Prezista
SIDE EFFECTS
The safety assessment is based on all safety data from the Studies TMC114-C213 and TMC114- C202 and the TMC114-C215/C208 analysis reported with the recommended dose PREZISTA/rtv 600/100 mg b.i.d. in the 458 subjects who initiated treatment with the recommended dose (de novo subjects). In Studies TMC114-C213 and TMC114-C202, the mean exposure in weeks for subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and comparator PI arm was 63.5 and 31.5, respectively. The mean exposure in weeks for subjects in the TMC114- C215/C208 analysis was 23.9.
The most common treatment-emergent adverse events (> 10%) reported in the de novo subjects, regardless of causality or frequency, were diarrhea, nausea, headache, and nasopharyngitis.
For subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and the comparator PI arm in the pooled analysis for Studies TMC114-C213 and TMC114-C202, diarrhea was reported in 19.8% and 28.2%, nausea in 18.3% and 12.9%, headache in 15.3% and 20.2%, and nasopharyngitis in 13.7% and 10.5%, of subjects, respectively. In the randomized trials, rates of discontinuation of therapy due to adverse events were 9% in subjects receiving PREZISTA/rtv and in 5% of subjects in the comparator PI arm.
Due to the need for co-administration of PREZISTA with 100 mg of ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.
Drug-related clinical adverse events of moderate or severe intensity (≥ Grade 2) occurring in ≥ 2% of subjects treated with PREZISTA/rtv for 1 to 96 weeks are presented in Table 12.
Table 12: Percentage of Subjects with Selected Treatment
Emergent, Drug-Related^ Adverse Events of at least Moderate Intensity (Grades
2-4) in ≥ 2% of Adult Subjects in Any PREZISTA/rtv Treatment Groups†
| System Organ Class, Preferred Term, % |
Randomized Studies TMC114-C213 and TMC114-C202 |
Non-randomized TMC114-C215/C208 Analysis |
|
| PREZISTA/rtv 600/100 mg b.i.d. +OBR N = 131 |
Comparator PI +OBR N = 124 |
PREZISTA/rtv 600/100 mg b.i.d. +OBR N = 327 |
|
| Gastrointestinal Disorders | |||
| Diarrhea | 2.3% | 3.2% | 2.8% |
| Vomiting | 1.5% | 1.6% | 2.4% |
| Abdominal Pain | 2.3% | 0.8% | 1.2% |
| Constipation | 2.3% | 0.8% | 0.6% |
| Nervous System Disorders | |||
| Headache | 3.8% | 2.4% | 0.9% |
| ^ Includes adverse events at least possibly, probably, or
very likely related to the drug N=total number of subjects per treatment group † Excludes laboratory abnormalities that were reported as Adverse Events (see Table 13: Treatment Emergent Grade 2 to 4 Laboratory Abnormalities Reported in ≥ 2% of Subjects) |
|||
Treatment-emergent adverse events occurring in less than 2% of de novo subjects (n=458) receiving PREZISTA/rtv, considered at least possibly related to treatment and of at least moderate intensity are listed below by body system:
Body as a Whole: folliculitis, asthenia, pyrexia, fatigue, rigors, hyperthermia, peripheral edema
Cardiovascular System: myocardial infarction, tachycardia, hypertension
Digestive System: flatulence, abdominal distension, dry mouth, dyspepsia, abdominal pain, nausea, constipation
Metabolic and Nutritional Disorders: anorexia, hypercholesterolemia, hyperlipidemia, diabetes mellitus, decreased appetite, obesity, fat redistribution, hyponatremia, polydipsia
Musculoskeletal System: arthralgia, pain in extremity, myalgia, osteopenia, osteoporosis
Nervous System: peripheral neuropathy, hypoesthesia, memory impairment, paresthesia, somnolence, transient ischemic attack, confusional state, disorientation, irritability, altered mood, nightmare, anxiety, headache
Respiratory System: dyspnea, cough, hiccups
Skin and Appendages: lipoatrophy, night sweats, allergic dermatitis, eczema, toxic skin eruption, alopecia, dermatitis medicamentosa, hyperhidrosis, skin inflammation, maculopapular rash
Special Senses: vertigo
Urogenital System: acute renal failure, renal insufficiency, nephrolothiasis, polyuria, gynecomastia
Laboratory abnormalities: The percentages of adult subjects treated with PREZISTA/rtv 600/100 mg b.i.d. with treatment- emergent Grade 2 to 4 laboratory abnormalities are presented in Table 13.
