Apo-Darunavir Product Monograph

RECENT MAJOR LABEL CHANGES

None at the time of the most recent authorization.

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .................................................................................................................. 4

1.1 Pediatrics ...................................................................................................................... 4

1.2 Geriatrics ....................................................................................................................... 4

2 CONTRAINDICATIONS ..................................................................................................... 4

4 DOSAGE AND ADMINISTRATION ..................................................................................... 5

4.1 Dosing Considerations .................................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ............................................................. 5

4.5 Missed Dose .................................................................................................................. 8

5 OVERDOSAGE ................................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................... 9

7 WARNINGS AND PRECAUTIONS ...................................................................................... 9

7.1 Special Populations ..................................................................................................... 14

7.1.1 Pregnant Women ........................................................................................................ 14

7.1.2 Breast-feeding ............................................................................................................ 14

7.1.3 Pediatrics .................................................................................................................... 15

7.1.4 Geriatrics ..................................................................................................................... 15

8 ADVERSE REACTIONS .................................................................................................... 15

8.1 Adverse Reaction Overview ........................................................................................ 15

8.2 Clinical Trial Adverse Reactions .................................................................................. 15

8.2.1 Clinical Trial Adverse Reactions – Pediatrics .............................................................. 20

8.3 Less Common Clinical Trial Adverse Reactions .......................................................... 20

8.4 Abnormal Hematologic and Clinical Chemistry Findings ............................................ 21

8.5 Post-Market Adverse Reactions ................................................................................. 27

9 DRUG INTERACTIONS .................................................................................................... 28

9.1 Serious Drug Interactions ........................................................................................... 28

9.2 Drug Interactions Overview ........................................................................................ 29

9.4 Drug-Drug Interactions ............................................................................................... 29

9.5 Drug-Food Interactions ............................................................................................... 57

9.6 Drug-Herb Interactions ............................................................................................... 57

9.7 Drug-Laboratory Test Interactions ............................................................................. 57

10 CLINICAL PHARMACOLOGY ........................................................................................ 57

10.1 Mechanism of Action .................................................................................................. 57

10.2 Pharmacodynamics..................................................................................................... 58

10.3 Pharmacokinetics ....................................................................................................... 58

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 65

PART II: SCIENTIFIC INFORMATION ...................................................................................... 66

13 PHARMACEUTICAL INFORMATION ............................................................................ 66

14 CLINICAL TRIALS ........................................................................................................ 66

14.1 Clinical Trials by Indication ......................................................................................... 67

14.2 Comparative Bioavailability Studies ........................................................................... 83

15 MICROBIOLOGY ........................................................................................................ 88

16 NON-CLINICAL TOXICOLOGY ...................................................................................... 92

17 SUPPORTING PRODUCT MONOGRAPHS ..................................................................... 94

PATIENT MEDICATION INFORMATION ................................................................................. 95

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

APO-DARUNAVIR (darunavir), co-administered with 100 mg ritonavir, and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in patients ≥ 40 kg.

For a description of the clinical data in support of this indication, refer to 14 CLINICAL TRIALS.

1.1 Pediatrics

Pediatrics (≥ 40 kg):

APO-DARUNAVIR co-administered with low-dose ritonavir, and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in treatment-experienced pediatric patients ≥ 40 kg (see 4 DOSAGE AND ADMINISTRATION and 7 WARNINGS AND PRECAUTIONS).

1.2 Geriatrics

Geriatrics (> 65 years of age)

Clinical studies of darunavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of APO-DARUNAVIR in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy (see 4 DOSAGE AND ADMINISTRATION, 7 WARNINGS AND PRECAUTIONS, and 10 CLINICAL PHARMACOLOGY).

2 CONTRAINDICATIONS

APO-DARUNAVIR is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, refer to 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

APO-DARUNAVIR is contraindicated in patients with severe (Child-Pugh Class C) hepatic insufficiency.

Co-administration of APO-DARUNAVIR/ritonavir (rtv) is contraindicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Co-administration of APO-DARUNAVIR/rtv is contraindicated with rifampin and St. John’s Wort as it may reduce plasma concentrations of darunavir which may result in loss of therapeutic effect and development of resistance. Drugs that are contraindicated with APO-DARUNAVIR are listed in Table 1 (also see 9.4 Drug-Drug Interactions, Table 13 and Table 14).

Table 1: Drugs that are Contraindicated with APO-DARUNAVIR/ritonavir (rtv)

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

APO-DARUNAVIR (darunavir) must always be given with ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral medicinal products. The prescribing information of ritonavir must, therefore, be consulted prior to initiation of therapy with APO-DARUNAVIR/rtv. The treatment history and, when available, genotypic or phenotypic testing should guide the use of APO-DARUNAVIR/rtv (see 4.2 Recommended Dose and Dosage Adjustment, Adults).

4.2 Recommended Dose and Dosage Adjustment

Patients who have difficulty swallowing APO-DARUNAVIR tablets should contact their physician as soon as possible regarding potential therapeutic alternatives, such as an oral suspension.

Adults

The recommended oral dosing regimens for adult patients are APO-DARUNAVIR 800 mg in combination with ritonavir (100 mg) once daily and with food, or 600 mg in combination with ritonavir (100 mg) twice daily and with food. The type of food does not affect exposure to darunavir (see 9.5 Drug-Food Interactions). The dosing schedule for APO-DARUNAVIR/rtv is presented in Table 2.

Table 2: Recommended Dose for Adult Patients for APO-DARUNAVIR Tablets with ritonavir (100 mg)

^a DRV-RAMs: V11I, V321, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

For antiretroviral treatment-experienced patients HIV genotypic testing is recommended. However, when HIV genotypic testing is not feasible, the APO-DARUNAVIR/rtv once-daily dosing regimen is recommended in protease inhibitor-naive patients and the twice daily dosing regimen is recommended in protease inhibitor-experienced patients.

The type of food does not affect exposure to darunavir. Ritonavir is used as a pharmacokinetic enhancer of darunavir (see 9.4 Drug-Drug Interactions, and 10.3 Pharmacokinetics ). A further increase in the dose of darunavir or ritonavir is not likely to result in any clinically relevant increase in antiviral activity.

Geriatric Patients

In general, caution should be exercised in the administration and monitoring of APO-DARUNAVIR in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see 1 INDICATIONS, 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).

Pediatric Patients

APO-DARUNAVIR/rtv should not be used in pediatric patients < 40 kg (see7 WARNINGS AND PRECAUTIONS and 16 NON-CLINICAL TOXICOLOGY).

Antiretroviral Treatment-Experienced Pediatric Patients ≥ 40 kg

The recommended dose of APO-DARUNAVIR for pediatric patients ≥ 40 kg is based on body weight (see Table 3) and should not exceed the recommended adult dose (darunavir/rtv 600/100 mg b.i.d.) (see 14 CLINICAL TRIALS). APO-DARUNAVIR should be taken with ritonavir twice daily and with food. The type of food does not affect exposure to darunavir (see 9.5 Drug-Food Interactions Effects of Food on Oral Absorption , ).

Before prescribing APO-DARUNAVIR children weighing greater than or equal to 40 kg should be assessed for the ability to swallow tablets. Patients who have difficulty swallowing APO-DARUNAVIR tablets should contact their physician as soon as possible regarding potential therapeutic alternatives, such as an oral suspension.

The following table provides recommended weight-based dosing for pediatric patients weighing ≥ 40 kg:

Table 3: Recommended Dose for Pediatric Patients weighing ≥ 40 kg who are treatment experienced with at least one darunavir resistance associated mutation (DRV-RAM)^a using APO-DARUNAVIR Tablets with ritonavir^b

^a DRV-RAMs: V11I, V321, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V ^b Given as a tablet or capsule, or with ritonavir oral solution: 80 mg/mL

Antiretroviral Treatment-Naïve Pediatric Patients

The safety and efficacy of darunavir/rtv in antiretroviral treatment-naïve pediatric patients have not been established.

Hepatic Impairment

The safety and efficacy of darunavir have not been established in patients with severe hepatic insufficiency (see 2 CONTRAINDICATIONS). No dose adjustment is required in patients with mild or moderate hepatic impairment (see 10.3 Pharmacokinetics).

Renal Impairment

No dose adjustment is required in patients with renal impairment (see 7 WARNINGS AND

PRECAUTIONS, Renal and 10.3 Pharmacokinetics).

Dosing with Didanosine

Dosing of enteric-coated didanosine and darunavir, co-administered with low-dose ritonavir, should be separated by at least 2 hours to avoid formulation incompatibility.

4.5 Missed Dose

Patients Taking 600 mg of APO-DARUNAVIR Twice Daily

The missed dose should be taken as soon as possible, if the dose was missed by less than 6 hours. The next dose of APO-DARUNAVIR and ritonavir should be taken at the regularly scheduled time. If the dose of APO-DARUNAVIR or ritonavir was missed by more than 6 hours, the next dose of APO-DARUNAVIR and ritonavir should be taken at the regularly scheduled time. Doses should not be doubled.

Patients Taking 800 mg of APO-DARUNAVIR Once Daily

The missed dose (one 800 mg tablet) should be taken as soon as possible, if the dose was missed by less than 12 hours. The next dose of APO-DARUNAVIR (one 800 mg tablet) and ritonavir should be taken at the regularly scheduled time. If the dose of APO-DARUNAVIR (one 800 mg tablet) or ritonavir was missed by more than 12 hours, the next dose of APO-DARUNAVIR (one 800 mg tablet) and ritonavir should be taken at the regularly scheduled time. Doses should not be doubled.

5 OVERDOSAGE

Human experience of acute overdose with darunavir/rtv is limited. Single dose up to 1,600 mg of the tablet formulation of darunavir co-administered with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.

