Darunavir

5 WARNINGS AND PRECAUTIONS 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 ) 5.1 Importance 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. 5.2 Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the clinical development program (N=3,063), 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=3,063), 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. 5.4 Sulfa 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. 5.5 Risk 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 )]. 5.6 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 (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. 5.7 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. 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including darunavir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP] or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barre syndrome and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral treatment. 5.9 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established. 5.10 Not Recommended in Pediatric Patients Below 3 Years of Age Darunavir/ritonavir in pediatric patients below 3 years of age is not recommended in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1,000 mg/kg) up to days 23 to 26 of age [see Use in Specific Populations ( 8.1 and 8.4 ) and Clinical Pharmacology ( 12.3 )] .

6 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 Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. Treatment 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 a 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 a Excluding laboratory abnormalities reported as ADRs. 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% 2.5 to ≤ 5 X ULN 9% 9% Grade 3 > 5 to ≤ 10 X ULN 3% 3% Grade 4 > 10 X ULN 2.5 to ≤ 5 X ULN 7% 10% Grade 3 > 5 to ≤ 10 X ULN 4% 2% Grade 4 > 10 X ULN 1% 3% Alkaline Phosphatase Grade 2 > 2.5 to ≤ 5 X ULN 1% 1% Grade 3 > 5 to ≤ 10 X ULN 0% 10 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN 2.5 to ≤ 5 X ULN < 1% 5 X ULN 0% 0% Triglycerides Grade 2 5.65 mmol/L to 8.48 mmol/L 500 mg/dL to 750 mg/dL 3% 10% Grade 3 8.49 mmol/L to 13.56 mmol/L 751 mg/dL to 1,200 mg/dL 2% 5% Grade 4 > 13.56 mmol/L > 1,200 mg/dL 1% 1% Total Cholesterol Grade 2 6.20 mmol/L to 7.77 mmol/L 240 mg/dL 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 mmol/L to 4.90 mmol/L 160 mg/dL to 190 mg/dL 14% 12% Grade 3 ≥ 4.91 mmol/L ≥ 191 mg/dL 9% 6% Elevated Glucose Levels Grade 2 6.95 mmol/L to 13.88 mmol/L 126 mg/dL to 250 mg/dL 11% 10% Grade 3 13.89 mmol/L to 27.75 mmol/L 251 mg/dL to 500 mg/dL 1% 27.75 mmol/L > 500 mg/dL 0% 0% Pancreatic Lipase Grade 2 > 1.5 to ≤ 3 X ULN 3% 2% Grade 3 > 3 to ≤ 5 X ULN 5 X ULN 0% 1.5 to ≤ 2 X ULN 5% 2% Grade 3 > 2 to ≤ 5 X ULN 5% 4% Grade 4 > 5 X ULN 0% < 1% Treatment-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 a 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 a Excluding laboratory abnormalities reported as ADRs 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% General Disorders and Administration Site Conditions Asthenia 3% 1% Fatigue 2% 1% Metabolism and Nutrition Disorders Anorexia 2% 2% Diabetes mellitus 2% 2.5 to ≤ 5 X ULN 7% 5% Grade 3 > 5 to ≤ 10 X ULN 2% 2% Grade 4 > 10 X ULN 1% 2% Aspartate Aminotransferase Grade 2 > 2.5 to ≤ 5 X ULN 6% 6% Grade 3 > 5 to ≤ 10 X ULN 2% 2% Grade 4 > 10 X ULN 2.5 to ≤ 5 X ULN 5 to ≤ 10 X ULN < 1% 10 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN 2.5 to ≤ 5 X ULN < 1% 5 X ULN 13.56 mmol/L > 1,200 mg/dL 3% 6% Total Cholesterol Grade 2 6.20 mmol/L to 7.77 mmol/L 240 mg/dL to 300 mg/dL 25% 23% Grade 3 > 7.77 mmol/L > 300 mg/dL 10% 14% Low-Density Lipoprotein Cholesterol Grade 2 4.13 mmol/L to 4.90 mmol/L 160 mg/dL to 190 mg/dL 14% 14% Grade 3 ≥ 4.91 mmol/L ≥ 191 mg/dL 8% 9% Elevated Glucose Levels Grade 2 6.95 mmol/L to 13.88 mmol/L 126 mg/dL to 250 mg/dL 10% 11% Grade 3 13.89 mmol/L to 27.75 mmol/L 251 mg/dL to 500 mg/dL 1% 27.75 mmol/L > 500 mg/dL 1.5 to ≤ 3 X ULN 3% 4% Grade 3 > 3 to ≤ 5 X ULN 2% 5 X ULN 1.5 to ≤ 2 X ULN 6% 7% Grade 3 > 2 to ≤ 5 X ULN 7% 3% Grade 4 > 5 X ULN 0% 0% Serious ADRs The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b and Phase 3 trials with darunavir/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 darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving darunavir/ritonavir who were not co-infected, except for increased hepatic enzymes [see Warnings and Precautions ( 5.2 )] . The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection. Clinical Trials Experience: Pediatric Patients Darunavir/ritonavir has been studied in combination with other antiretroviral agents in 3 Phase 2 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-naïve HIV-1 infected pediatric patients aged from 12 to less than 18 years and weighing at least 40 kg were included. The TMC114-C212 and C228 trials evaluated darunavir/ritonavir twice daily dosing and the TMC114-C230 trial evaluated darunavir/ritonavir once daily dosing [see Use in Specific Populations ( 8.4 ) and Clinical Studies ( 14.4 )] . Frequency, type and severity of ADRs in pediatric subjects were comparable to those observed in adults. TMC114-C212 Clinical ADRs to darunavir/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%). TMC114-C228 Clinical ADRs to darunavir/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 trial. TMC114-C230 Clinical ADRs to darunavir/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 trial. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of darunavir. Because these reactions 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. Metabolism and Nutrition Disorders: Redistribution of body fat Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and darunavir/ritonavir) Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions ( 5.3 )] Renal and Urinary Disorders: Crystal nephropathy, crystalluria

