Prezista

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Prezista

Adult Patients

Prezista®, co-administered with ritonavir (Prezista/ritonavir), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

Pediatric Patients

 Prezista, co-administered with ritonavir (Prezista/ritonavir), and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in pediatric patients 3 years of age and older [see Use in Specific Populations (8.4)].

 This indication is based on 24-week analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 open-label Phase 2 trials in antiretroviral treatment-experienced pediatric patients (one trial in patients 6 to less than 18 years of age and one trial in patients 3 to less than 6 years of age).

In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with Prezista/ritonavir:

• Treatment history and, when available, genotypic or phenotypic testing should guide the use of Prezista/ritonavir [see Clinical Pharmacology (12.4)].


• The use of other active agents with Prezista/ritonavir is associated with a greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14.3)].

Prezista Dosage and Administration

Adult Patients

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

 Patients who have difficulty swallowing Prezista tablets can use the 100 mg/mL Prezista oral suspension.

 Treatment-Naïve Adult Patients

 The recommended oral dose of Prezista is 800 mg (two 400 mg tablets or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL of a 80 mg/mL ritonavir oral solution) once daily and with food.

 Treatment-Experienced Adult Patients

Treatment-Experienced Adult Patients
* V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V † An 8 mL dose should be taken as two 4 mL administrations with the included oral dosing syringe
With no darunavir resistance associated substitutions*	With at least one darunavir resistance associated substitution*
Prezista 800 mg (two 400 mg tablets or 8 mL†) once daily with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL) once daily and with food	Prezista 600 mg (e.g. one 600 mg tablet or 6 mL) twice daily with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL) twice daily and with food

For antiretroviral treatment-experienced patients genotypic testing is recommended. However, when genotypic testing is not feasible, Prezista/ritonavir 600/100 mg twice daily dosing is recommended.

Pediatric Patients (age 3 to less than 18 years)

Do not use once daily dosing in pediatric patients.

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

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

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

 The recommended dose of Prezista/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 1, 2 and 3) and should not exceed the recommended treatment-experienced adult dose (Prezista/ritonavir 600/100 mg twice daily). Prezista should be taken with ritonavir twice daily and with food.

 Dosing recommendations for pediatric patients weighing at least 10 kg but less than 15 kg

 The weight-based dose in pediatric patients weighing less than 15 kg is Prezista 20 mg/kg with ritonavir 3 mg/kg which can be dosed using the following table:

Table 1: Recommended Dose for Pediatric Patients with Prezista Oral Suspension (100 mg/mL) and Ritonavir Oral Solution* for Pediatric Patients Weighing 10 kg to Less Than 15 kg

Body weight (kg)	Dose (twice daily with food)
* with ritonavir oral solution: 80 mg/mL
Greater than or equal to 10 kg to less than 11 kg	Prezista 200 mg (2 mL) with ritonavir 32 mg (0.4 mL)
Greater than or equal to 11 kg to less than 12 kg	Prezista 220 mg (2.2 mL) with ritonavir 32 mg (0.4 mL)
Greater than or equal to 12 kg to less than 13 kg	Prezista 240 mg (2.4 mL) with ritonavir 40 mg (0.5 mL)
Greater than or equal to 13 kg to less than 14 kg	Prezista 260 mg (2.6 mL) with ritonavir 40 mg (0.5 mL)
Greater than or equal to 14 kg to less than 15 kg	Prezista 280 mg (2.8 mL) with ritonavir 48 mg (0.6 mL)

 Dosing recommendations for pediatric patients weighing at least 15 kg

 Pediatric patients who weigh at least 15 kg and are able to swallow tablets can be dosed using the following table:

Table 2: Recommended Dose for Pediatric Patients with Prezista Tablets and Ritonavir Oral Solution or Tablets/Capsules for Pediatric Patients Weighing At Least 15 kg

Body Weight (kg)	Dose (twice daily with food)
* with ritonavir oral solution: 80 mg/mL † with ritonavir capsules or tablets: 100 mg
Greater than or equal to 15 kg to less than 30 kg	Prezista 375 mg with ritonavir* 50 mg (0.6 mL)
Greater than or equal to 30 kg to less than 40 kg	Prezista 450 mg with ritonavir* 60 mg (0.75 mL)
Greater than or equal to 40 kg	Prezista 600 mg with ritonavir†100 mg

 Pediatric patients who weigh at least 15 kg but are unable to swallow tablets can be dosed using the following table:

Table 3: Recommended Dose for Pediatric Patients with Prezista Oral Suspension (100 mg/mL) and Ritonavir Oral Solution* for Pediatric Patients Weighing At Least 15 kg

Body Weight (kg)	Dose (twice daily with food)
* with ritonavir oral solution: 80 mg/mL † The 375 mg dose refers to the dose using darunavir tablets for this weight group, which is rounded off to 3.8 mL for suspension dosing. ‡ The 450 mg dose refers to the dose using darunavir tablets for this weight group, which is rounded off to 4.6 mL for suspension dosing.
Greater than or equal to 15 kg to less than 30 kg	Prezista 375 mg† (3.8 mL) with ritonavir 50 mg (0.6 mL)
Greater than or equal to 30 kg to less than 40 kg	Prezista 450 mg‡ (4.6 mL) with ritonavir 60 mg (0.75 mL)
Greater than or equal to 40 kg	Prezista 600 mg (6 mL) with ritonavir 100 mg (1.25 mL)

Do not use Prezista/ritonavir in pediatric patients below 3 years of age [see Warnings and Precautions (5.11) and Nonclinical Toxicology (13.2)].