There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 4 – Dosage Forms, Strengths, Composition and Packaging

APO-DARUNAVIR 600 mg Tablets

APO-DARUNAVIR 600 mg tablets are orange, oval, biconvex, coated tablets, engraved “APO” on one side and “D600” on the other side. Each tablet contains 600 mg of darunavir.

APO-DARUNAVIR 800 mg Tablets

APO-DARUNAVIR 800 mg tablets are dark red, oval, biconvex, coated tablets, engraved “APO” on one side and “D800” on the other side. Each tablet contains 800 mg of darunavir.

APO-DARUNAVIR tablets are packaged in the following configuration:

600 mg tablets—bottles of 60 tablets and blister packs of 60 tablets (6 strips of 10s)

800 mg tablets—bottles of 30 tablets and blister packs of 30 tablets (3 strips of 10s)

7 WARNINGS AND PRECAUTIONS

General

APO-DARUNAVIR (darunavir) must be administered with low-dose ritonavir to ensure its therapeutic effect (4 DOSAGE AND ADMINISTRATION; 9.4 Drug-Drug Interactions, and 10.3

Pharmacokinetics). Failure to correctly co-administer APO-DARUNAVIR with ritonavir will result in reduced plasma levels of darunavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed accordingly. Please refer to the ritonavir Product Monograph for additional information on precautionary measures.

APO-DARUNAVIR is not a cure for HIV-1 infection or AIDS. Patients receiving darunavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

Darunavir therapy has not been shown to reduce the risk of transmission of HIV-1 to others.

Due to inhibition of CYP3A by darunavir, co-administration of darunavir with quetiapine may result in increased quetiapine concentrations. Serious and life-threatening quetiapine- related adverse reactions have been reported with CYP3A inhibitors. Darunavir should not be used in combination with quetiapine (see 9 DRUG INTERACTIONS). Monitoring and dose reductions may be required if necessary.

Carcinogenesis and Mutagenesis

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. 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. These findings are considered to be of limited relevance to humans. Based on AUC measurements, exposure to darunavir at the dose levels studied was below or approximately equivalent to exposure in humans at the recommended therapeutic dose (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity and Genotoxicity).

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity and Genotoxicity).

Endocrine and Metabolism

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing 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.

Hematologic

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established; however, the frequency of bleeding episodes should be closely monitored in patients on APO-DARUNAVIR/rtv.

Lipid Elevations

Treatment with darunavir has resulted in increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating APO-DARUNAVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See Table 11 and Table 12 for additional information on potential drug interactions with APO-DARUNAVIR and HMG-CoA reductase inhibitors/other lipid modifying agent.

Hepatic/Biliary/Pancreatic

Hepatic Impairment

APO-DARUNAVIR is contraindicated in patients with severe hepatic insufficiency (Child-Pugh Class C) (see 2 CONTRAINDICATIONS ). Patients with mild or moderate hepatic impairment (Child- Pugh Class A or B, respectively) should be closely monitored.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. Limited data are currently available for the use of darunavir co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C.

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/rtv. During the clinical development program (n=3,063), hepatitis has been reported in 0.5% of patients receiving combination therapy with darunavir/rtv.

Post-marketing cases of clinical hepatitis and hepatic decompensation, including some fatalities have been reported. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution inflammatory syndrome. A causal relationship with darunavir/rtv therapy has not been established.

Patients with pre-existing liver dysfunction including chronic hepatitis B or C have an increased frequency of liver function abnormalities during combination antiretroviral therapy. Appropriate monitoring should be conducted prior to initiating therapy with APO-DARUNAVIR/rtv and increased monitoring should be considered in patients with elevated baseline transaminase levels, active hepatitis B or C and in patients with underlying liver disease, especially during the first several months of APO-DARUNAVIR/rtv 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 and hepatomegaly) in patients on APO-DARUNAVIR/rtv, should prompt consideration to interrupt or discontinue treatment.

For information on the multi-dose pharmacokinetics of darunavir in hepatically impaired patients, see 10 CLINICAL PHARMACOLOGY.

Pancreatic

Pancreatitis has been observed in patients receiving darunavir/rtv therapy, including those who developed marked triglyceride elevations. Although a causal relationship to darunavir has not been established, marked triglyceride elevation is a risk factor for development of pancreatitis (see 7 WARNINGS AND PRECAUTIONS, Lipid Elevations). Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during darunavir/rtv therapy.

Immune

Immune Reconstitution Inflammatory Syndrome

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex (MAC), cytomegalovirus (CMV) infection, Pneumocystis jirovecii pneumonia, and tuberculosis (TB), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, autoimmune hepatitis, polymyositis and Guillain-Barré syndrome) 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 treatment.

Renal

Renal Impairment

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected patients with moderate renal impairment (CrCL between 30 to 60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease. However, since the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis (see 4 DOSAGE AND ADMINISTRATION and 10.3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

Sensitivity/ Resistance

Darunavir contains a sulfonamide moiety. APO-DARUNAVIR (darunavir) should be used with caution in patients with a known sulfonamide allergy. The potential for cross-sensitivity between drugs in the sulfonamide class and darunavir is unknown. In clinical studies with darunavir/ritonavir, the incidence and severity of rash was similar in patients with or without a history of sulphonamide allergy.

Skin

Severe Skin Reactions

During the clinical development program (n=3,063), severe skin reactions, which may be accompanied by fever and/or elevations of transaminases, have been reported in 0.4% of patients. Stevens-Johnson Syndrome was rarely (< 0.1%) reported; and during post-marketing experience toxic epidermal necrolysis, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and acute generalized exanthematous pustulosis have been reported very rarely (< 0.01%).

Discontinue APO-DARUNAVIR 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 patients treated with darunavir (see 8 ADVERSE REACTIONS). 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 patients using darunavir/rtv was 0.5%.

Darunavir contains a sulfonamide moiety. APO-DARUNAVIR should be used with caution in patients with a known sulfonamide allergy. In clinical studies with darunavir/rtv, the incidence and severity of rash was similar in patients with or without a history of sulfonamide allergy.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/rtv + raltegravir compared to subjects receiving darunavir/rtv without raltegravir or raltegravir without darunavir/rtv. 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.

7.1 Special Populations

7.1.1 Pregnant Women

APO-DARUNAVIR should not be used during pregnancy unless the potential benefit justifies the potential risk.

There are no adequate and well-controlled studies with darunavir in pregnant women.

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. The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6 to 12 weeks). Virologic response was preserved throughout the study period in both arms. No mother to child transmission occurred in the infants born to the 31 subjects who stayed on the antiretroviral treatment through delivery. 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 (see 10.3 Pharmacokinetics).

Studies in animals have not shown evidence of developmental toxicity or effect on reproductive function and fertility. However, due to limited bioavailability and/or dosing limitations, animal exposures (based on AUC) were only 50% (mice and rats) and 5% (rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

The Antiretroviral Pregnancy Registry has received prospective reports of exposure to darunavir- containing regimens during pregnancies resulting in live births. The majority had first exposure in the first trimester. No safety concern relating to darunavir has been identified to date.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to APO-DARUNAVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

7.1.2 Breast-feeding

HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted into the milk of lactating rats and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both the potential for HIV transmission and the potential for serious adverse events in nursing infants, mothers should be instructed not to breast-feed if they are receiving APO-DARUNAVIR (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

7.1.3 Pediatrics

Pediatrics (<40 kg)

The pharmacokinetics, safety, tolerability and efficacy of APO- DARUNAVIR in pediatric patients < 40 kg have not been established.

Treatment-Naïve Pediatric Patients

The pharmacokinetics, safety, tolerability and efficacy of darunavir in antiretroviral treatment-naïve pediatric patients have not been established.

7.1.4 Geriatrics

Geriatrics (> 65 years of age)

Clinical studies of darunavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of APO-DARUNAVIR in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

During the clinical development program (n=3063), 65.9% of patients experienced at least one adverse drug reaction (ADR). The total mean exposure for patients was 57.5 weeks. The most common ADRs were diarrhea (23.7%), nausea (14.9%), headache (13.8%), and rash (10.3%). The majority of ADRs were mild or moderate in severity. The overall incidence of any Grade 3 or 4 ADR was 15.1%. The most common Grade 3 or 4 ADRs were diarrhea (1.3%) and those related to laboratory abnormalities, i.e., hepatic enzyme increased (3.4%), hypertriglyceridemia (2.9%), pancreatic enzyme increased (2.7%), and hypercholesterolemia (1.4%). Treatment discontinuation due to ADRs was frequent (2.5%). The most common ADRs leading to treatment discontinuation were hepatic enzyme increased (0.6%), rash (0.5%), diarrhea (0.3%), and nausea (0.3%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Antiretroviral Treatment-Naïve Adult Patients

The safety assessment is based on all safety data from the randomized, controlled, open-label Phase 3 trial TMC114-C211 comparing darunavir/rtv 800/100 mg q.d. versus lopinavir/ritonavir 800/200 mg per day in antiretroviral treatment-naïve HIV-1-infected adult patients. The total mean exposure in weeks for patients in the darunavir/rtv 800/100 mg q.d. arm and the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5, respectively.

Discontinuation due to adverse events/HIV-related events occurred in 4.7% of patients in the darunavir/rtv group and in 12.7% of patients in the LPV/rtv group.

The majority of the ADRs reported during treatment with darunavir/rtv 800/100 mg q.d. were mild in severity. The most common ADRs to darunavir/rtv 800/100 mg q.d. (≥5%) of at least moderate intensity (≥ Grade 2) were diarrhea, headache and abdominal pain.

ADRs to darunavir/rtv 800/100 mg q.d. of at least moderate intensity (≥ Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult patients are presented in Table 5.