Table 13: Treatment Emergent Grade 2 to 4 Laboratory Abnormalities
Reported in ≥ 2% of Subjects
| Randomized Studies TMC114-C213 and TMC114-C202 |
Non- randomized TMC114- C215/C208 Analysis |
|||
| Laboratory Parameter Preferred Term, % |
Limit | PREZISTA/ rtv 600/100 mg b.i.d. + OBR N = 131 |
Comparator PI + OBR N = 124 |
PREZISTA/ rtv 600/100 mg b.i.d. N = 327 |
| Biochemistry | ||||
| Aspartate Aminotransferase | > 2.5 X ULN | 10.0% | 13.0% | 5.3% |
| Alanine Aminotransferase | > 2.5 X ULN | 6.9% | 9.8% | 5.6% |
| Gamma Glutamyl Transferase | > 2.5 X ULN | 9.2% | 8.9% | 8.4% |
| Hyperbilirubinemia | > 1.5 X ULN | 2.3% | 15.4% | 0.9% |
| Alkaline Phosphatase | > 2.5 X ULN | 4.6% | 0% | 2.8% |
| Pancreatic Amylase | > 1.5 X ULN | 16.9% | 8.9% | 10.8% |
| Pancreatic Lipase | > 1.5 X ULN | 8.5% | 4.1% | 6.2% |
| Hyperglycemia | ≥ 161 mg/dL | 2.3% | 8.1% | 5.9% |
| Hypoglycemia | ≤ 54 mg/dL | 1.5% | 1.6% | 3.7% |
| Total Cholesterol | ≥ 240 mg/dL | 9.2% | 3.3% | 8.0% |
| Triglycerides | > 400 mg/dL | 25.4% | 26.0% | 18.9% |
| Hypoalbuminemia | < 3 g/dL | 3.1% | 1.6% | 4.3% |
| Hyperuricemia | ≥ 9.9 mg/dL | 6.9% | 6.5% | 2.2% |
| Bicarbonate | < 15 mmol/L | 3.1% | 4.1% | 3.4% |
| Hypocalcemia | ≤ 7.8 mg/dL | 0% | 0.8% | 4.0% |
| Hyponatremia | ≤ 129 meq/L | 0.8% | 0% | 2.5% |
| Hypernatremia | ≥ 151 meq/L | 2.3% | 0% | 0% |
| Hematology | ||||
| White Blood Cell Count decrease | < 3000 count/mm3 | 15.4% | 18.7% | 13.0% |
| Total Absolute Neutrophil Count decrease | ≤ 999 mm3 | 6.9% | 9.8% | 11.5% |
| Lymphocytes decrease | < 1000 count/mm3 | 4.6% | 19.5% | 10.9% |
| Partial Thromboplastin Time increase | > 1.66 X ULN | 7.8% | 4.1% | 4.3% |
| Plasma Prothrombin Time increase | > 1.25 X ULN | 3.9% | 0.8% | 0.6% |
| Platelet Count decrease | < 75,000/mm3 | 3.1% | 1.6% | 2.8% |
Additional adverse reactions identified in clinical studies, occurring in less than 1% of the patients, are listed below by body system:
Hepatobiliary System: acute hepatitis, cytolytic hepatitis, hepatotoxicity, hyperbilirubinemia
Skin and Appendages: erythema multiforme, Stevens-Johnson Syndrome
Patients co-infected with hepatitis B and/or hepatitis C virus:
In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes (see WARNINGS, Hepatotoxicity). The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.
DRUG INTERACTIONS
PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Tables 10 and 11).
Drugs that are contraindicated and not recommended for co-administration with PREZISTA/rtv are included in Table 10. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Table 10: Drugs That Should Not Be Co-administered With PREZISTA/rtv
| Drug Class: Drug Name | Clinical Comment |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with phenobarbital, phenytoin, or carbamazepine as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
| Antihistamines: astemizole,terfenadine |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin |
Rifampin is a potent inducer of CYP450 metabolism. PREZISTA/rtv 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. |
| Ergot Derivatives: dihydroergotamine, ergonovine,ergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Gastrointestinal Motility Agent: cisapride |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Herbal Products: St. John's wort (Hypericum perforatum) |
PREZISTA/rtv should not be used concomitantly with products containing St. John's wort (Hypericum perforatum) because co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
| HMG-CoA Reductase Inhibitors: lovastatin,simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.For dosing recommendation regarding atorvastatin and pravastatin, 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. |
| Neuroleptic: pimozide |
CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Sedative/Hypnotics: midazolam,triazolam |
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
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 4 and 5)
| Concomitant DrugClass: Drug Name |
Effect on Concentration of Darunaviror Concomitant Drug |
Clinical Comment |
| HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| Efavirenz | ↓ darunavir ↑ efavirenz |
Co-administration of darunavir/rtv and efavirenz decreased darunavir AUC by 13% and Cmin by 31%. The AUC of efavirenz increased by 21% and Cmin increased by 17%. The clinical significance has not been established. The combination of PREZISTA/rtv and efavirenz should be used with caution. |
| Nevirapine | ↔ darunavir ↑ nevirapine |
PREZISTA/rtv and nevirapine can be co- administered without any dose adjustments. |
| HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
| Didanosine | ↔ darunavir ↔ didanosine |
PREZISTA/rtv (600/100 mg b.i.d.) did not significantly affect didanosine exposure. The combination of PREZISTA co-administered with 100 mg ritonavir and didanosine can be used without dose adjustments. It is recommended that didanosine be administered on an empty stomach. Therefore, didanosine should be administered one hour before or two hours after PREZISTA/rtv (which are administered with food). |
| Tenofovir Disoproxil Fumarate | ↔ darunavir ↑ tenofovir |
PREZISTA/rtv and tenofovir |
| disoproxil fumarate can be co-administered without any dose adjustments. | ||
