WARNINGS
ALERT: Find out about medicines that should not be taken with PREZISTA/rtv. This statement is included on the product's bottle label.
General
PREZISTA (darunavir) must be co-administered with ritonavir and food to exert its therapeutic effect (see DOSAGE and ADMINISTRATION). Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect.
Please refer to ritonavir prescribing information for additional information on precautionary measures.
Skin Rash
During the clinical development program, severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in 7% of subjects treated with PREZISTA; the discontinuation rate due to rash was 0.3%. Rashes were generally mild-to-moderate, self-limited maculopapular skin eruptions. Treatment with PREZISTA should be discontinued if severe rash develops.
Sulfa Allergy
Darunavir contains a sulfonamide moiety. PREZISTA (darunavir) should be used with caution in patients with a known sulfonamide allergy.
Drug Interactions
PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA/rtv with drugs 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 sections CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions).
Diabetes Mellitus / Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.
PRECAUTIONS
Patients with co-existing conditions
Hepatic Impairment
Darunavir is primarily metabolized by the liver, hence, caution should be exercised when PREZISTA/rtv is given to patients with hepatic impairment, because increased plasma concentrations are expected in patients with hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA/rtv should be used with caution in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE AND ADMINISTRATION).
Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening of liver disease in such patients, interruption or discontinuation of treatment must be considered.
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). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease; however, since 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, Pharmacokinetics in Adults, Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION).
Hemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitor therapy and these episodes has not been established.
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jeroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.
Resistance/Cross-Resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in PREZISTA/rtv treated patients, it is unknown what effect therapy with PREZISTA will have on the activity of subsequently administered protease inhibitors.
Information for Patients
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with PREZISTA. A Patient Package Insert for PREZISTA is available for patient information.
Patients should be informed that PREZISTA is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of PREZISTA are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with PREZISTA can reduce the risk of transmitting HIV to others.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using PREZISTA.
Patients should be advised to take PREZISTA and ritonavir (NORVIR®) with food every day as prescribed. The type of food does not affect exposure to PREZISTA. Patients should be instructed to swallow whole tablets with a drink such as water or milk. PREZISTA must always be used with 100 mg of ritonavir (NORVIR®) in combination with other antiretroviral drugs. Patients should not alter the dose of either PREZISTA or ritonavir (NORVIR®), discontinue ritonavir (NORVIR®), or discontinue therapy with PREZISTA without consulting their physician. If a patient misses a dose of PREZISTA or ritonavir (NORVIR®) by more than 6 hours, the patient should be told to wait and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If the patient misses a dose of PREZISTA or ritonavir (NORVIR®) by less than 6 hours, the patient should be told to take PREZISTA and ritonavir (NORVIR®) immediately, and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If a dose of PREZISTA or ritonavir (NORVIR®) is skipped, the patient should not double the next dose. Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA or ritonavir (NORVIR®) at any one time.
PREZISTA/rtv may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
Patients receiving estrogen-based contraceptives should be instructed to use alternate contraceptive measures during therapy with PREZISTA/rtv because hormonal levels may decrease.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZISTA/rtv, and that the cause and long-term health effects of these conditions are not known at this time.
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 |
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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.
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Antihistamines:
astemizole,
terfenadine | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
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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.
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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.
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Gastrointestinal Motility Agent:
cisapride | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
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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.
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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.
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Neuroleptic:
pimozide | CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
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Sedative/Hypnotics:
midazolam,
triazolam | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
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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 Drug Class: Drug Name | Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
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| 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 | | 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.
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| HIV-Antiviral Agents: HIV-Protease Inhibitors (PIs) |
Atazanavir
(The reference regimen for atazanavir was atazanavir/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 by 53%, 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.
|
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.
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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 of clarithromycin 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 of darunavir/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.
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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.
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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.
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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.
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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.
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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.
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Narcotic Analgesic:
methadone | ↓ methadone | When methadone is co-administered with PREZISTA/rtv, patients should be monitored for opiate abstinence syndrome, as ritonavir is known to induce the metabolism of methadone, leading to a decrease in its plasma concentrations. An increase in methadone dosage may be considered based on the clinical response.
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Oral Contraceptives/estrogen:
ethinyl estradiol
norethindrone | ↓ ethinyl estradiol
↓ norethindrone
| Plasma concentrations of ethinyl estradiol may be decreased due to induction of its metabolism by ritonavir. Alternative or additional contraceptive measures should be used when estrogen-based contraceptives are co-administered with PREZISTA/rtv.
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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.
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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.
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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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Long-term carcinogenicity studies of darunavir in rodents have not been completed. Darunavir, however, was tested negative in the in vitro Ames reverse mutation assay and in vitro chromosomal aberration assay in human lymphocytes, both tested in the absence and presence of metabolic activation system. Darunavir does not induce chromosomal damage in the in vivo micronucleus test in mice.
Impairment of Fertility
There were no effects on fertility and early embryonic development with darunavir in rats and darunavir has shown no teratogenic potential in mice (in the presence or absence of ritonavir), rats and rabbits.
Pregnancy
Pregnancy Category B
Reproduction studies conducted with darunavir have shown no embryotoxicity or teratogenicity in mice, rats and rabbits. Because of limited bioavailability of darunavir in animals and/or dosing limitations, the plasma exposures (AUC values) were approximately 50% in mice and rats and 5% in the rabbit of those obtained in humans at the recommended clinical dose boosted with ritonavir.
In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility or mating performance of offspring was not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.
There are, however, no adequate and well-controlled studies in pregnant women. PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk.
Antiretroviral Pregnancy Registry : To monitor maternal-fetal outcomes of pregnant women exposed to PREZISTA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of PREZISTA did not include sufficient numbers of patients aged 65 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.
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