Table 5: Adverse Drug Reactions^a of At Least Moderate Intensity (≥ Grade 2) Reported in ≥1% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Patients Who Received Darunavir/rtv 800/100 mg q.d.

Antiretroviral Treatment-Experienced Adult Patients

The safety assessment is based on all safety data from the randomized, controlled, open-label Phase 3 trial TMC114-C214 comparing darunavir/rtv 600/100 mg b.i.d. versus lopinavir/ritonavir 400/100 mg b.i.d. in antiretroviral treatment-experienced HIV-1-infected adult patients. The total mean exposure in weeks for patients in the darunavir/rtv 600/100 mg b.i.d. arm and the lopinavir/ritonavir 400/100 mg b.i.d. arm was 80.7 and 76.4, respectively.

Discontinuation due to adverse events/HIV-related events occurred in 7.7% of patients in the darunavir/rtv group and in 8.1% of patients in the LPV/rtv group.

The majority of the ADRs reported during treatment with darunavir/rtv 600/100 mg b.i.d. were mild in severity. The most common ADRs to darunavir/rtv 600/100 mg b.i.d. (≥5%) of at least moderate intensity (≥ Grade 2) were diarrhea, hypertriglyceridemia, hypercholesterolemia, nausea, abdominal pain, vomiting, lipodystrophy, hepatic enzymes increased and rash.

ADRs of at least moderate intensity (≥ Grade 2) and reported in ≥1% of patients treated with darunavir/rtv 600/100 mg b.i.d. in antiretroviral treatment-experienced HIV-1-infected adult patients are presented in Table 6.

Table 6: Adverse Drug Reactions^a of At Least Moderate Intensity (≥ Grade 2) Reported in ≥1% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Patients Who Received Darunavir/rtv 600/100 mg b.i.d.

Additional safety data was obtained from the randomized, controlled, open-label trial TMC114- C229 comparing darunavir/rtv 800/100 mg q.d. to darunavir/rtv 600/100 mg b.i.d. in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated mutations. ADRs of at least moderate intensity (≥ Grade 2) and reported in ≥1% of patients treated with darunavir are presented in Table 7.

Table 7: Adverse Drug Reactions^a of At Least Moderate Intensity (≥ Grade 2) Reported in ≥1% of Antiretroviral Treatment-Experienced HIV-1 Infected Adult Patients with No DRV-RAMs Who Received Darunavir/rtv 800/100 mg Once Daily and Darunavir/rtv 600/100 b.i.d.

Additional ADRs to darunavir/rtv Identified in Adult Patients in Other Clinical Trials

The additional ADRs of interest identified from other clinical trials were osteonecrosis (0.4%).

Serious ADRs

The following serious ADRs of at least moderate intensity (> Grade 2) occurred in the Phase 2b studies and Phase 3 studies with darunavir/rtv: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution inflammatory 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

The incidence of adverse events or clinical chemistry abnormalities, except for increased hepatic enzymes, was comparable in patients co-infected with hepatitis B or C virus and patients who were not co-infected. Patients co-infected with hepatitis B or C virus receiving darunavir/rtv were more likely to have baseline and treatment-emergent hepatic transaminase elevations than those without chronic viral hepatitis. Patients with chronic hepatitis B and/or C co-infection should be monitored appropriately.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The safety assessment in children and adolescents is based on the safety data from two Phase 2 trials: DELPHI (TMC114-C212) in which 80 antiretroviral treatment-experienced HIV-1- infected pediatric patients 6 to < 18 years of age and weighing at least 44 lbs (20 kg) received darunavir tablets in combination with low dose ritonavir and other antiretroviral agents (24- week data), and ARIEL (TMC114-C228) in which 21 antiretroviral treatment-experienced HIV-1 infected pediatric patients aged from 3 to < 6 years and weighing ≥10 kg to < 20 kg received darunavir oral suspension in combination with low dose ritonavir and other antiretroviral agents (48-week data) (see 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics and 14 CLINICAL TRIALS).

In DELPHI (TMC114-C212), the mean duration of patient exposure to DRV/rtv at the time of the data cut-off for the Week 24 analysis was 39.5 (±11.02) weeks. Total patient years of exposure was 60.8 years. Frequency, type and severity of adverse drug reactions in pediatric patients were comparable to those observed in adults. The overall incidence of ADRs was 40%. The most common ADRs (all Grades, ≥ 3%) were vomiting (12.5%), diarrhea (11.3%), 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%). The majority of ADRs were mild or moderate in severity. There were no ADRs leading to treatment discontinuation in the Week 24 analysis of the TMC114-C212 trial.

In ARIEL (TMC114-C228), the mean duration of patient exposure to DRV/rtv at the time of the data cut-off for the Week 48 analysis was 47.93 (±2.350) weeks. Total patient-years of exposure was 19.4. Frequency, type and severity of adverse drug reactions in pediatric patients were comparable to those observed in adults, and in treatment-experienced children between 6 and 18 years of age. The overall incidence of ADRs was 47.9%. The most common ADRs (all Grades, ≥ 3%) were diarrhea (24%), vomiting (19%), rash (14%), abdominal pain (5%), anorexia (5%), and hyperglycemia (5%). All laboratory abnormalities, except one (Grade 3 decreased neutrophils), were Grade 1 or 2 in severity.

8.3 Less Common Clinical Trial Adverse Reactions

Antiretroviral Treatment-Naïve Adult Patients: Less Common Clinical Trial Adverse Drug Reactions (<1%)

Adverse drug reactions occurring in less than 1% of patients receiving darunavir/rtv considered at least possibly related to treatment and of at least moderate intensity are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence

General Disorders and Administration Site Conditions: asthenia, fatigue

Hepatobiliary Disorders: acute hepatitis

Immune System Disorders: (drug) hypersensitivity^†, immune reconstitution inflammatory syndrome

Metabolism and Nutrition Disorders: diabetes mellitus

Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis

Psychiatric Disorders: abnormal dreams

Skin and Subcutaneous Tissue Disorders: angioedema^†, lipodystrophy (lipohypertrophy, lipodystrophy and lipoatrophy), pruritus, Stevens-Johnson Syndrome, urticaria^†

^†Adverse drug reaction also identified from post-marketing experience

Antiretroviral Treatment-Experienced Adult Patients: Less Common Clinical Trial Adverse Drug Reactions (<1%)

Adverse drug reactions occurring in less than 1% of patients receiving darunavir/rtv, considered at least possibly related to treatment and of at least moderate intensity are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, flatulence

Immune System Disorders: immune reconstitution inflammatory syndrome

Psychiatric Disorders: abnormal dreams

Reproductive and Breast Disorders: gynecomastia

Skin and Subcutaneous Tissue Disorders: urticaria^†

^†Adverse drug reaction also identified from post-marketing experience

8.4 Abnormal Hematologic and Clinical Chemistry Findings

Antiretroviral Treatment-Naïve Adult Patients

The percentages of antiretroviral treatment-naïve HIV-1-infected adult patients treated with darunavir/rtv 800/100 mg q.d. with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 8.

Table 8: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1- Infected Adult Patients

Antiretroviral Treatment-Experienced Adult Patients

The percentages of antiretroviral treatment-experienced HIV-1-infected adult patients treated with darunavir/rtv 600/100 mg b.i.d. with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 9.

Table 9: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV- 1-Infected Adult Patients

Except for a lower incidence of diarrhea and Grade 3 or 4 increases in triglycerides, and a higher incidence of rash-related AEs with DRV/rtv than with LPV/rtv, there were no clinically relevant differences in the overall safety profile for DRV/rtv 600/100 mg b.i.d. and LPV/rtv 400/100 mg b.i.d in the TMC114-C214 study.

The percentages of antiretroviral treatment-experienced HIV-1-infected adult patients with no darunavir resistance-associated mutations treated with darunavir/rtv 800/100 mg once daily and darunavir/rtv 600/100 b.i.d. with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 10.

Table 10: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Patients with No RAMS

8.5 Post-Market Adverse Reactions

In addition to adverse events identified in clinical trials, the following post-marketing events have been included due to their seriousness, frequency of reporting, potential causal association with darunavir/rtv, or a combination of these factors. Because they are reported spontaneously from a population of unknown size, estimates of incidence cannot be made.

Blood and Lymphatic System Disorders: anemia, pancytopenia, thrombocytopenia and neutropenia

Cardiac Disorders: bradycardia, myocarditis

Eye Disorders: eye swelling, uveitis, maculopathy, blurred vision

Gastrointestinal Disorders: pancreatitis, pancreatitis relapsing, rectal hemorrhage, gastritis

Hepatobiliary Disorders: bile duct obstruction, hepatic cirrhosis, hepatic failure, hepatitis, hepatotoxicity, jaundice

Infections and Infestations: clostridial infection, cryptosporidiosis infection, cytomegalovirus encephalitis, hepatitis B, esophageal candidiasis, progressive multifocal leukoencephalopathy, sepsis

Investigations: blood alkaline phosphatase increased, blood bilirubin increased, abnormal liver function test

Immune System Disorder: drug hypersensitivity, immune reconstitution inflammatory syndrome, autoimmune disorders such as Graves’ disease and autoimmune hepatitis.

