2.1 Testing Prior to Initiation of Darunavir/ritonavir

In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus [seeMicrobiology (12.4)]. Refer to Dosage and Administration (2.3), (2.4) and (2.5)for dosing recommendations.

Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with darunavir/ritonavir [seeWarnings and Precautions (5.2)].

2.2 Monitoring During Treatment with Darunavir/ritonavir

Patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases should be monitored for elevation in serum liver biochemistries, especially during the first several months of darunavir/ritonavir treatment [seeWarnings and Precautions (5.2)].

2.3 Recommended Dosage in Adult Patients

Darunavir tablets must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer darunavir tablets with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

Patients who have difficulty swallowing darunavir tablets can use the 100 mg per mL darunavir oral suspension.

Treatment-Naïve Adult Patients
The recommended oral dose of darunavir is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet or capsule or 1.25 mL of a 80 mg per mL ritonavir oral solution) once daily and with food. An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.

Treatment-Experienced Adult Patients
The recommended oral dosage for treatment-experienced adult patients is summarized in Table 1.

Baseline genotypic testing is recommended for dose selection. However, when genotypic testing is not feasible, darunavir 600 mg taken with ritonavir 100 mg twice daily is recommended.

2.4 Recommended Dosage During Pregnancy

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.

2.5 Recommended Dosage in Pediatric Patients (age 3 to less than 18 years)

Healthcare professionals should pay special attention to accurate dose selection of darunavir tablets, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should select the appropriate dose of darunavir/ritonavir for each individual child based on body weight (kg) and should not exceed the recommended dose for adults.

Before prescribing darunavir tablets, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of darunavir oral suspension should be considered.

The recommended dose of darunavir/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose. Darunavir tablets should be taken with ritonavir and with food.

The recommendations for the darunavir/ritonavir dosage regimens were based on pediatric clinical trial data and population pharmacokinetic modeling and simulation [seeUse in Specific Populations (8.4)andClinical Pharmacology (12.3)].

Dosing Recommendations for Treatment-Naïve Pediatric Patients or Antiretroviral Treatment-Experienced Pediatric Patients with No Darunavir Resistance Associated Substitutions
Pediatric Patients Weighing At Least 10 kg but Less than 15 kg
The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is darunavir 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table:

Pediatric Patients Weighing At Least 15 kg
Pediatric patients weighing at least 15 kg can be dosed with darunavir oral tablet(s) or suspension using the following table:

Dosing Recommendations for Treatment-Experienced Pediatric Patients with At Least One Darunavir Resistance Associated Substitutions
Pediatric Patients Weighing At Least 10 kg but Less than 15 kg
The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is darunavir 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table:

Pediatric Patients Weighing At Least 15 kg
Pediatric patients weighing at least 15 kg can be dosed with darunavir oral tablet(s) or suspension using the following table:

The use of darunavir/ritonavir in pediatric patients below 3 years of age is not recommended [seeWarnings and Precautions (5.10)andUse in Specific Populations (8.4)].

2.6 Not Recommended in Patients with Severe Hepatic Impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment. No data are available regarding the use of darunavir/ritonavir when co-administered to subjects with severe hepatic impairment; therefore, darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment [seeUse in Specific Populations (8.6)andClinical Pharmacology (12.3)].

5.1 Importance of Co-administration with Ritonavir

Darunavir tablets must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer darunavir tablets 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=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 [seeAdverse 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 tablets 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, and Guillain-Barré 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 1000 mg/kg) up to days 23 to 26 of age [seeUse in Specific Populations (8.1and 8.4) and Clinical Pharmacology (12.3)].

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.

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.

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.

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.

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 [seeWarnings 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 [seeUse in Specific Populations (8.4)andClinical 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 [seeWarnings and Precautions (5.3)]

Renal and Urinary Disorders: Crystal nephropathy, crystalluria

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 [seeContraindications (4)andClinical 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.

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.

8.1 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 15-20%. 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 [seeDosage and Administration (2.4)andClinical 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 (6-12 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 (6-12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen [seeClinical 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 6-12 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 6-12 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) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 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 [seeUse 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 1000 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 [seeDrug 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 1000 mg/kg) up to days 23 to 26 of age [seeWarnings and Precautions (5.10),Use in Specific Populations (8.1)andClinical 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 weighing 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) [seeAdverse Reactions (6.1),Clinical Pharmacology (12.3)andClinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [seeAdverse 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) [seeAdverse Reactions (6.1), Clinical Pharmacology (12.3)andClinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [seeAdverse 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 [seeClinical 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 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 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 [seeClinical 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 [seeDosage and Administration (2.6)andClinical 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 30-60 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 [seeClinical Pharmacology (12.3)].

12.1 Mechanism of Action

Darunavir is an HIV-1 antiviral drug [seeMicrobiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology
In a thorough QT/QTc study in 40 healthy subjects, darunavir/ritonavir doses of 1.33 times the maximum recommended dose did not affect the QT/QTc interval.

12.3 Pharmacokinetics

Pharmacokinetics in Adults
General
Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.

