Generic: DARUNAVIR
Protease Inhibitor [EPC]
1 INDICATIONS AND USAGE Darunavir, 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 y...
1 INDICATIONS AND USAGE Darunavir, 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 must be co-administered with ritonavir (darunavir/ritonavir) and with other antiretroviral agents. ( 1 )
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, tox...
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 o...
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% < 1% Nervous System Disorders Headache 7% 6% Skin and Subcutaneous Tissue Disorders Rash 6% 7% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-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 Laboratory 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 a (Trial TMC114-C211) N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate a Grade 4 data not applicable in Division of AIDS grading scale. 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 X ULN 9% 9% Grade 3 > 5 to ≤ 10 X ULN 3% 3% Grade 4 > 10 X ULN < 1% 3% Aspartate Aminotransferase Grade 2 > 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% < 1% Grade 4 > 10 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN < 1% 5% Grade 3 > 2.5 to ≤ 5 X ULN < 1% < 1% Grade 4 > 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% < 1% Grade 4 > 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 < 1% 1% Grade 4 > 5 X ULN 0% < 1% Pancreatic Amylase Grade 2 > 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% < 1% Nervous System Disorders Headache 3% 3% Skin and Subcutaneous Tissue Disorders Rash 7% 3% Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving darunavir/ritonavir 600/100 mg twice daily are listed below by body system: Gastrointestinal Disorders : acute pancreatitis, flatulence Musculoskeletal and Connective Tissue Disorders : myalgia Psychiatric Disorders : abnormal dreams Skin and Subcutaneous Tissue Disorders : pruritus, urticaria Laboratory Abnormalities Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with darunavir/ritonavir 600/100 mg twice daily are presented in Table 9. Table 9 Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects a (Trial TMC114-C214) N=total number of subjects per treatment group; OBR=optimized background regimen a Grade 4 data not applicable in Division of AIDS grading scale Laboratory parameter, % Limit Darunavir/ritonavir 600/100 mg twice daily + OBR Lopinavir/ ritonavir 400/100 mg twice daily + OBR Biochemistry Alanine Aminotransferase Grade 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 < 1% 2% Alkaline Phosphatase Grade 2 > 2.5 to ≤ 5 X ULN < 1% 0% Grade 3 > 5 to ≤ 10 X ULN < 1% < 1% Grade 4 > 10 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN < 1% 2% Grade 3 > 2.5 to ≤ 5 X ULN < 1% < 1% Grade 4 > 5 X ULN < 1% 0% Triglycerides Grade 2 5.65 mmol/L to 8.48 mmol/L 500 mg/dL to 750 mg/dL 10% 11% Grade 3 8.49 mmol/L to 13.56 mmol/L 751 mg/dL to 1,200 mg/dL 7% 10% Grade 4 > 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% < 1% Grade 4 > 27.75 mmol/L > 500 mg/dL < 1% 0% Pancreatic Lipase Grade 2 > 1.5 to ≤ 3 X ULN 3% 4% Grade 3 > 3 to ≤ 5 X ULN 2% < 1% Grade 4 > 5 X ULN < 1% 0% Pancreatic Amylase Grade 2 > 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
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