Injury, Poisoning and Procedural Complications: drug toxicity

Metabolism and Nutrition Disorders: dehydration, hyperkalemia, metabolic acidosis

Musculoskeletal and Connective Tissue Disorders: myositis, osteonecrosis, rhabdomyolysis, sensation of heaviness, arthritis, bone pain, pain in extremities, arthropathy

Neoplasms Benign, Malignant and Unspecified: diffuse large B-cell neoplasm, malignant hepatic neoplasm, lymphoma

Nervous System Disorders: altered state of consciousness, cerebrovascular accident, dizziness, facial palsy, grand mal convulsion, ischemic cerebral infarction, nervous system disorder, neuromyopathy, petit mal epilepsy

Psychiatric Disorders: completed suicide, anxiety, depression

Renal and Urinary Disorders: acute renal failure, hematuria, renal tubular necrosis, creatinine renal decreased, GFR decreased, renal failure, proteinuria, crystal nephropathy

Respiratory, Thoracic and Mediastinal Disorders: acute respiratory distress syndrome, pharyngeal lesion, pneumothorax, respiratory failure, pulmonary edema, epistaxis

Skin and Subcutaneous Tissue Disorders: angioedema, rash, swelling face, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, acute generalized exanthematous pustulosis, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms)

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

APO-DARUNAVIR should not be used in combination with other antiretrovirals that are also administered with a pharmacokinetic enhancer (e.g. ritonavir or cobicistat).

Darunavir and ritonavir are both inhibitors of the cytochrome P450 isoform CYP3A4 and CYP2D6 and the transporter P-gp. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A4, CYP2D6, or transported by P-gp and/or OATP1B may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions, Tables 11 and 12). Co-administration of darunavir/cobi or darunavir/rtv 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 9.4 Drug-Drug Interactions, Table 12).

9.4 Drug-Drug Interactions

Drugs that are contraindicated and not recommended for co-administration with darunavir/ rtv are included in Table 11. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Drug-drug interactions presented by drug class including drug name examples are presented below. This list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with darunavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.

Table 11: Drugs that are CONTRAINDICATED with darunavir/rtv

Established and other potentially significant drug interactions with darunavir/rtv are included in Table 12. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 12: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (See Tables 14 and 15)

Other NRTIs

Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and darunavir/rtv.

Other Protease Inhibitors

The co-administration of darunavir/rtv and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.

CCR5 Antagonist

When used in combination with darunavir/rtv, the dose of maraviroc should be 150 mg twice daily.

An interaction trial between darunavir/rtv (600/100 mg b.i.d.) and maraviroc (150 mg b.i.d.) demonstrated that in the presence of darunavir/rtv the exposure of maraviroc was increased by 305%. There was no apparent effect of maraviroc on darunavir/ritonavir exposure.

See also 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS.

Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co- administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong the therapeutic effect and adverse events.

Darunavir and ritonavir are metabolized by CYP3A. 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 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 13 (effect of other drugs on darunavir) and Table 14 (effect of darunavir on other drugs).

Table 13: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co- administered Drugs

Table 14: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir

9.5 Drug-Food Interactions

Darunavir, when given as a tablet and co-administered with low-dose ritonavir as a pharmacokinetic enhancer, should be taken with food. The type of food does not affect the exposure to darunavir.

Effects of Food on Oral Absorption

When administered without food, the relative bioavailability of darunavir in the presence of low-dose ritonavir is 30% lower as compared to intake with food. Therefore, APO-DARUNAVIR tablets should be taken with ritonavir and with food.

9.6 Drug-Herb Interactions

Concomitant use of darunavir/rtv and St. John’s wort (Hypericum perforatum) or products containing St. John’s wort is contraindicated. Co-administration of protease inhibitors (PIs), including darunavir/rtv, with St. John’s wort is expected to substantially decrease PI concentrations and may result in suboptimal concentrations of darunavir and lead to loss of virologic response and possible resistance to darunavir/rtv or to the class of PIs (see 9.4 Drug- Drug Interactions, Table 11).

Interactions with other herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Darunavir is an inhibitor of the dimerization and of the catalytic activity of the HIV-1 protease.

It selectively inhibits the cleavage of HIV-encoded Gag-Pol polyproteins in virus-infected cells, thereby preventing the formation of mature infectious virus particles.

Darunavir tightly binds to the HIV-1 protease with a K_D of 4.5 x 10^-12 M.

Darunavir is not an inhibitor of any of 13 tested human cellular proteases.

10.2 Pharmacodynamics

Electrocardiogram (Effect on QT Intervals)

In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were administered supratherapeutic doses of darunavir/ritonavir 1,600/100 mg once daily and 800/100 mg twice daily for seven days.

At the mean maximum darunavir concentration of 6,599 ng/mL observed in this study, the mean increase in QTcF was 2.2 ms with a 90% two-sided confidence interval (CI) of –2.0 to 6.3 ms. When evaluating the two-sided 90% CI on the time-matched mean changes in QTcF versus placebo control, the upper bounds of both darunavir/ritonavir groups never exceeded the 10 ms boundary. In the setting of this trial, darunavir/ritonavir did not appear to prolong the QTc interval.

10.3 Pharmacokinetics

General

Darunavir is primarily metabolized by CYP3A4. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally co-administered with ritonavir at 100 mg b.i.d. Therefore, darunavir should only be co-administered with 100 mg of ritonavir as a pharmacokinetic enhancer.

Table 15: Pharmacokinetic Parameters of Darunavir 600 mg and Darunavir/rtv at 600/100 mg b.i.d.

Absorption

Absorption and Bioavailability

Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low-dose ritonavir is generally achieved within 2.5 to 4.0 hours.

The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg b.i.d. ritonavir. Increasing the dose of ritonavir to above 100 mg b.i.d. did not significantly affect darunavir concentrations. It is not recommended to alter the dose of ritonavir. In vivo data suggest that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporter.

The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1-infected patients. Exposure to darunavir was higher in HIV-1-infected patients than in healthy patients. Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.

Table 16 displays the mean plasma concentrations of darunavir at steady-state for the darunavir/ritonavir 800/100 mg q.d. dose.

Table 16: Mean Steady-State Plasma Concentration-Time Profiles of Darunavir and Ritonavir at 800/100 mg q.d. at Week 4 (Study TMC114-C211)

Table 17 displays the mean plasma concentrations of darunavir and ritonavir at steady-state for the darunavir/ritonavir 600/100 mg b.i.d. dose.

Table 17: Mean Steady-State Plasma Concentration-Time Profiles of Darunavir and Ritonavir at 600/100 mg b.i.d. at Week 4 (Integrated Data from POWER 1 and POWER 2, Primary 24- Week Analysis)

APO-DARUNAVIR tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir (See 4 DOSAGE AND ADMINISTRATION and 9.5 Drug-Food Interactions).

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 the hepatic CYP system, and almost exclusively by isozyme CYP3A4. A ¹⁴C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir/ritonavir dose was due to the parent drug. At least three oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild-type HIV.

Elimination

After a 400/100 mg ¹⁴C-darunavir/ritonavir dose, approximately 79.5% and 13.9% of the administered dose of ¹⁴C-darunavir could be retrieved in 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 combined with ritonavir. The intravenous clearance of darunavir alone (150 mg) and in the presence of low-dose ritonavir was 32.8 L/h and 5.9 L/h, respectively.

Special Populations and Conditions

• Pediatrics: The pharmacokinetics of darunavir in combination with ritonavir in 74 antiretroviral treatment- experienced HIV-1-infected pediatric patients 6 to <18 years of

  • age and weighing at least 44 lbs (20 kg) showed that the administered weight-based dosages resulted in darunavir exposure comparable to that in adults receiving darunavir/rtv 600/100 mg b.i.d. (see 4 DOSAGE AND ADMINISTRATION).

Table 18: Population Pharmacokinetic Estimates of Darunavir Exposure (Study TMC114-C212) Following Administration of Doses in Table3^a

• Geriatrics: Population pharmacokinetic analysis in HIV-1-infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected patients (n=12, age ≥ 65) (see 7.1.4 Geriatrics).
• Sex: Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV-1-infected females (n=68) compared to males. This difference is not considered clinically relevant.

• Pregnancy and Breast-feeding

  Pregnancy and Postpartum

  The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg b.i.d and darunavir/ritonavir 800/100 mg q.d. as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Table 19 and Table 20). However, for unbound (i.e., active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.

  Table 19: Pharmacokinetic Results of Total darunavir After Administration of darunavir/ritonavir at 600/100 mg bid as Part of an Antiretroviral Regimen, During the 2^nd Trimester of Pregnancy, the 3^rd Trimester of Pregnancy and Postpartum

Table 20: Pharmacokinetic Results of Total darunavir After Administration of darunavir/ritonavir at 800/100 mg qd as Part of an Antiretroviral Regimen, During the 2^nd Trimester of Pregnancy, the 3^rd Trimester of Pregnancy and Postpartum

In women receiving darunavir/ritonavir 600/100 mg b.i.d during the 2^nd trimester of pregnancy, mean intra-individual values for total darunavir C_max, AUC_12h and C_min were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the 3^rd trimester of pregnancy, total darunavir C_max, AUC_12h and C_min values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg q.d during the 2^nd trimester of pregnancy, mean intra-individual values for total darunavir C_max, AUC_24h and C_min were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the 3^rd trimester of pregnancy, total darunavir C_max, AUC_24h and C_min values were 29%, 32% and 50% lower, respectively, as compared with postpartum.

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

• Hepatic Insufficiency

  Hepatic Impairment

  In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the steady-state pharmacokinetic parameters of darunavir in patients with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy patients. The effect of severe hepatic impairment of on the pharmacokinetics of darunavir has not been studied (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS, and 4 DOSAGE AND ADMINISTRATION).

  Hepatitis B or Hepatitis C Virus Co-infection

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

• Renal Insufficiency: 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. Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected patients with moderate renal impairment (CrCL between 30–60 mL/min, n=20) (see 4.2 Recommended Dose and Dosage Adjustment, Renal Impairment and 7 WARNINGS AND PRECAUTIONS, Renal).

