Darunavir tablets, co-administered with ritonavir (darunavir/ritonavir), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adult and pediatric patients 3 years of age and older [ see Use in Specific Populations (8.4) and Clinical Studies (14) ]. Darunavir is a human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV-1 infection in adult and pediatric patients 3 years of age and older.
Darunavir tablets must be co-administered with ritonavir (darunavir/ritonavir) and with other antiretroviral agents. ( 1 )
Contraindications
Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below [ see Drug Interactions (7.3) ]. Due to the need for co-administration of darunavir with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.
Alpha 1-adrenoreceptor antagonist: alfuzosin Anti-gout: colchicine, in patients with renal and/or hepatic impairment Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Cardiac Disorders: dronedarone, ivabradine, ranolazine Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine Herbal product: St. John's wort (Hypericum perforatum) Hepatitis C direct acting antiviral: elbasvir/grazoprevir Lipid modifying agents: lomitapide, lovastatin, simvastatin Opioid Antagonist: naloxegol PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension Sedatives/hypnotics: orally administered midazolam, triazolam Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index).
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. Post-marketing cases of liver injury, including some fatalities, have been reported. ( 5.2 ) Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, have been reported.
Discontinue treatment if severe reaction develops. ( 5.3 ) Use with caution in patients with a known sulfonamide allergy. ( 5.4 ) Patients may develop new onset diabetes mellitus or hyperglycemia. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. ( 5.6 ) Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome. ( 5.7 , 5.8 ) Patients with hemophilia may develop increased bleeding events.
( 5.9 ) Darunavir/ritonavir is not recommended in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age. ( 5.10 )
5.1Importance of Co-administration with Ritonavir
Darunavir must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer darunavir with ritonavir and food may result in a loss of efficacy of darunavir. Please refer to ritonavir prescribing information for additional information on precautionary measures.
5.2Hepatotoxicity
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir. 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.
Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir/ritonavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavir and patients should be monitored during treatment.
Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir/ritonavir treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment.
5.3 Severe Skin Reactions During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported.
Discontinue darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with darunavir/ritonavir [ see Adverse Reactions (6) ].
Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using darunavir/ritonavir was 0.5%. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir + raltegravir compared to subjects receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir.
However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
5.4Sulfa Allergy
Darunavir contains a sulfonamide moiety. Darunavir should be used with caution in patients with a known sulfonamide allergy. In clinical studies with darunavir/ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.
5.5Risk of Serious Adverse
Reactions due to Drug Interactions Initiation of darunavir/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving darunavir/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of darunavir/ritonavir, respectively.
These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications. Clinically significant adverse reactions from greater exposures of darunavir/ritonavir. Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s). Loss of therapeutic effect of darunavir/ritonavir and possible development of resistance from lower exposures of darunavir/ritonavir.
See Table 10 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during darunavir/ritonavir therapy; review concomitant medications during darunavir/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7) ] .
5.6Diabetes 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 (PI) 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 PI 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 PI therapy and these events have not been established.
5.7Fat 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.
5.8Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including darunavir. During th
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Interactions
Co-administration of darunavir/ritonavir with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of darunavir. The potential drug-drug interactions must be considered prior to and during therapy. ( 4 , 5.5 , 7 , 12.3 )
7.1Potential
for darunavir/ritonavir to Affect Other Drugs Darunavir co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of darunavir 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. Darunavir co-administered with ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 10 ).
7.2Potential 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 10 ).
7.3Established and Other Potentially Significant Drug Interactions Table
10 provides dosing recommendations as a result of drug interactions with darunavir/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. The table includes examples of potentially significant interactions but is not all inclusive [see Contraindications (4) and Clinical Pharmacology (12.3) ] , and therefore the label of each drug that is co-administered with darunavir/ritonavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co-administration.
Table 10: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction (see Contraindications (4) for a list of examples of contraindicated drugs) [see Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 15 and 16 ] Concomitant Drug Class Drug Name Examples 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 darunavir/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.) lopinavir/ritonavir saquinavir Other HIV protease inhibitors, except atazanavir [see Drug Interactions(7.4) ] ↑ darunavir ↑ indinavir ↓ darunavir ↔ lopinavir ↓ darunavir ↔ saquinavir The appropriate dose of indinavir in combination with darunavir/ritonavir has not been established.
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and darunavir, with or without ritonavir. Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and darunavir, with or without ritonavir. As co-administration with darunavir/ritonavir has not been studied, co-administration is not recommended.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists maraviroc ↑ maraviroc When used in combination with darunavir/ritonavir, the dose of maraviroc should be 150 mg twice daily. Other Agents Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antibacterial: clarithromycin ↔ darunavir ↑ clarithromycin No dose adjustment of the combination is required for patients with normal renal function.
For co-administration of clarithromycin and darunavir/ritonavir in patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of <30 mL/min, the dose of clarithromycin should be reduced by 75%. Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban dabigatran etexilate edoxaban Other Anticoagulants warfarin ↑ apixaban ↑rivaroxaban ↑dabigatran ↑edoxaban ↓ warfarin ↔ darunavir Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with darunavir/ritonovir depends on the apixaban dose.
Refer to apixaban dosing instructions for co-administration with P-gp and strong CYP3A inhibitors in apixaban prescribing information. Co-administration of darunavir /ritonavir and rivaroxaban is not recommended because it may lead to an increased bleeding risk. Refer to the dabigatran etexilate or edoxaban prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the co-administered P-gp inhibitors on the concentration of dabigatran or edoxaban.
Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with darunavir/ritonavir. Warfarin concentrations are decreased when co-administered with darunavir/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with darunavir/ritonavir. Anticonvulsants: 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. clonazepam phenobarbital, phenytoin ↑ clonazepam ↔ darunavir ↓ phenytoin ↓ phenobarbital Clinical monitoring of anticonvulsants that are metabolized by CYP3A is recommended. Phenytoin and phenobarbital levels should be monitored when co-administering with darunavir/ritonavir. Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) : paroxetine, sertraline Tricyclic Antidepressants (TCAs) : amitriptyline, desipramine, imipramine, nortriptyline Other : trazodone ↓ paroxetine ↓ sertraline ↑ amitriptyline ↑ desipramine ↑ imipramine ↑ nortriptyline ↑ trazodone If either sertraline or paroxetine is initiated in patients receiving darunavir/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 darunavir/ritonavir. Use a lower dose of the tricyclic antidepressants and trazodone due to potential increased adverse events such as nausea, dizziness, hypotension and syncope. Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole voriconazole ↑ darunavir ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole ↓ voriconazole Monitor for increased darunavir/ritonavir and/or antifungal adverse events with concomitant use of these antifungals.
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 is not recommended for patients receiving darunavir/ritonavir unless an
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Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to darunavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Available limited data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [ see Data ].
The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose [ see Data ].
Clinical Considerations The recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food. Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].
Data Human Data Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial through the postpartum period (6 to 12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.
The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6 to 12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen [ see Clinical Pharmacology (12.3) ]. Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6 to 12 week postpartum visit.
Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for 11% (2/18) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6 to 12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).
Darunavir/ritonavir was well tolerated during pregnancy and postpartum. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 infected adults Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum.
All 31 infants received antiretroviral prophylactic treatment containing zidovudine. Based on prospective reports to the APR of over 980 exposures to darunavir containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 - exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6.% (95% CI: 2.3% to 5.3.%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens.
Animal Data Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6 to 15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7 to 19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8 to 20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.
Adverse reactions
The following adverse reactions are discussed in other sections of labeling: Hepatotoxicity [see Warnings and Precautions (5.2) ] Severe Skin Reactions [see Warnings and Precautions (5.3) ] Diabetes Mellitus/Hyperglycemia [see Warnings and Precautions (5.6) ] Fat Redistribution [see Warnings and Precautions (5.7) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.8) ] Hemophilia [see Warnings and Precautions (5.9) ] Due to the need for co-administration of darunavir with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.
The most common clinical adverse drug reactions to darunavir/ritonavir (incidence greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. T r e a tment Naïve-Adults: TMC114-C211 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing darunavir/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 darunavir/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 darunavir/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to darunavir/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 darunavir/ritonavir arm discontinued treatment due to ADRs.
ADRs to darunavir/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 6 and subsequent text below the table. Table 6: Selected Clinical Adverse Drug Reactions to Darunavir/Ritonavir 800/100 mg Once Daily Excluding laboratory abnormalities reported as ADRs. of at Least Moderate Intensity (≥Grade 2) Occurring in ≥2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Trial TMC114-C211) N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate System organ class, preferred term, % Darunavir/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% Le ss 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 darunavir/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 La b o r a tory Abnormalities: Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with darunavir/ritonavir 800/100 mg once daily are presented in Table 7 .
Table 7: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects Grade 4 data not applicable in Division of AIDS grading scale. (Trial TMC114-C211) N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate Laboratory parameter % Limit Darunavir/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 to 8.48 mmol/L 500 to 750 mg/dL 3% 10% Grade 3 8.49 to 13.56 mmol/L 751 to 1200 mg/dL 2% 5% Grade 4 >13.56 mmol/L >1200 mg/dL 1% 1% Total Cholesterol Grade 2 6.20 to 7.77 mmol/L 240 to 300 mg/dL 23% 27% Grade 3 >7.77 mmol/L >300 mg/dL 1% 5% Low-Density Lipoprotein Cholesterol Grade 2 4.13 to 4.90 mmol/L 160 to 190 mg/dL 14% 12% Grade 3 ≥4.91 mmol/L ≥191 mg/dL 9% 6% Elevated Glucose Levels Grade 2 6.95 to 13.88 mmol/L 126 to 250 mg/dL 11% 10% Grade 3 13.89 to 27.75 mmol/L 251 to 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% T r eatment-Experienced Adults: TMC114-C214 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing darunavir/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 darunavir/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 darunavir/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to darunavir/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 darunavir/ritonavir arm discontinued treatment due to ADRs.
ADRs to darunavir/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 8 and subsequent text below the table. Table 8: Selected Clinical Adverse Drug Reactions to Darunavir/Ritonavir 600/100 mg Twice Daily Excluding laboratory abnormalities reported as ADRs of at Least Moderate Intensity (≥Grade 2) Occurring in ≥2% of Antiretroviral Treatment- Experienced HIV-1-Infected Adult Subjects (Trial TMC114-C214) N=total number of subjects per treatment group; OBR=optimized background regimen System organ class, preferred term, % Darunavir/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% Gene
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Composition
Active ingredients
DARUNAVIR 300MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Darunavir
Drug class
Antivirals for treatment of HIV infections, combinations, Protease inhibitors