| HIV-Antiviral Agents: HIV-Protease Inhibitors (PIs) | ||
| Atazanavir (The reference regimen for atazanavir wasatazanavir/ritonavir 300/100 mg q.d.) |
↔ darunavir ↔ atazanavir |
PREZISTA/rtv and atazanavir (300 mg q.d.) can be co-administered. |
| Indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg b.i.d.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/rtv has not been established. |
| Lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Due to decrease in the exposure (AUC) of darunavir, appropriate doses of the combination have not been established. Hence, it is not recommended to co- administer lopinavir/ritonavir and PREZISTA, with or without an additional low- dose of ritonavir. |
| Saquinavir | ↓ darunavir ↔ saquinavir |
Due to a decrease in the exposure (AUC) of darunavir by 26%, appropriate doses of the combination have not been established. Hence, it is not recommended to co- administer saquinavir and PREZISTA, with or without low-dose ritonavir. |
| Other Agents | ||
| Antiarrhythmics: bepridil,lidocaine (systemic), quinidine, amiodarone |
↑ antiarrhythmics | Concentrations of bepridil, lidocaine, quinidine and amiodarone may be increased when co-administered with PREZISTA/rtv. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co- administered with PREZISTA/rtv. |
| digoxin | ↑ digoxin | Concomitant use of PREZISTA/rtv with digoxin results in a significant increase in serum concentrations of digoxin. It is recommended that 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 may be affected when co- administered with PREZISTA/rtv. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/rtv. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and PREZISTA/rtv may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A inhibitor such as PREZISTA/rtv, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | No dose adjustment of darunavir or clarithromycin is required for patients
with normal renal function. For 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 ofclarithromycin should be reduced by 75%. |
| 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 ofdarunavir/ritonavir. When co- administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. Co-administration of voriconazole with darunavir/ritonavir has not been studied. Administration of voriconazole with ritonavir (100 mg twice daily) decreased the AUC of voriconazole by an average of 39%. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. |
| Antimycobacterial: rifabutin |
↑ rifabutin ↓ darunavir |
Rifabutin is an inducer and substrate of CYP450 enzymes. Concomitant use of rifabutin and darunavir in the presence of ritonavir is expected to increase rifabutin plasma concentrations and decrease darunavir plasma concentrations. When indicated, it is recommended to administer rifabutin at a dosage of 150 mg once every other day when co- administered with PREZISTA/rtv. |
| Calcium Channel Blockers: felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g. felodipine, nifedipine, nicardipine) may increase when PREZISTA/rtv are co- administered. Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: dexamethasone fluticasone propionate |
↓ darunavir ↑ fluticasone propionate |
Use with caution. Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. Concomitant use of inhaled fluticasone propionate and PREZISTA/rtv may increase plasma concentrations of fluticasone propionate. Alternatives should be considered, particularly for long term use. |
| HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
When PREZISTA/rtv was administered with pravastatin, the mean increase in pravastatin AUC was 81%. However, pravastatin AUC increased by up to 5-fold in some subjects. The mechanism of the interaction is not known. |
| Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/rtv. | ||
| H2-Receptor Antagonists and Proton Pump Inhibitors: omeprazole, ranitidine |
↔ darunavir | PREZISTA/rtv can be co- administered with H2- receptor antagonists and proton pump inhibitors without any dose adjustments. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/rtv. Therapeutic concentration monitoring of the immunosuppressive agent is recommended for immunosuppressant agents when co-administered with PREZISTA/rtv. |
| Narcotic Analgesic: methadone |
↓ methadone | No adjustment of methadone dosage is required when initiating coadministration of PREZISTA/rtv. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
| 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 | Concomitant use of PDE-5 inhibitors with PREZISTA/rtv should be done with caution. If concomitant use of PREZISTA/rtv with sildenafil, vardenafil, or tadalafil is required, 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, is recommended. |
| Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/rtv, 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/rtv should be monitored for antidepressant response. |
Other 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/rtv.
Other protease inhibitors:
The co-administration of PREZISTA/rtv and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.
Generic Name: Darunavir
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