Population Pharmacokinetics in HIV-1 patients

Population pharmacokinetic analysis in HIV-1-infected patients showed that darunavir pharmacokinetics is not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected patients. Population pharmacokinetic analysis showed a slightly higher darunavir exposure in HIV-1-infected females compared to males. This difference is not considered clinically relevant.

Population pharmacokinetic analysis of darunavir in HIV-1-infected patients indicated that race had no apparent effect on the exposure to darunavir. The steady-state pharmacokinetic parameters of darunavir in patients with mild and moderate hepatic impairment were comparable with those in healthy patients, therefore, no dose adjustment is required in patients with mild or moderate hepatic impairment. Darunavir has not been studied in patients with severe hepatic impairment.

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected patients with moderate renal impairment. There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease. However, since the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment.

The population pharmacokinetics derived geometric mean (SD) C0h and AUC_12h for darunavir in 119 HIV-1-infected patients (TMC114-C213 and TMC114-C202, Primary 24-Week Analysis) receiving [600/100 mg b.i.d. darunavir/ritonavir] is 3578 (±1151) ng/mL and 62349 (±16143) ng.h/mL, respectively.

The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected patients. Table 21 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir/rtv 600/100 mg twice daily [based on sparse sampling in 285 patients in study TMC114-C214 and 119 patients (integrated data) from Studies TMC114-C202 and TMC114-C213] and darunavir/rtv 800/100 mg once daily [based on sparse sampling in 335 patients in Study TMC114-C211 and 280 patients in Study TMC114-C229] to HIV-1-infected patients.

Table 21: Population Pharmacokinetic Estimates of Darunavir at darunavir/rtv 800/100 mg once daily (Study TMC114-C211, 48-Week Analysis and Study TMC114-C229, 48-Week Analysis) and darunavir/rtv 600/100 mg twice daily (Study TMC114-C214, 48-Week Analysis and Integrated data from Studies TMC114-C213 and TMC114-C202, Primary 24-Week Analysis)

N = number of patients with data. ^a AUC_24h is calculated as AUC_12h *2

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15°C to 30°C.

Keep out of reach and sight of children.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Darunavir

Chemical name: [(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester

Molecular formula and molecular mass: C₂₇H₃₇N₃O₇S and 547.66 g/mol

Structural formula:

O O NH N S O O NH₂ CH₃ CH₃ OH O O

Physicochemical properties:

Physical Description: Darunavir is a white to off-white powder.

Solubility: Soluble in DMSO

14 CLINICAL TRIALS

General

The evidence of efficacy of darunavir/rtv is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211 [ARTEMIS]) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214 [TITAN]) HIV-1-infected adult patients, and the analysis of 48-week data from one randomized, open-label Phase 3 trial in early treatment experienced HIV-1-infected adult patients (TMC114-C229 [ODIN]).

In addition, 96-week data is included from 2 randomized, controlled Phase 2b trials, TMC114-

C213 (POWER 1) and TMC114-C202 (POWER 2), in antiretroviral treatment-experienced HIV- 1-infected adult patients, and 96-week data is included from the open label trial TMC114-C215 (POWER 3) in patients who initiated darunavir/rtv at the recommended dose.

14.1 Clinical Trials by Indication

Antiretroviral Treatment-Naïve Adult Patients

TMC114-C211 (ARTEMIS)

Demographics and Trial Design

The evidence of efficacy of darunavir/rtv 800/100 mg q.d. is based on the analyses of 192- week data from the randomized, controlled, open-label, Phase 3 trial TMC114-C211 in antiretroviral treatment-naïve HIV-1-infected patients comparing darunavir/rtv 800/100 mg q.d. with lopinavir/rtv 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg q.d. (TDF) and emtricitabine 200 mg q.d. (FTC).

HIV-1 infected patients who were eligible for this trial had plasma HIV-1 RNA > 5000 copies/mL. Randomization was stratified by screening plasma viral load and screening CD4+ cell count. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load < 50 copies/mL. Analyses included 689 patients in Study TMC114-C211 who had completed 48 and 192 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the darunavir/rtv arm and the lopinavir/rtv arm (see Table 22). Table 22 compares the demographic and baseline characteristics between patients in the darunavir/rtv 800/100 mg q.d. arm and patients in the lopinavir/ritonavir 800/200 mg per day arm in the ARTEMIS trial. The 343 patients on darunavir/rtv 800/100 mg q.d. had a median age of 34 years (range 18 to 70), 70% were male, 40% white, 23% black, 23% hispanic, and 13% asian. The mean baseline plasma HIV-1 RNA was 4.86 log₁₀ copies/mL and the median baseline CD4+ cell count was 228 x 10⁶ cells/L (range 4 – 750 x 10⁶ cells/L).

Table 22: Demographic and Baseline Characteristics of Patients in TMC114-C211 Trial

Study Results

According to the statistical methods for analysis at Week 48 and Week 192 in the TMC114- C211 protocol, if at each time point, the lower limit of the 95% two-sided CI of the difference between DRV/rtv and LPV/rtv exceeded -12% (for the On-Protocol (OP) population), noninferiority of DRV/rtv versus LPV/rtv could be concluded for that time point. Noninferiority in virologic response (HIV-1 RNA < 50 copies/mL) with darunavir/rtv 800/100 mg q.d. compared to treatment with lopinavir/ritonavir 800/200 mg per day was demonstrated through 48 weeks of treatment (83.7% in the darunavir/rtv 800/100 mg q.d arm versus 78.3% in the lopinavir/ritonavir 800/200 mg per day arm) (p< 0.001). The difference (95% CI) in response at Week 48 between DRV and LPV is 5.5% (-0.4 to 11.4) for <50 copies/mL and 2.7% (-2.4 to 7.8) for 400 copies/mL.

Analyses of the data at 192 weeks of treatment in the ARTEMIS trial demonstrated sustained antiretroviral efficacy and immunological benefit of the darunavir/rtv arm. In the 192-week analysis, virologic response (HIV-1 RNA<50 copies/mL) in the ITT population was 68.8% and 57.2% for the darunavir/rtv and lopinavir/rtv arm, respectively. Non-inferiority in virologic response was demonstrated (p<0.001) for both ITT and OP population. Furthermore, statistical superiority of the darunavir/rtv arm over the lopinavir/rtv arm was demonstrated (p=0.002) for both ITT and OP population.

Week 48 and 192 week outcomes for patients in the On-Protocol population on darunavir/rtv

800/100 mg q.d. from the ARTEMIS trial are shown in Table 23.

Table 23: Outcomes of Randomized Treatment Through Week 48 and 192 of the TMC114-C211 Trial for the On-Protocol Population

The mean changes in plasma HIV-1 RNA from baseline in the ITT population were –2.77 log₁₀ copies/mL at 48 weeks (-2.35 log₁₀ copies/mL at 192 weeks) in the arm receiving darunavir/rtv 800/100 mg q.d. and –2.65 log₁₀ copies/mL at 48 weeks (-2.03 log₁₀ copies/mL at 192 weeks) for the arm receiving lopinavir/ritonavir 800/200 mg per day. The median increase from baseline in CD4+ cell counts was comparable for both treatment groups (148 cells/mm³ and 148 cells/mm³ at 48 weeks (266 cells/mm³ and 269 cells/mm³ at 192 weeks) in the darunavir/rtv 800/100 mg q.d. arm and the lopinavir/ritonavir 800/200 mg per day arm, respectively).

The virological response (< 50 copies/mL) by baseline viral load for all ITT patients is presented in Table 24. For patients with baseline VL < 100,000 copies/mL, responses were similar for darunavir/rtv and lopinavir/ritonavir; patients with baseline VL ≥100,000 copies/mL receiving darunavir/ritonavir had a statistically superior virological response (< 50 copies/mL) than lopinavir/rtv (67.5 % vs. 51.7%; p= 0.012).

Table 24: Virological Response (< 50 copies/mL) at 192 Weeks by BaselineViral Load and Baseline CD4+ Cell Count

Antiretroviral Treatment-Experienced Adult Patients

The evidence of comparable efficacy of darunavir/rtv 800/100 mg q.d. and darunavir/rtv 600/100 mg b.i.d. in treatment-experienced patients with no darunavir resistance associated mutations is based on the 48 week analysis of the Phase 3 trial TMC114-C229 (ODIN).

The evidence of efficacy of darunavir/rtv 600/100 mg b.i.d. in treatment experienced patients is based on the 96 week analysis of the Phase 3 trial TMC114-C214 (TITAN) in treatment experienced, lopinavir/rtv naïve patients and on the analyses of 96 week data from the Phase 2b trials POWER 1, 2 and 3, in patients with high level of PI resistance.

TMC114-C229 (ODIN)

Demographics and Trial Design

Study TMC114-C229 is a randomized, open-label trial comparing darunavir/rtv 800/100 mg q.d.

to darunavir/rtv 600/100 mg b.i.d. in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated mutations (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T47P, L76V, I84V, L89V) and a screening viral load of >1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of ≥2 NRTIs selected by the investigator.

HIV-1-infected patients who were eligible for this trial were on a stable highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load <50 copies/mL. Analyses included 590 patients who had completed 48 weeks of treatment or discontinued earlier (ITT population). Table 25 compares the demographic and baseline characteristics between patients in the darunavir/rtv 800/100 mg q.d. and patients in the darunavir/rtv 600/100 mg b.i.d. arm in study TMC114- C229. No imbalances between the two arms were noted. The majority of the patient population (>87%) was not co-infected with hepatitis B and/or hepatitis C virus.

Table 25: Demographic and Baseline Characteristics of Patients in Study TMC114-C229 (ITT Population^a)

The evidence of comparable efficacy of darunavir/rtv 800/100 mg q.d. and darunavir/rtv 600/100 mg b.i.d. in treatment-experienced patients with no darunavir resistance associated mutations is based on the 48 week analysis of the Phase 3 trial TMC114-C229 (ODIN).