The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 11 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in trial TMC114-C214, 278 patients in trial TMC114-C229 and 119 patients [integrated data] from trials TMC114-C202 and TMC114-C213) and darunavir/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in trial TMC114-C211 and 280 patients in trial TMC114-C229) to HIV-1-infected patients.

N=number of subjects with data

Absorption and Bioavailability
Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a T max of approximately 2.5-4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that darunavir/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.

Effects of Food on Oral Absorption
When darunavir tablets were administered with food, the C max and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).

Distribution
Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

Metabolism
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.

Elimination
A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

Special Populations
Hepatic Impairment
Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [seeDosage and Administration (2.6)andUse in Specific Populations (8.6)].

Hepatitis B or Hepatitis C Virus Co-infection
The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

Renal Impairment
Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease [seeUse in Specific Populations (8.7)].

Gender
Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.

Race
Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.

Geriatric Patients
Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65) [seeUse in Specific Populations (8.5)].

Pediatric Patients
Darunavir/ritonavir administered twice daily
The pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving darunavir/ritonavir 600/100 mg twice daily [seeDosage and Administration (2.5)].

Darunavir/ritonavir administered once daily
The pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment‑naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving darunavir/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naïve adults receiving darunavir/ritonavir 800/100 mg once daily [seeDosage and Administration (2.5)].

Based on population pharmacokinetic modeling and simulation, the proposed darunavir/ritonavir once daily dosing regimens for pediatric patients 3 to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-naïve adults receiving darunavir/ritonavir 800/100 mg once daily [seeDosage and Administration (2.5)].

The population pharmacokinetic parameters in pediatric subjects with darunavir/ritonavir administered once or twice daily are summarized in the table below:

N=number of subjects with data.

Pregnancy and Postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Table 13, Table 14 and Figure 1).

Due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum, unbound darunavir exposures were less reduced during pregnancy as compared to postpartum. Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen (see Figure 1).

Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir After Administration of Darunavir/ritonavir at 600/100 mg Twice Daily or 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 ndand 3 rdTrimester of Pregnancy Compared to Postpartum

Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio. Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

Drug Interactions
[See alsoContraindications (4),Warnings and Precautions (5.5)andDrug Interactions (7). ]

Darunavir co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of darunavir and ritonavir with drugs 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 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.

Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, C max, and C min values are summarized in Table 15 (effect of other drugs on darunavir) and Table 16 (effect of darunavir on other drugs). For information regarding clinical recommendations, seeDrug Interactions (7).

Several interaction studies have been performed with a dose other than the recommended dose of the co-administered drug or darunavir; however, the results are applicable to the recommended dose of the co-administered drug and/or darunavir.

N = number of subjects with data

N = number of subjects with data;- = no information available

12.4 Microbiology

Mechanism of Action
Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Antiviral Activity
Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC 50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G), and group O primary isolates with EC 50 values ranging from less than 0.1 to 4.3 nM. The EC 50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.

Resistance
Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC 50 values ranging from 125 nM to 3461 nM.

Clinical trials of darunavir/ritonavir in treatment-experienced subjects: In a pooled analysis of the 600/100 mg darunavir/ritonavir twice daily arms of trials TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine trials TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M developed most frequently on darunavir/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (less than 50 copies/mL). Other substitutions that developed frequently in darunavir/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had a greater than 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some darunavir/ritonavir virologic failure isolates. In trial TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on darunavir/ritonavir.

In the 96-week as-treated analysis of the Phase 3 trial TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving darunavir/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on darunavir/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes greater than 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V. These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (greater than 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (greater than 10-fold) to lopinavir at baseline.

In the 48-week analysis of the Phase 3 trial TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving darunavir/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving darunavir/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on darunavir/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on darunavir/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the darunavir/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the darunavir/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the darunavir/ritonavir 800/100 mg once daily and darunavir/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60; 12%) and 4 (4/42; 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.

Clinical trials of darunavir/ritonavir in treatment-naïve subjects: In the 192-week as-treated analysis censoring those who discontinued before Week 4 of the Phase 3 trial TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving darunavir/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the darunavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43). However, none of the darunavir virologic failures had a decrease in darunavir susceptibility (greater than 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or resistance to emtricitabine, which was included in the fixed background regimen, was identified in 4 virologic failures from the darunavir/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm.

Cross-resistance
Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.

Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed a fold change in EC 50 values less than 3 for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In trials TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change greater than 3) achieved less than 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily (greater than 7-fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).

In trial TMC114-C214, the 7 darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos)-amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these 7 were resistant to saquinavir and 5 were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline.

Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely because the viral targets are different.

Baseline Genotype/Phenotype and Virologic Outcome Analyses
Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of darunavir/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as-treated analyses using pooled data from the Phase 2b trials (Trials TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine trials TMC125-C206 and TMC125-C216 at Week 24 (n=591).

Diminished virologic responses were observed in subjects with 5 or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 17).

IAS Primary PI Substitutions (2008): D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M

The presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to darunavir/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, 2 and greater than or equal to 3 of these substitutions, respectively.

Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 18. These baseline phenotype groups are based on the select patient populations in the trials TMC114-C213, TMC114-C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for darunavir/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.

Impairment of Fertility
No effects on fertility or early embryonic development were observed with darunavir in rats.

14.1 Description of Adult Clinical Trials

The evidence of efficacy of darunavir/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.

14.2 Treatment-Naïve Adult Subjects

TMC114-C211
TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm 3 or greater than or equal to 200 cells/mm 3). Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in trial TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 19). Table 19 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in trial TMC114-C211.

Week 192 outcomes for subjects on darunavir/ritonavir 800/100 mg once daily from trial TMC114-C211 are shown in Table 20.

N = total number of subjects with data; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate

In trial TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm 3 in the darunavir/ritonavir 800/100 mg once daily arm and 263 cells/mm 3 in the lopinavir/ritonavir 800/200 mg per day arm. Of the darunavir/ritonavir subjects with a confirmed virologic response of <50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the darunavir/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.

14.3 Treatment-Experienced Adult Subjects

TMC114-C229
TMC114-C229 is a randomized, open-label trial comparing darunavir/ritonavir 800/100 mg once daily to darunavir/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.

HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.

Table 21 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 800/100 mg once daily arm and subjects in the darunavir/ritonavir 600/100 mg twice daily arm in trial TMC114-C229. No imbalances between the 2 arms were noted.

OBR=optimized background regimen

Week 48 outcomes for subjects on darunavir/ritonavir 800/100 mg once daily from trial TMC114-C229 are shown in Table 22.

N = total number of subjects with data; OBR=optimized background regimen

The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm 3 and 112 cells/mm 3in the darunavir/ritonavir 800/100 mg once daily arm and the darunavir/ritonavir 600/100 mg twice daily arm, respectively).

TMC114-C214
TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 400 copies/mL. Analyses included 595 subjects in trial TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 23). Table 23 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in trial TMC114-C214.

OBR=optimized background regimen

Week 96 outcomes for subjects on darunavir/ritonavir 600/100 mg twice daily from trial TMC114-C214 are shown in Table 24.

N = total number of subjects with data; OBR=optimized background regimen

In trial TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm 3 in the darunavir/ritonavir 600/100 mg twice daily arm and 93 cells/mm 3 in the lopinavir/ritonavir 400/100 mg twice daily arm.

TMC114-C213 and TMC114-C202
TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to darunavir/ritonavir received the recommended dose of 600/100 mg twice daily.

HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.

The virologic response rate was evaluated in subjects receiving darunavir/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log 10 versus baseline.

In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the comparator PI arm (see Table 25). Table 25 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of trials TMC114-C213 and TMC114-C202.

OBR=optimized background regimen

Week 96 outcomes for subjects on the recommended dose darunavir/ritonavir 600/100 mg twice daily from the pooled trials TMC114-C213 and TMC114-C202 are shown in Table 26.

OBR=optimized background regimen

In the pooled trials TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving darunavir/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log 10 copies/mL in the arm receiving darunavir/ritonavir 600/100 mg twice daily and –0.37 log 10copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving darunavir/ritonavir 600/100 mg twice daily (103 cells/mm 3) than in the comparator PI arm (17 cells/mm 3).

14.4 Pediatric Patients

The pharmacokinetic profile, safety and antiviral activity of darunavir/ritonavir were evaluated in 3 randomized, open-label, multicenter studies.

TMC114-C212
Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received darunavir tablets with either ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of darunavir/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

The 80 randomized pediatric subjects had a median age of 14 (range 6 to less than 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log 10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm 3 (range: 6 to 1505 cells/mm 3). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ≥100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.

Seventy-seven pediatric subjects (96%) completed the 24-week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation.

The proportion of pediatric subjects with HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL was 64% and 50%, respectively. The mean increase in CD4+ cell count from baseline was 117 cells/mm 3.

TMC114-C228
Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received darunavir oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of darunavir/ritonavir.

The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log 10 copies/mL, the median baseline CD4+ cell count was 927 x 10 6 cells/L (range: 209 to 2,429 x 10 6 cells/L) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 NRTIs, 62% of subjects had used greater than or equal to 1 NNRTI and 76% had previously used at least one HIV PI.

Twenty subjects (95%) completed the 48 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%. The mean increase in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 187 x 10 6 cells/L.

TMC114-C230
Treatment-naïve pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of darunavir/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.

The 12 randomized pediatric subjects had a median age of 14.4 years (range 12.6 to 17.3 years), and were 33.3% male, 58.3% Caucasian and 41.7% Black. The mean baseline plasma HIV-1 RNA was 4.72 log 10 copies/mL, and the median baseline CD4+ cell count was 282 cells/mm 3 (range: 204 to 515 cells/mm 3). Overall, 41.7% of pediatric subjects had baseline plasma HIV-1 RNA ≥100,000 copies/mL.

All subjects completed the 48 week treatment period.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 83.3% and 91.7%, respectively. The mean increase in CD4+ cell count from baseline was 221 x 10 6 cells/L.