7 DRUG 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 ) 7.1 Potential 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). 7.2 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 10). 7.3 Established 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.) ↑ darunavir ↑ indinavir The appropriate dose of indinavir in combination with darunavir/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 darunavir, 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 darunavir, with or without ritonavir. Other HIV protease inhibitors, except atazanavir [see Drug Interactions (7.4)] 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 mL/min 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 ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with darunavir/ritonavir depend on the apixaban dose. Refer to apixaban dosing instructions for co-administration with P-gp and strong CYP3A inhibitors in apixaban prescribing information. rivaroxaban ↑ rivaroxaban Co-administration of darunavir/ritonavir and rivaroxaban is not recommended because it may lead to an increased bleeding risk. dabigatran etexilate edoxaban ↑ dabigatran ↑ edoxaban 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. Other Anticoagulants warfarin ↓ warfarin ↔ darunavir 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 ↑ clonazepam Clinical monitoring of anticonvulsants that are metabolized by CYP3A is recommended. phenobarbital, phenytoin ↔ darunavir ↓ phenytoin ↓ phenobarbital Phenytoin and phenobarbital levels should be monitored when co-administering with darunavir/ritonavir. Antidepressants : Selective Serotonin Reuptake Inhibitors (SSRIs): paroxetine, sertraline ↓ paroxetine ↓ sertraline 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. 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, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole 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 ↓ voriconazole 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 Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. For patients without renal or hepatic impairment: Treatment of gout-flares – co-administration of colchicine in patients on darunavir/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on darunavir/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 darunavir/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimalarial : artemether/lumefantrine ↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir The combination of darunavir/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. Antimycobacterials : rifampin ↓ darunavir Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin (The reference regimen for rifabutin was 300 mg once daily.) ↑ darunavir ↑ rifabutin ↑ 25- O- desacetylrifabutin Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. rifapentine ↓ darunavir Co-administration of darunavir/ritonavir with rifapentine is not recommended. Antineoplastics: dasatinib, nilotinib ↑ 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. vinblastine, vincristine 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 darunavir/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: lurasidone ↑ lurasidone Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. pimozide ↑ pimozide Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. quetiapine ↑ quetiapine Initiation of darunavir 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 darunavir with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. e.g. perphenazine, risperidone, thioridazine ↑ antipsychotics A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with darunavir/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 darunavir/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. Cardiac Disorders : ranolazine, ivabradine ↑ ranolazine ↑ ivabradine Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. dronedarone ↑ dronedarone Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Other 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 darunavir/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. Corticosteroids: dexamethasone (systemic) ↓ darunavir Co-administration of darunavir/ritonavir with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to darunavir. Consider alternative corticosteroids. Corticosteroids primarily metabolized by CYP3A: e.g. betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone ↑ corticosteroids Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use. Endothelin receptor antagonist : bosentan ↑ bosentan Co-administration of bosentan in patients on darunavir/ritonavir: In patients who have been receiving darunavir/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 darunavir/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of darunavir/ritonavir. After at least 10 days following the initiation of darunavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Ergot derivatives: e.g. dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Co-administration is 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. Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir ↑ elbasvir/grazoprevir Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Co-administration of darunavir/ritonavir with glecaprevir/pibrentasvir is not recommended. Herbal product: St. John's wort ( Hypericum perforatum ) ↓ darunavir Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. Hormonal contraceptives : Effective alternative (non-hormonal) contraceptive method or a barrier method of contraception is recommended [see Use in Specific Populations (8.3)] . ethinyl estradiol, norethindrone, drospirenone ↓ ethinyl estradiol ↓ norethindrone drospirenone: effects unknown For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. No data are available to make recommendations on co-administration with other hormonal contraceptives. Immunosuppressants : e.g. cyclosporine, tacrolimus, sirolimus ↑ immunosuppressants Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with darunavir/ritonavir. Immunosuppressant/neoplastic: everolimus Co-administration of everolimus and darunavir/ritonavir is not recommended. irinotecan ↑ salmeterol Discontinue darunavir/ritonavir at least 1 week prior to starting irinotecan therapy. Do not administer darunavir/ritonavir with irinotecan unless there are no therapeutic alternatives. Lipid Modifying Agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. atorvastatin, pravastatin, rosuvastatin ↑ HMG-CoA reductase inhibitors Co-administration of darunavir/ritonavir with HMG-CoA 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. Other lipid modifying agents: lomitapide ↑ lomitapide Co-administration is contraindicated due to potential for markedly increased transaminases. Narcotic analgesics metabolized by CYP3A: e.g. fentanyl, oxycodone ↑ fentanyl ↑ oxycodone Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. tramadol ↑ tramadol A dose decrease may be needed for tramadol with concomitant use. Narcotic analgesics/treatment of opioid dependence : buprenorphine, buprenorphine/naloxone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of darunavir/ritonavir. Clinical monitoring is recommended if darunavir/ritonavir and buprenorphine or buprenorphine/naloxone are co-administered. methadone ↓ methadone No adjustment of methadone dosage is required when initiating co-administration of darunavir/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. Opioid Antagonist naloxegol ↑ naloxegol Co-administration of darunavir/ritonavir and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms. 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 darunavir/ritonavir) Co-administration with darunavir/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): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection and syncope). The following dose adjustments are recommended for use of tadalafil with darunavir/ritonavir: Co-administration of tadalafil in patients on darunavir/ritonavir: In patients receiving darunavir/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 darunavir/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of darunavir/ritonavir. Stop tadalafil at least 24 hours prior to starting darunavir/ritonavir. After at least one week following the initiation of darunavir/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 darunavir/ritonavir and avanafil is not recommended. Platelet aggregation inhibitor: ticagrelor ↑ ticagrelor Co-administration of darunavir/ritonavir and ticagrelor is not recommended. clopidogrel ↓ clopidogrel active metabolite Co-administration of darunavir/ritonavir and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. prasugrel ↔ prasugrel active metabolite No dose adjustment is needed when prasugrel is co-administered with darunavir/ritonavir. Proton pump inhibitor: omeprazole ↓ omeprazole ↔ darunavir When omeprazole is co-administered with darunavir/ritonavir, monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with darunavir may cause large increases in the concentrations of these benzodiazepines. metabolized by CYP3A e.g. buspirone, diazepam, estazolam, zolpidem ↑ sedatives/hypnotics Titration is recommended when co-administering darunavir/ritonavir with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for adverse events. parenterally administered midazolam 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. Urinary antispasmodics fesoterodine ↑ fesoterodine When fesoterodine is co-administered with darunavir/ritonavir, do not exceed a fesoterodine dose of 4 mg once daily. solifenacin ↑ solifenacin When solifenacin is co-administered with darunavir/ritonavir, do not exceed a solifenacin dose of 5 mg once daily. 7.4 Drugs without Clinically Significant Interactions with Darunavir No dosage adjustments are recommended when darunavir/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine or rilpivirine.