Study Results

In the 48-week primary analysis, the virologic response defined as a confirmed plasma HIV-1 RNA viral load <50 copies/mL (ITT, TLOVR), was 72.1% for the darunavir/rtv q.d. arm and 70.9% for the darunavir/rtv b.i.d. arm (difference = 1.2%, 95% CI = [-6.1; 8.5]). Statistical comparisons between the treatment arms at Week 48 based on a normal approximation of the difference in virologic response, confirmed non-inferiority of darunavir/rtv q.d. versus darunavir/rtv b.i.d. for both the ITT and OP populations (p-value<0.001). A summary of all Week 48 outcomes for patients on darunavir/rtv 800/100 mg q.d. from study TMC114-C229 are shown in Table 26.

Table 26: Outcomes of Randomized Treatment Through Week 48 of Study TMC114-C229

At Week 48, the mean change in log₁₀viral load from baseline in the ITT population was -1.84 and -1.80 log₁₀ copies/mL for the DRV/rtv q.d. and DRV/rtv b.i.d. groups, respectively. The difference in mean change and 95% confidence interval in log₁₀ viral load from baseline between treatment groups at Week 48 was -0.04 (-0.24, 0.16). Statistical comparison (ITT-ANCOVA) showed an estimated difference (difference between LS Means and the 95% CI) between the DRV/rtv q.d. and the b.i.d. treatment groups at 48 weeks of -0.003 (-0.188, 0.182) (p=0.977).

The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm³ and 112 cells/mm³ in the darunavir/rtv 800/100 mg q.d. arm and the darunavir/rtv 600/100 mg b.i.d. arm, respectively).

Study TMC114-C214 (TITAN)

Demographics and Trial Design

Study TMC114-C214 was an ongoing randomized, controlled, open label Phase 3 trial comparing darunavir/rtv 600/100 mg b.i.d. versus lopinavir/rtv 400/100 mg b.i.d. in antiretroviral treatment-experienced, lopinavir/rtv naïve HIV-1 infected adult patients. Both arms used an optimized background regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

HIV-1 infected patients who were eligible for this trial had plasma HIV-1 RNA > 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 < 400 copies/mL. Analyses included 595 patients in the TITAN trial who had completed 96 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the darunavir/rtv arm and the lopinavir/ritonavir arm. Table 27 compares the demographic and baseline characteristics between patients in the darunavir/rtv 600/100 mg b.i.d. arm and patients in the lopinavir/ritonavir 400/100 mg b.i.d. arm in study TMC114-C214.

Table 27: Demographic and Baseline Characteristics of Patients in Study TMC114-C214

Study Results

According to the statistical methods in the TMC114-C214 protocol, if the lower limit of the 95% 2-sided CI of the difference between DRV/rtv and LPV/rtv exceeded –12% (for the On-protocol (OP) population), noninferiority of DRV/rtv versus LPV/rtv was concluded. Week 48 and 96 outcomes for patients on darunavir/rtv 600/100 mg b.i.d. from study TMC114-C214 are shown in Table 28.

Table 28: Outcomes of Randomized Treatment Through Week 48 and 96 of Study TMC114-C214

Through 96 weeks of treatment, there was a significantly greater proportion of patients with HIV-1 RNA < 400 copies/mL and with HIV-1 RNA < 50 copies/mL in the arm receiving darunavir/rtv 600/100 mg b.i.d. (67.5% and 61.4%, respectively) compared to the arm receiving lopinavir/ritonavir 400/100 mg b.i.d. (59.5% and 55.8%, respectively). The difference (95% CI) in response at Week 96 between DRV and LPV is 8.0% (0.1 to 15.8) for <400 copies/mL and 5.6% (2.4 to 13.7) for <50 copies/mL.

Noninferiority in virologic response (HIV-1 RNA < 400 copies/mL) with darunavir/rtv 600/100 mg b.i.d. compared to treatment with lopinavir/ritonavir 400/100 mg b.i.d. was demonstrated (p < 0.001), furthermore superiority of darunavir/rtv over the lopinavir/rtv arm was demonstrated (p = 0.033).

The proportion of patients with at least 1 log₁₀ HIV-1 RNA below baseline was 77.7% in the arm receiving darunavir/rtv 600/100 mg b.i.d. compared to 69.3% in the arm receiving lopinavir/ritonavir 400/100 mg b.i.d. At week 96, the mean changes in plasma HIV-1 RNA from baseline were -1.72 log₁₀ copies/mL in the arm receiving darunavir/rtv 600/100 mg b.i.d. and -1.54 log₁₀ copies/mL for the arm receiving lopinavir/ritonavir 400/100 mg b.i.d. The median increase from baseline in CD4+ cell counts was comparable for both treatment groups (81 cells/mm³ and 96 cells/mm³ in the darunavir/rtv 600/100 mg b.i.d. arm and lopinavir/ritonavir 400/100 mg b.i.d. arm, respectively).

TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2)

Demographics and Trial Design

Studies TMC 114-C213 (Power 1) and TMC114-C202 (Power 2) are randomized, controlled Phase 2b trials in patients 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 patients randomized to darunavir/rtv received the recommended dose of 600/100 mg b.i.d.

HIV-1-infected patients who were eligible for these trials had plasma HIV-1 RNA > 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, I84A/C/V, 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 patients receiving darunavir/rtv plus an optimized background regimen (OBR) versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Based on resistance testing and prior medical history, selected PIs in the control arm included: lopinavir/ritonavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 23% of the control patients used dual-boosted PIs. Approximately 47% of all patients used enfuvirtide (ENF), and 35% of the use was in patients who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log₁₀ versus baseline.

In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the darunavir/rtv arm and the comparator PI arm. Table 29 compares the demographic and baseline characteristics between patients in the darunavir/rtv 600/100 mg b.i.d. arm and patients in the comparator PI arm in the pooled analysis of studies TMC114-C213 and TMC114-C202.

Table 29: Demographic and Baseline Characteristics of Patients in Studies TMC114-C213 and TMC114-C202 (Pooled Analysis)

Study Results

Week 48 outcomes for patients on the recommended dose darunavir/rtv 600/100 mg b.i.d. from the pooled studies TMC114-C213 and TMC114-C202 are shown in Table 30.

Table 30: Outcomes of Randomized Treatment Through Week 48 of the Studies TMC114-C213 and TMC114-C202 (Pooled Analysis)

In the pooled TMC114-C213 and TMC114-C202 analysis through 48 weeks of treatment, the proportion of patients with HIV-1 RNA < 400 copies/mL in the arm receiving darunavir/rtv 600/100 mg b.i.d. compared to the comparator PI arm was 55.0% and 14.5%, respectively (p<0.001). In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log₁₀ copies/mL in the arm receiving darunavir/rtv 600/100 mg b.i.d. and –0.37 log₁₀ copies/mL for the comparator PI arm (p<0.001). The mean increase from baseline in CD4+ cell counts was higher in the arm receiving darunavir/rtv 600/100 mg b.i.d. (103 cells/mm³) than in the comparator PI arm (17 cells/mm³) (p<0.001).

Analyses of the data through 96 weeks of treatment in the pooled TMC114-C213 and TMC114- C202 trials demonstrated sustained antiretroviral efficacy and immunological benefit. Treatment with darunavir/rtv 600/100 mg b.i.d. resulted in 56.5% of patients with a decrease of at least 1 log₁₀ HIV-1 RNA versus baseline and 38.9% of patients reaching less than 50 HIV-1 RNA copies/mL. At Week 96, 49.6% of patients reached less than 400 HIV-1 RNA copies/mL, and the mean change in plasma HIV-1 RNA from baseline was -1.58 log₁₀ copies/mL. The mean increase in CD4+ cell count versus baseline was 133 cells/mm³ at Week 96.

TMC114-C215 (POWER 3)

Demographics and Trial Design

Additional data on the efficacy of darunavir/rtv 600/100 mg b.i.d. have been obtained in treatment-experienced patients participating in the non-randomized trial TMC114-C215. The 318 patients included in the 96-week efficacy analysis initiated therapy with darunavir/rtv with the recommended dose of 600/100 mg b.i.d. The OBR consisted of at least two NRTIs with or without enfuvirtide. Entry criteria for Study TMC114-C215 were the same as those for TMC114- C213 (POWER 1) and TMC114-C202 (POWER 2) trials.

Baseline characteristics of the patients included in TMC114-C215 trial were comparable to those patients in TMC114-C213 and TMC114-C202 trials.

Study Results

The TMC114-C215 48-week efficacy analysis supported the viral load reduction and CD4+ cell count increases observed in the TMC114-C213 and TMC114-C202 trials. Of the 334 patients at Week 48, 58.7% had a virologic response defined as a decrease of at least 1.0 log₁₀ HIV-1 RNA versus baseline and 46.4% of the patients reached less than 50 HIV-1 RNA copies/mL. At Week 48, 54.8% of the patients reached less than 400 HIV-1 RNA copies/mL, and the mean changes in plasma HIV-1 RNA from baseline were -1.62 log₁₀ copies/mL. The mean increase in CD4+ cell count versus baseline was 105 cells/mm³ at Week 48.

Analyses of the data through 96 weeks of treatment in the non-randomized trial TMC114-C215 demonstrated sustained antiretroviral efficacy and immunological benefit. Of the 318 patients at Week 96, 52.2% had a virologic response defined as a decrease of at least 1.0 log₁₀ HIV-1 RNA versus baseline and 42.1% of the patients reached less than 50 HIV-1 RNA copies/mL. At Week 96, 50.0% of the patients reached less than 400 HIV-1 RNA copies/mL, and the mean change in plasma HIV-1 RNA from baseline was -1.43 log₁₀ copies/mL. The mean increase in CD4+ cell count versus baseline was 103 cells/mm³ at Week 96.

