June 29, 2016
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Prezista

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Prezista




Side Effects
Interactions

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 postmarketing 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-Nave 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-nave 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-nave 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-Nave HIV-1-Infected Adult Subjects

System Organ Class, Preferred Term, % Randomized Study TMC114-C211
PREZISTA/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-nave 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-nave 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-Nave HIV-1-Infected 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
PREZIS TA/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. 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-nave 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%), 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%), 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 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, acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms 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, 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).

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).

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 When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
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.
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%.
Anticoagulant: apixaban, dabigatran etexilate, ↑ anticoagulant Concomitant use of apixaban and PREZISTA/ritonavir is not recommended.
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.
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
Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: Selective Serotonin Reuptake Inhibitors (SSRIs): paroxetine, sertraline ↓ paroxetine
↓ sertraline
If either sertraline or paroxetine is initated 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 darunavir/ritonavir unless an assessment comparing predicted benefit to risk ratio justifies the use of voriconazole.
Anti-gout: colchicine ↑ colchicine Treatment of sout-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).
Co-administration of PREZISTA/ritonavir with colchicine in patients with renal or hepatic impairment is CONTRAINDICATED.
Antimalarials: 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.
Antimycobacterial: rifabutin The reference regimen for rifabutin was 300 mg once daily rifapentine ↑ darunavir
↑ rifabutin
↑ 25-Odesacetylrifabutin
↓ darunavir
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. Co-administration of PREZISTA/ritonavir with rifapentine is not recommended.
Antineoplastics:
dasatinib
nilotinib
vinblastine
vincristine
↑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. 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: quetiapine e.g. risperidone, thioridazine ↑ 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.
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.
Corticosteroid (systemic): dexamethasone
Corticosteroid (systemic): metabolized by CYP3A e.g. budesonide
prednisolone
↓ darunavir
↑ corticosteroid
Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Concomitant use of corticosteroids metabolized by CYP3A may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Alternatives should be considered, particularly for long-term use.
Corticosteroid (inhaled/nasal): budesonide, fluticasone ↑ corticosteroid Alternatives should be considered, particularly for long-term 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
simeprevir
↓ darunavir
↓ boceprevir
↓ telaprevir
↑ simeprevir
↑ darunavir
Co-administration of boceprevir or telaprevir and PREZISTA/ritonavir is not recommended.
Co-administration of darunavir/ritonavir and simeprevir is not recommended
HMG-CoA Reductase Inhibitors: 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/neoplastic: everolimus ↑immunosuppressants Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. 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 Analgesic/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone ↔ buprenorphine,
naloxone
↑ norbuprenorphine
(metabolite)
↓ 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. 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.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone ↓ ethinyl estradiol
↓ norethindrone
Alternative methods of nonhormonal contraception are recommended.
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):
  • Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see CONTRAINDICATIONS].
  • 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.
Sedatives/Hypnotics: Metabolized by CYP3A e.g. buspirone, diazepam, estazolam, parenterally administered midazolam, zoldipem ↑sedatives/hypnotics Titration is recommended when coadministering PREZISTA/ritonavir with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for adverse events.
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. Co-administration of oral midazolam or triazolam with PREZISTA/ritonavir is CONTRAINDICATED.

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, and rilpivirine. Using cross-trial comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of darunavir. Darunavir/ritonavir had no clinically significant effect on the pharmacokinetics of dolutegravir. Pitavastatin had no clinically significant effect on the pharmacokinetics of darunavir/ritonavir.

Acid modifying medications are not predicted to alter darunavir exposure.

Other Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Based on the different elimination pathways of the other NRTIs (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine) 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.

Integrase Strand Transfer Inhibitors

No dose adjustments are needed for either raltegravir or darunavir based on pharmacokinetic data from literature references. Please refer to the elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate U.S. prescribing information for information regarding concomitant use with other antiretroviral medications.

Read the Prezista Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/4/2016

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