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Total darunavir exposures were generally lower during pregnancy compared to postpartum period. The reduction in darunavir exposures during pregnancy were greater for once daily dosing compared to the twice daily dosing regimen. ( 8.1 , 12.3 ) Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 ) Pediatrics: Not recommended for patients less than 3 years of age. ( 8.4 ) 8.1 Pregnancy 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 weeks 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 weeks 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 week 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 week 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 1,000 mg/kg from gestation day (GD) 6 to 15 with darunavir alone) and rats (doses up to 1,000 mg/kg from GD 7 to 19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1,000 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. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of darunavir in human milk, the effects on the breastfed infant or the effects on milk production. Darunavir is present in the milk of lactating rats [see Data] . Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving darunavir [see Use in Specific Populations ( 8.4 )] . Data Animal Data Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1,000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir. 8.3 Females and Males of Reproductive Potential Contraception Use of darunavir may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia [see Drug Interactions ( 7.3 )] . 8.4 Pediatric Use Darunavir/ritonavir is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1,000 mg/kg) up to days 23 to 26 of age [see Warnings and Precautions ( 5.10 ) , Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )] . The safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age) [see Adverse Reactions ( 6.1 ) , Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.4 )] . Frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions ( 6.1 )] . Refer to Dosage and Administration ( 2.5 ) for twice-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg. In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects) [see Adverse Reactions ( 6.1 ) , Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.4 )] . Frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions ( 6.1 )] . Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although a darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted darunavir exposures for the dosing recommendations in this age group [see Clinical Pharmacology ( 12.3 )] . Please see Dosage and Administration ( 2.5 ) for once-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg. Juvenile Animal Data In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1,000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels. 8.5 Geriatric Use Clinical studies of darunavir did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] . 8.6 Hepatic Impairment No dosage adjustment of darunavir/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of darunavir/ritonavir in subjects with severe hepatic impairment. Therefore, darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration ( 2.6 ) and Clinical Pharmacology ( 12.3 )] . 8.7 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 mL/min to 60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because 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 ( 12.3 )] .

8.1 Pregnancy 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 weeks 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 weeks 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 week 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 week 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 1,000 mg/kg from gestation day (GD) 6 to 15 with darunavir alone) and rats (doses up to 1,000 mg/kg from GD 7 to 19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1,000 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.

8.4 Pediatric Use Darunavir/ritonavir is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1,000 mg/kg) up to days 23 to 26 of age [see Warnings and Precautions ( 5.10 ) , Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )] . The safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age) [see Adverse Reactions ( 6.1 ) , Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.4 )] . Frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions ( 6.1 )] . Refer to Dosage and Administration ( 2.5 ) for twice-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg. In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects) [see Adverse Reactions ( 6.1 ) , Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.4 )] . Frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions ( 6.1 )] . Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although a darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted darunavir exposures for the dosing recommendations in this age group [see Clinical Pharmacology ( 12.3 )] . Please see Dosage and Administration ( 2.5 ) for once-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg. Juvenile Animal Data In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1,000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.