Patients with Hepatic Impairment

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

Dosage Forms and Strengths

Prezista 100 mg/mL Oral Suspension

Prezista (darunavir) 100 mg/mL oral suspension is supplied as a white to off-white opaque suspension for oral use, containing darunavir ethanolate equivalent to 100 mg of darunavir per mL of suspension.

Prezista 75 mg Tablets

Prezista (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with "75" on one side and "TMC" on the other side.

Prezista 150 mg Tablets

Prezista (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with "150" on one side and "TMC" on the other side.

Prezista 400 mg Tablets

Prezista (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 400 mg of darunavir per tablet. Each tablet is debossed with "400MG" on one side and "TMC" on the other side.

Prezista 600 mg Tablets

Prezista (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with "600MG" on one side and "TMC" on the other side.

Contraindications

Co-administration of Prezista/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed in Table 4 [also see Drug Interactions (7.3), Table 9].

Table 4: Drugs That Are Contraindicated With Prezista/ritonavir

Drug Class	Drugs Within Class That Are Contraindicated With Prezista/ritonavir	Clinical Comment
Alpha 1-adrenoreceptor antagonist	Alfuzosin	Potential for serious and/or life-threatening reactions such as hypotension.
Ergot Derivatives	Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine	Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent	Cisapride	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Neuroleptic	Pimozide	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics	Orally administered Midazolam, Triazolam	Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with Prezista/ritonavir may cause large increases in the concentrations of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Herbal Products	St. John's Wort (Hypericum perforatum)	Patients taking Prezista/ritonavir should not use products containing St. John's wort because co-administration may result in reduced plasma concentrations of darunavir. This may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors	Lovastatin, Simvastatin	Potential for serious reactions such as myopathy including rhabdomyolysis. For dosing recommendation regarding atorvastatin and pravastatin, see Table 9: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.
Antimycobacterial	Rifampin	Rifampin is a potent inducer of CYP450 metabolism. Prezista/ritonavir should not be used in combination with rifampin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to Prezista.
PDE-5 inhibitor	Sildenafil for treatment of pulmonary arterial hypertension	A safe and effective dose for the treatment of pulmonary arterial hypertension has not been established with Prezista/ritonavir. There is an increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).

Due to the need for co-administration of Prezista with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.

Warnings and Precautions

General

Prezista must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer Prezista with ritonavir and food may result in a loss of efficacy of darunavir.

Please refer to ritonavir prescribing information for additional information on precautionary measures.

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with Prezista/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with Prezista/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with Prezista/ritonavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with Prezista/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Prezista/ritonavir treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on Prezista/ritonavir should prompt consideration of interruption or discontinuation of treatment.

Severe Skin Reactions

 During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis has been reported. Discontinue Prezista/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

 Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with Prezista/ritonavir [also see Adverse Reactions (6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using Prezista/ritonavir was 0.5%.

 Rash occurred more commonly in treatment-experienced subjects receiving regimens containing Prezista/ritonavir + raltegravir compared to subjects receiving Prezista/ritonavir without raltegravir or raltegravir without Prezista/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Sulfa Allergy

Darunavir contains a sulfonamide moiety. Prezista should be used with caution in patients with a known sulfonamide allergy. In clinical studies with Prezista/ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Drug Interactions

See Table 4 for a listing of drugs that are contraindicated for use with Prezista/ritonavir due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to Prezista [see Contraindications (4)]. Please refer to Table 9 for established and other potentially significant drug-drug interactions [see Drug Interactions (7.3)].

Diabetes Mellitus / Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution 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, cytomegalovirus, Pneumocystis jirovecii pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.

Resistance/Cross-Resistance

Because the potential for HIV cross-resistance among PIs has not been fully explored in Prezista/ritonavir treated patients, the effect therapy with Prezista will have on the activity of subsequently administered PIs is unknown [see Microbiology (12.4)].

Pediatric Patients

Do not administer Prezista/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Use in Specific Populations (8.1 and 8.4), Clinical Pharmacology (12.3), and Nonclinical Toxicology (13.2)].

Adverse Reactions

The overall safety profile of Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Due to the need for co-administration of Prezista with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

Clinical Trials Experience: Treatment-Naïve Adults

Study TMC114-C211

The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing Prezista/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the Prezista/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively.

