please see the dabigatran US prescribing information for specific recommendations. rivaroxaban Co-administration of PREZISTA/ritonavir and rivaroxaban is not recommended. 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. 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, ketoconazole, posaconazole ↑ darunavir ↑ itraconazole (not studied) ↑ ketoconazole ↔ posaconazole (not studied) Monitor for increased PREZISTA/ritonavir adverse events with concomitant use of itraconazole, ketoconazole, or posaconazole. 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 (not studied) 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 The coadministration of PREZISTA/ritonavir with colchicine in patients with renal or hepatic impairment is contraindicated [see Contraindications (4)] . 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: For contraindicated antimycobacterials, [see Contraindications (4)]. 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: For contraindicated antipsychotics, [see Contraindications (4)]. 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. risperidone, thioridazine ↑ antipsychotics A dose decrease may be needed for these drugs 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. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g. betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↓ darunavir ↑ corticosteroids 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. Co-administration with corticosteroids 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 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. Hepatitis C virus (HCV): Direct-Acting Antivirals: For contraindicated HCV Direct-Acting Antivirals, [see Contraindications (4)] . simeprevir ↑ simeprevir ↑ darunavir Co-administration of PREZISTA/ritonavir and simeprevir is not recommended HMG-CoA reductase inhibitors: For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)]. 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. 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. 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. 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 coadministered. 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. Oral contraceptives/estrogen: ethinyl estradiol, norethindrone ↓ ethinyl estradiol ↓ norethindrone Effective alternative contraceptive method or barrier method of contraception is recommended [see Use in Specific Populations (8.3)] . 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 of PREZISTA/ritonavir and sildenafil for treatment of pulmonary arterial hypertension is contraindicated [see Contraindications (4)] . 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. 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: For contraindicated sedatives/hypnotics, [see Contraindications (4)] . metabolized by CYP3A e.g. buspirone, diazepam, estazolam, zoldipem ↑ 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. 7.4 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, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, or rilpivirine.

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Category Value
Authorisation number NDA021976
Agency product number 33O78XF0BW
Orphan designation No
Product NDC 70518-0689
Date Last Revised 21-08-2017
Type HUMAN PRESCRIPTION DRUG
Storage and handling Storage PREZISTA Oral Suspension Store at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F). Do not refrigerate or freeze. Avoid exposure to excessive heat. Store in the original container. Shake well before each usage. PREZISTA Tablets Store at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F).
Marketing authorisation holder REMEDYREPACK INC.