TMC114-C213, TMC114-C202 and TMC114-C215 Trials

Out of the 206 patients who responded with complete viral suppression (< 50 HIV-1 RNA copies/mL) at Week 48, 86% of patients remained responders at Week 96.

Pediatric Patients

Treatment-Experienced Pediatric Patients

The evidence of efficacy of darunavir/rtv in antiretroviral treatment-experienced pediatric patients is based on one Phase 2 trial.

TMC114-C212 (DELPHI)

Demographics and Trial Design

Study TMC114-C212 (DELPHI) is an open-label, Phase 2 trial of 48 week duration evaluating the pharmacokinetics, safety, tolerability, and efficacy of darunavir/rtv in 80 antiretroviral treatment-experienced HIV-1-infected pediatric patients 6 to < 18 years of age and weighing at least 44 lbs (20 kg).

At Week 24, the virologic response rate was evaluated in pediatric patients receiving darunavir/rtv in combination with other antiretroviral agents (see 4 DOSAGE AND ADMINISTRATION)for dosage recommendations per body weight). Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log₁₀ versus baseline. The mean baseline plasma HIV-1 RNA was 4.64 log₁₀ copies/mL, and the median baseline CD4+ cell count was 330 cells/mm³ (range: 6 to 1505 cells/mm³).

In the study, pediatric patients 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 patients taking ritonavir oral solution, 23 patients switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

Study Results

At Week 24, 73.8% of pediatric patients had at least 1 log₁₀ HIV-1 RNA decrease from baseline. The proportion of pediatric patients reaching undetectable viral load (< 50 HIV-1 RNA copies/mL) was 50.0%, and the proportion of pediatric patients with < 400 HIV-1 RNA copies/mL was 63.8%. The mean change in plasma HIV-1 RNA from baseline was -1.98 log₁₀ copies/mL. The mean CD4+ cell count increase from baseline was 117 cells/mm³ and the median CD4+ cell count increase was 96 cells/mm³ (range: -232 to 465 cells/mm³).

14.2 Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of APO-DARUNAVIR 800 mg tablets (Apotex Inc.) and PREZISTA® 800 mg tablets (Janssen Inc.), with co-administration of NORVIR® (ritonavir) 100 mg tablets (Abbott Laboratories Ltd.) twice daily, was conducted in healthy, adult, male subjects under high-fat, high-calorie fed conditions. Comparative bioavailability data from 42 subjects that were included in the statistical analysis are presented in the following table:

¹ APO-DARUNAVIR (darunavir) tablets, 800 mg (Apotex Inc.)

² PREZISTA^® (darunavir) tablets, 800 mg (Janssen Inc.)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

TMC114-TiDP3-C162

In a Phase 1, open-label, randomized, two-panel, two-way crossover bioavailability trial the rate and extent of absorption of darunavir following administration of two tablet strengths (in the presence of low-dose ritonavir) under fed and fasted conditions was assessed in 96 healthy subjects.

In Panel 1, 47 male and female subjects randomly received under fasted conditions a single oral 600 mg dose of darunavir formulated as the 300 mg tablet (2 x 300 mg; Treatment A) in one session, followed by a single oral 600 mg dose formulated as the 600 mg tablet (1 x 600 mg; Treatment B) in the second session. The results indicate that the bioavailability of a 1 x 600 mg dose of darunavir is comparable to the bioavailability of a 2 x 300 mg dose of darunavir.

In Panel 2, 46 male and female subjects randomly received under fed conditions a single oral 600 mg dose of darunavir formulated as the 300 mg tablet (2 x 300 mg; Treatment C) in one session and a single oral 600 mg dose of darunavir formulated as the 600 mg tablet (1 x 600 mg; Treatment D) in the second session. The results indicate that the bioavailability of a 1x 600 mg dose of darunavir is comparable to the bioavailability of a 2 x 300 mg dose of darunavir.

The summary of results is presented in Table 31.

Table 31: Summary Table of the Comparative Bioavailability Data Under Fed and Fasting Conditions

^a Based on least square mean estimates

^b Darunavir 300 mg tablet (F016)

^c Darunavir 600 mg tablet (F032)

^d Expressed arithmetic median (range) only

^e Expressed as the arithmetic mean (CV%) only

TMC114-TiDP3-C176

In a Phase 1, open-label, randomized two-panel, two-way crossover bioavailability trial the rate and extent of absorption of darunavir following administration of two tablet strengths (in the presence of low-dose ritonavir) under fed and fasted conditions was assessed in 124 healthy subjects.

In Panel 1, 78 male and female subjects randomly received under fasted conditions a single oral 800 mg dose of darunavir formulated as the 400 mg tablet (2 x 400 mg; Treatment A) in one session, followed by a single oral 800 mg dose formulated as the 800 mg tablet (1 x 800 mg; Treatment B) in the second session. The results indicate that the bioavailability of a 1 x 800 mg dose of darunavir is comparable to the bioavailability of a 2 x 400 mg dose of darunavir.

In Panel 2, 40 male and female subjects randomly received under fed conditions a single oral 800 mg dose of darunavir formulated as the 400 mg tablet (2 x 400 mg; Treatment C) in one session, followed by a single oral 800 mg dose formulated as the 800 mg tablet (1 x 800 mg; Treatment D) in the second session. The results indicate that the bioavailability of a 1 x 800 mg dose of darunavir is comparable to the bioavailability of a 2 x 400 mg dose of darunavir.

The summary of results is presented in Table 32.

Table 32: Summary Table of the Comparative Bioavailability Data Under Fed and Fasting Conditions

^a Based on least square mean estimates

^b Darunavir 400 mg tablet (F030)

^c Darunavir 800 mg tablet (G002)

^d Expressed as the median (range) only

^e Expressed as the mean (CV%) only

TMC114-TiDP3-C169

In a Phase 1, open-label, randomized, three-way crossover bioavailability trial the rate and extent of absorption of darunavir following administration of two different formulations (tablets or suspension) (in the presence of low-dose ritonavir) under fed and fasted conditions was assessed in 20 healthy subjects.

Seventeen male and female subjects randomly received a single oral 600 mg dose of darunavir formulated as the 300 mg tablet (2 x 300 mg; Treatment A) under fed conditions, followed by a single oral 600 mg dose formulated as the 100 mg/mL suspension (6 x 100 mg/mL; Treatment B) under fasted conditions, followed by a single oral 600 mg dose of darunavir formulated as the 100 mg/mL suspension (6 x 100 mg/mL; Treatment C) under fed conditions. The results indicate that the bioavailability of a 2 x 300 mg dose of darunavir under fed conditions is comparable to the bioavailability of a 6 mL x 100 mg/mL dose of darunavir under fasted or fed conditions.

The summary of results for the comparison between the 300 mg tablet and the 100 mg/mL suspension under fed conditions is presented in Table 33.

Table 33: Summary Table of the Comparative Bioavailability Data Under Fed Conditions

^a Based on least square mean estimates

^b Darunavir 300 mg tablet (F016)

^c Darunavir 100 mg/mL suspension (F051)

^d Expressed as the median (range) only

^e Expressed as the mean (CV%) only

15 MICROBIOLOGY

Antiviral Activity In Vitro

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 EC₅₀ values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC₅₀ values ranging from < 0.1 to 4.3 nM.

These EC₅₀ values are well below the 50% cellular toxicity concentration range of 87 mcM to > 100 mcM. The EC₅₀ value of darunavir increases by a median factor of 5.4 in the presence of human serum.

Darunavir showed synergistic antiviral activity when studied in combination with the PIs ritonavir, nelfinavir, or amprenavir, and additive antiviral activity when studied in combination with the PIs indinavir, saquinavir, lopinavir, atazanavir, or tipranavir, the nucleoside (nucleotide) reverse transcriptase inhibitors (N(t)RTIs) zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, or tenofovir, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine, rilpivirine or etravirine, or efavirenz, and the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of these antiretrovirals in vitro.

Resistance In Vitro

In vitro selection of darunavir-resistant virus from wild-type HIV-1 was lengthy (more than 2 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 220 nM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23- to 50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. The decreased susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained by the emergence of these protease mutations.

In vitro selection of darunavir-resistant HIV-1 (range: 53- to 641-fold change in EC₅₀ values) from 9 HIV-1 strains harbouring multiple PI resistance-associated mutations (RAMs) resulted in the overall emergence of 22 mutations in the protease, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were present in more than 50% of the 9 darunavir-resistant isolates. A minimum of 8 of these darunavir in vitro selected mutations, from which at least 2 were already present in the protease prior to selection, were required in the HIV-1 protease to render a virus resistant (fold change (FC) > 10) to darunavir.

In 1113 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir, and in 886 baseline isolates from the patients enrolled in the TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) trials and in the TMC114-C215 (POWER 3) analysis, only the subgroups with > 10 PI resistance-associated mutations showed a median FC for darunavir > 10.

Cross-Resistance In Vitro

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

Seven of the 9 darunavir-resistant viruses selected from PI-resistant viruses had phenotypic data for tipranavir. Six of those showed a FC in EC₅₀ value < 3 for tipranavir, indicative of limited cross-resistance between these 2 PIs.

Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors, the entry inhibitors, or the integrase inhibitor is unlikely because the viral targets for those inhibitors are different.

