Prezista
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Prezista
SIDE EFFECTS
The overall safety profile of PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.
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.
Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.
Clinical Trials Experience: Treatment-Naïve Adults
Study 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* of at Least Moderate Intensity ( ≥
Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Naïve
HIV-1-Infected Adult Subjects
| System Organ Class, Preferred Term, % | Randomized Study TMC114-C211 | |
| PREZIS TA/ritonavir 800/100 mg once daily + TDF/FTC N = 343 |
lopinavir/ritonavir 800/200 mg per day + TDF/FTC N = 346 |
|
| 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% |
| N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine * Excluding laboratory abnormalities reported as ADRs |
||
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-1Infected Adult Subjects*
| Laboratory Parameter Preferred Term, % | Limit | Randomized Study TMC114-C211 | |
| PREZISTA/ ritonavir 800/100 mg once daily + TDF/FTC | lopinavir/ ritonavir 800/200 mg per day + TDF/FTC | ||
| Biochemistry | |||
| Alanine Aminotransferase | |||
| Grade 2 | > 2.5 to ≤ 5.0 X ULN | 9% | 9% |
| Grade 3 | > 5.0 to ≤ 10.0 X ULN | 3% | 3% |
| Grade 4 | > 10.0 X ULN | < 1% | 3% |
| Aspartate Aminotransferase | |||
| Grade 2 | > 2.5 to ≤ 5.0 X ULN | 7% | 10% |
| Grade 3 | > 5.0 to ≤ 10.0 X ULN | 4% | 2% |
| Grade 4 | > 10.0 X ULN | 1% | 3% |
| Alkaline Phosphatase | |||
| Grade 2 | > 2.5 to ≤ 5.0 X ULN | 1% | 1% |
| Grade 3 | > 5.0 to ≤ 10.0 X ULN | 0% | < 1% |
| Grade 4 | > 10.0 X ULN | 0% | 0% |
| Hyperbilirubinemia | |||
| Grade 2 | > 1.5 to ≤ 2.5 X ULN | < 1% | 5% |
| Grade 3 | > 2.5 to ≤ 5.0 X ULN | < 1% | < 1% |
| Grade 4 | > 5.0 X 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 X ULN | 3% | 2% |
| Grade 3 | > 3.0 to ≤ 5.0 X ULN | < 1% | 1% |
| Grade 4 | > 5.0 X ULN | 0% | < 1% |
| Pancreatic Amylase | |||
| Grade 2 | > 1.5 to ≤ 2.0 X ULN | 5% | 2% |
| Grade 3 | > 2.0 to ≤ 5.0 X ULN | 5% | 4% |
| Grade 4 | > 5.0 X ULN | 0% | < 1% |
| N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine * Grade 4 data not applicable in Division of AIDS grading scale. |
|||
Clinical Trials Experience: Treatment-Experienced Adults
Study 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* of at Least Moderate Intensity ( ≥
Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Experienced
HIV-1-Infected Adult Subjects
| System Organ Class, Preferred Term, % | Randomized Study TMC114-C214 | |
| PREZISTA/ ritonavir 600/100 mg twice daily + OBR N = 298 |
lopinavir/ ritonavir 400/100 mg twice daily + OBR N = 297 |
|
| 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% |
| N=total number of subjects per treatment group OBR =
optimized background regimen * Excluding laboratory abnormalities reported as ADRs |
||
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*
| Laboratory Parameter Preferred Term, % | Limit | Randomized Study TMC114-C214 | |
| PREZISTA/ ritonavir 600/100 mg twice daily + OBR | lopinavir/ ritonavir 400/100 mg twice daily + OBR | ||
| Biochemistry | |||
| Alanine Aminotransferase | |||
| Grade 2 | > 2.5 to ≤ 5.0 X ULN | 7% | 5% |
| Grade 3 | > 5.0 to ≤ 10.0 X ULN | 2% | 2% |
| Grade 4 | > 10.0 X ULN | 1% | 2% |
| Aspartate Aminotransferase | |||
| Grade 2 | > 2.5 to ≤ 5.0 X ULN | 6% | 6% |
| Grade 3 | > 5.0 to ≤ 10.0 X ULN | 2% | 2% |
| Grade 4 | > 10.0 X ULN | < 1% | 2% |
| Alkaline Phosphatase | |||
| Grade 2 | > 2.5 to ≤ 5.0 X ULN | < 1% | 0% |
| Grade 3 | > 5.0 to ≤ 10.0 X ULN | < 1% | < 1% |
| Grade 4 | > 10.0 X ULN | 0% | 0% |
| Hyperbilirubinemia | |||
| Grade 2 | > 1.5 to ≤ 2.5 X ULN | < 1% | 2% |
| Grade 3 | > 2.5 to ≤ 5.0 X ULN | < 1% | < 1% |
| Grade 4 | > 5.0 X 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 X ULN | 3% | 4% |
| Grade 3 | > 3.0 to ≤ 5.0 X ULN | 2% | < 1% |
| Grade 4 | > 5.0 X ULN | < 1% | 0% |
| Pancreatic Amylase | |||
| Grade 2 | > 1.5 to ≤ 2.0 X ULN | 6% | 7% |
| Grade 3 | > 2.0 to ≤ 5.0 X ULN | 7% | 3% |
| Grade 4 | > 5.0 X ULN | 0% | 0% |
| N=total number of subjects per treatment group OBR =
optimized background regimen * Grade 4 data not applicable in Division of AIDS grading scale |
|||
Serious ADRs
The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b studies and Phase 3 studies 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]. 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 II trials. TMC114C212, 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 and Clinical Studies].
Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults.
Study TMC114-C212
Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), reported as ADRs, 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%).
Study 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 study.
Study TMC114-C230
Clinical ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), excluding reported as ADRs, were vomiting (33%), nausea (25%), diarrhea (16.7%), abdominal pain (8.3%), decreased appetite (8.3%), prurirtus (8.3%), and rash (8.3%).
There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.
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 and acute generalized exanthematous pustulosis have been reported rarely [see WARNINGS AND PRECAUTIONS].
Read the Prezista (darunavir) Side Effects Center for a complete guide to possible side effects »
DRUG INTERACTIONS
See also CONTRAINDICATIONS and CLINICAL PHARMACOLOGY.
Potential for PREZISTA/ritonavir to Affect Other Drugs
PREZISTA co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 11).
Potential for Other Drugs to Affect Darunavir
Darunavir and ritonavir are metabolized by CYP3A. 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 may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 11).
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.
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 CLINICAL
PHARMACOLOGY for Magnitude of Interaction, Tables 14 and 15]
| 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 (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) | ↑darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| 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. |
| HIV-1-Antiviral Agents: CCR5 co-receptor antagonists | ||
| maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
| Other Agents | ||
| Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone | ↑antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and 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. |
| Anticoagulant: 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. |
| Anticonvulsant: carbamazepine | ↔darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
| Anticonvulsant: phenobarbital, phenytoin | ↔darunavir ↑phenytoin ↑phenobarbital |
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
| Antidepressant: trazodone, desipramine | ↑ trazodone ↑desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered. |
| Anti-infective: clarithromycin | ↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
| Antifungals: ketoconazole, itraconazole, voriconazole | ↑ketoconazole ↑darunavir ↑itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. |
| Anti-gout:colchicine | ↑colchicine | Treatment of eout-flares - co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of sout-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). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
| Antimalarials: artemether/lumefantrine | ↓artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir |
The combination of PREZISTA 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. |
| Antimycobacterial: 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. |
| β-Blockers: metoprolol, timolol | ↑beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
| Benzodiazepines: parenterally administered midazolam | ↑midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration 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. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
| Calcium Channel Blockers: felodipine, nifedipine, nicardipine | ↑calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: Systemic: dexamethasone | ↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
| Corticosteroid: Inhaled/Nasal: fluticasone | ↑fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for longterm use. |
| Endothelin receptor antagonists: 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 Agents: NS3-4A protease inhibitors: boceprevir telaprevir | ↓ darunavir ↓ boceprevir ↓ telaprevir |
Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir. |
| HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin | ↑pravastatin ↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus | ↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
| Inhaled beta agonist: salmeterol | ↑ salmeterol | Concurrent 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 Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone | ↓ methadone ↔buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
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. 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. |
| Neuroleptics: risperidone, thioridazine | ↑neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
| Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone | ↓ ethinyl estradiol ↓norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
| PDE-5 inhibitors: sildenafil, vardenafil, tadalafil | ↑ 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):
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. |
| Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine | ↔darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
In addition to the drugs included in Table 11, the interaction between PREZISTA/ritonavir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see CLINICAL PHARMACOLOGY]: atazanavir, efavirenz, etravirine, nevirapine, omeprazole, ranitidine, rilpivirine, and tenofovir disoproxil fumarate.
Other nucleoside reverse transcriptase inhibitors (NRTIs): Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and PREZISTA/ritonavir.
Other PIs: The co-administration of PREZISTA/ritonavir and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.
Last reviewed on RxList: 5/13/2013
This monograph has been modified to include the generic and brand name in many instances.
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