In Vivo Selection of Viral Resistance During Darunavir/ritonavir Therapy

In the 192-week analysis of the TMC114-C211 (ARTEMIS) trial, the number of virologic failures was lower in the group of patients receiving darunavir/rtv 800/100 mg q.d. than in patients receiving lopinavir/ritonavir 800/200 mg per day (16.0% vs. 20.5%, respectively). In the virologic failures of the darunavir/rtv arm with paired baseline/endpoint genotype data, four patients with developing PI RAMs were identified. In the virologic failures of the lopinavir/ritonavir arm with paired baseline/endpoint genotype data, nine patients with developing PI RAMs at endpoint were identified. This was not associated with a loss in susceptibility to lopinavir. None of the developing mutations in the darunavir/rtv group or in the lopinavir/rtv group were primary (i.e., major) PI mutations. In four virologic failures in the darunavir/rtv arm and seven virologic failures in the lopinavir/ritonavir arm, a maximum of two developing NRTI RAMs were identified. The development of the NRTI RAM at position 184 (n= 9) was identified, which was associated with a decreased susceptibility to emtricitabine (FTC) included in the fixed background regimen.

In the 48-week analysis of the TMC114-C229 (ODIN) trial, the number of virologic failures was comparable in the darunavir/rtv 800/100 mg q.d. group and the darunavir/rtv 600/100 mg b.i.d. group (22.1% vs. 18.2%, respectively). Of the virologic failures, the darunavir/rtv 800/100 mg q.d. group reported 7 (12%) patients with developing PI RAMs compared to 4 (10%) patients in the darunavir/rtv 600/100 mg b.i.d group. Only 1 subject, in the DRV/rtv q.d. group, developed primary (major) PI mutations (V32I, M46I, L76V and I84V), which included 3 DRV RAMs (V32I, L76Vand I84V). The emergence of these DRV RAMs was associated with loss of DRV susceptibility.

All virologic failures from the darunavir/rtv 600/100 mg b.i.d. group retained susceptibility to darunavir. Four (6.7%) and 3 (7.1%) virologic failures developed 1 or 2 NRTI RAMs in the darunavir/rtv 800/100 mg q.d. and the darunavir/rtv 600/100 mg b.i.d. groups, respectively. In 3 and 2 of these virologic failures in the darunavir/rtv 800/100 mg q.d. and the darunavir/rtv 600/100 mg b.i.d. groups, respectively, the development of these NRTI RAMs (V75I+M184V; M184V; T215Y in the q.d. group and M184V; M41L+T215Y in the b.i.d. group) was associated with a decreased susceptibility to a NRTI included in the background regimen.

In the 96-week analysis of the TMC114-C214 (TITAN) trial, the number of virologic failures was lower in the group of patients receiving darunavir/rtv 600/100 mg b.i.d. than in patients receiving lopinavir/ritonavir 400/100 mg b.i.d. (41/298, 13.8% versus 76/297, 25.6%, respectively). Examination of patients who failed on darunavir/rtv 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 6 patients (6/39; 15%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Five of the 6 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes > 7. The most common emerging PI substitutions in the virologic failures were V32I, I47V, T74P, and L76V.

For the lopinavir/ritonavir arm, baseline and endpoint genotype was available for 72 of 76 virologic failures. Comparing patients with available baseline and endpoint genotypes, fewer virologic failures treated with darunavir/rtv 600/100 mg b.i.d. than with lopinavir/ritonavir 400/100 mg b.i.d. developed primary (i.e. major) PI mutations (7 vs. 25, respectively) or NRTI RAMS (4 vs. 20, respectively) or lost susceptibility to the PI (3 vs. 17, respectively) or NRTI(s) (4 vs. 20, respectively) used in the treatment regimen.

In a pooled analysis of the POWER and DUET trials, the percentage of rebounders (patients who lost a viral load >1.0 log₁₀ below baseline) was 17.6% (188 out of 1071 patients). Baseline and endpoint genotype was available for 185 out of 188 rebounders. The most common protease mutations that developed in ≥ 20% of the isolates from patients who experienced virological failure by rebound were V32I, I54L, and L89V. Amino acid substitutions that developed in 10 to 20% of the isolates were V11I, I13V, L33F, I50V, and F53L. The percentage of never suppressed patients (patients that never achieved a viral load >1.0 log₁₀ below baseline at 2 consecutive visits) was 19.7% (211 out of 1071 patients). Baseline and endpoint genotype was available for 197 out of the 211 never suppressed patients. The most common protease mutations that developed in >20% of the analyzed never suppressed patients were V32I and I54L. Mutations that developed in 10 to 20% of these never suppressed patients were V11I, I15V, L33F, I47V and L89V.

In Vivo Cross-Resistance with Other Protease Inhibitors

In the virologic failures of the ARTEMIS trial, no cross-resistance with other PIs was observed.

Of the viruses isolated from patients receiving darunavir/rtv 800/100 mg q.d. experiencing virologic failure in the ODIN trial, 98% remained susceptible to darunavir after treatment. In the same group of patients, 96% to 100% that were susceptible at baseline to amprenavir, atazanavir, indinavir, lopinavir, saquinavir or tipranivir remained susceptible to these protease inhibitors after treatment. In the virologic failures receiving darunavir/rtv 600/100 mg b.i.d. no cross- resistance with other PIs was observed.

In the TITAN trial, the number of virologic failures was lower in the DRV/rtv group than in the LPV/rtv group and fewer virologic failures treated with DRV/rtv than with LPV/rtv lost susceptibility to PIs. Of the viruses isolated from patients receiving darunavir/rtv 600/100 mg b.i.d. experiencing virologic failures in the TITAN trial, 8% of those susceptible to darunavir at baseline developed decreased susceptibility to darunavir during treatment. In the same group of patients, 97% to 100% that were susceptible at baseline to amprenavir, atazanavir, indinavir, lopinavir, saquinavir or tipranavir remained susceptible after darunavir/rtv treatment.

Of the viruses isolated from patients experiencing virologic failure by rebound from the darunavir/rtv 600/100 mg b.i.d. group, of the POWER and DUET trials, 85% that were susceptible to darunavir at baseline developed decreased susceptibility to darunavir during treatment. In the same group of patients, 71% of viruses that were susceptible to tipranavir at baseline remained susceptible after treatment. In the POWER trials, patients with resistance to tipranavir (FC > 3) at baseline showed a mean change in viral load at Week 24 of -1.38 log₁₀. Cross resistance with the other PIs could not be studied in the POWER and DUET trials, since most of the baseline viruses were already resistant to these PIs. Patients with no susceptible PI at baseline (excluding tipranavir) showed a mean change in viral load at Week 24 of -1.57 log₁₀.

Baseline Genotype or Phenotype and Virologic Outcome

In a pooled analysis of the 600/100 mg b.i.d. groups of the POWER and DUET trials, the presence at baseline of three or more of the darunavir- specific mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V) was associated with a decreased virologic response to darunavir/rtv. In early treatment-experienced patients (TITAN) three or more of these mutations were only found in 4% of the patients at baseline.

Table 34: Response (HIV-1 RNA < 50 copies/mL at week 24) to darunavir/rtv 600/100 mg b.i.d. by baseline genotype^a and by use of enfuviritide: As-treated analysis of the POWER and DUET trials

Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be the most predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 35. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir.

Table 35: Response (HIV-1 RNA < 50 copies/mL at week 24) to darunavir/rtv 600/100 mg b.i.d. by baseline darunavir phenotype and by use of enfuvirtide: As-treated analysis of the POWER and DUET trials

In deciding on a new regimen for patients who have failed an antiretroviral regimen, careful consideration should be given to the treatment history and to resistance testing results where available.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Animal toxicology studies have been conducted with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.

In chronic toxicology studies in rats and dogs, there were only limited effects of treatment with darunavir. In the rat the key target organs identified were the hematopoietic system, the blood coagulation system, liver and thyroid, observed at 100 mg/kg/day and above and at exposures below clinical levels. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated PTT. The observed liver and thyroid changes were considered to reflect an adaptive response to enzyme induction in the rat rather than an adverse effect. In combination toxicity studies with ritonavir, no additional target organs of toxicity were reported in rats. In the dog, no major toxicity findings or key target organs were identified at doses up to 120 mg/kg/day and exposures equivalent to clinical exposure at the recommended dose.

Carcinogenicity:

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 were administered to rats. A dose related increase in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or 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 (based on AUC) to darunavir 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).

Genotoxicity:

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

Reproductive and Developmental Toxicology:

Investigation of fertility and early embryonic development was performed in rats, teratogenicity studies were conducted in mice, rats and rabbits, and the pre- and post-natal development study was conducted in rats.

In the fertility and early embryonic development study, a significant decrease in body weight gain with subsequent related reduction in the number of ovulations resulting in a reduction in the number of live fetuses was observed in female rats treated with 1000 mg/kg. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1000 mg/kg/day and exposure levels below (AUC 0.5-fold) that in humans at the clinically recommended dose. Up to the same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those observed with the recommended clinical dose in humans. In addition, rats treated in combination with ritonavir showed no teratogenicity when exposed to higher levels of darunavir than those achieved with the recommended clinical dose in humans. In a pre- and post-natal development assessment in rats, darunavir with and without ritonavir caused a transient reduction in body weight gain of the offspring during lactation. This was attributed to drug exposure via the milk. No post-weaning functions were affected with darunavir alone or in combination with ritonavir.

Juvenile Toxicity:

In juvenile rats directly dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age, mortality was observed and, in some of the animals, convulsions. Within this age range exposures in plasma, liver and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. No treatment-related mortalities were noted in juvenile rats dosed at 1000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats. In humans, the activity of drug-metabolizing enzymes approaches adult values by 3 years of age.

17 SUPPORTING PRODUCT MONOGRAPHS

1 PREZISTA^® Darunavir Tablets, 75 mg, 150 mg, 600 mg, 800 mg and oral suspension 100 mg/mL submission control: 268362, Product Monograph, Janssen Inc. (MAR 03, 2023)