The majority of the adverse drug reactions (ADRs) reported during treatment with Prezista/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to Prezista/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the Prezista/ritonavir arm discontinued treatment due to ADRs.

ADRs to Prezista/ritonavir 800/100 mg once daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 5 and subsequent text below the table.

Table 5: Selected Clinical Adverse Drug Reactions to Prezista/ritonavir 800/100 mg Once Daily* of at Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects

	Randomized Study TMC114-C211
System Organ Class, Preferred Term, %	Prezista/ritonavir 800/100 mg once daily + TDF/FTC N = 343	lopinavir/ritonavir 800/200 mg per day + TDF/FTC N = 346
N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine
* Excluding laboratory abnormalities reported as ADRs
Gastrointestinal Disorders
Abdominal pain	6%	6%
Diarrhea	9%	16%
Nausea	4%	4%
Vomiting	2%	4%
General Disorders and Administration Site Conditions
Fatigue	< 1%	3%
Metabolism and Nutrition Disorders
Anorexia	2%	< 1%
Nervous System Disorders
Headache	7%	6%
Skin and Subcutaneous Tissue Disorders
Rash	6%	7%

Less Common Adverse Reactions

Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Prezista/ritonavir 800/100 mg once daily are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence

General Disorders and Administration Site Conditions: asthenia

Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)

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

Metabolism and Nutrition Disorders: diabetes mellitus

Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis

Psychiatric Disorders: abnormal dreams

Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticaria

Laboratory abnormalities:

Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with Prezista/ritonavir 800/100 mg once daily are presented in Table 6.

Table 6: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects*

		Randomized Study TMC114-C211
Laboratory Parameter Preferred Term, %	Limit	Prezista/ritonavir 800/100 mg once daily + TDF/FTC	lopinavir/ritonavir 800/200 mg per day + TDF/FTC
N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine
* Grade 4 data not applicable in Division of AIDS grading scale.
Biochemistry
Alanine Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 × ULN	9%	9%
Grade 3	> 5.0 to ≤ 10.0 × ULN	3%	3%
Grade 4	> 10.0 × ULN	< 1%	3%
Aspartate Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 × ULN	7%	10%
Grade 3	> 5.0 to ≤ 10.0 × ULN	4%	2%
Grade 4	> 10.0 × ULN	1%	3%
Alkaline Phosphatase
Grade 2	> 2.5 to ≤ 5.0 × ULN	1%	1%
Grade 3	> 5.0 to ≤ 10.0 × ULN	0%	< 1%
Grade 4	> 10.0 × ULN	0%	0%
Hyperbilirubinemia
Grade 2	> 1.5 to ≤ 2.5 × ULN	< 1%	5%
Grade 3	> 2.5 to ≤ 5.0 × ULN	< 1%	< 1%
Grade 4	> 5.0 × ULN	0%	0%
Triglycerides
Grade 2	5.65–8.48 mmol/L 500–750 mg/dL	3%	10%
Grade 3	8.49–13.56 mmol/L 751–1200 mg/dL	2%	5%
Grade 4	> 13.56 mmol/L > 1200 mg/dL	1%	1%
Total Cholesterol
Grade 2	6.20–7.77 mmol/L 240–300 mg/dL	23%	27%
Grade 3	> 7.77 mmol/L > 300 mg/dL	1%	5%
Low-Density Lipoprotein Cholesterol
Grade 2	4.13–4.90 mmol/L 160–190 mg/dL	14%	12%
Grade 3	≥ 4.91 mmol/L ≥ 191 mg/dL	9%	6%
Elevated Glucose Levels
Grade 2	6.95–13.88 mmol/L 126–250 mg/dL	11%	10%
Grade 3	13.89–27.75 mmol/L 251–500 mg/dL	1%	<1%
Grade 4	> 27.75 mmol/L > 500 mg/dL	0%	0%
Pancreatic Lipase
Grade 2	> 1.5 to ≤ 3.0 × ULN	3%	2%
Grade 3	> 3.0 to ≤ 5.0 × ULN	< 1%	1%
Grade 4	> 5.0 × ULN	0%	< 1%
Pancreatic Amylase
Grade 2	> 1.5 to ≤ 2.0 × ULN	5%	2%
Grade 3	> 2.0 to ≤ 5.0 × ULN	5%	4%
Grade 4	> 5.0 × ULN	0%	< 1%

Clinical Trials Experience: Treatment-Experienced Adults

Study TMC114-C214

The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing Prezista/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the Prezista/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively.

The majority of the ADRs reported during treatment with Prezista/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to Prezista/ritonavir 600/100 mg twice daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the Prezista/ritonavir arm discontinued treatment due to ADRs.

ADRs to Prezista/ritonavir 600/100 mg twice daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 7 and subsequent text below the table.

Table 7: Selected Clinical Adverse Drug Reactions to Prezista/ritonavir 600/100 mg Twice Daily* of at Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects

	Randomized Study TMC114-C214
System Organ Class, Preferred Term, %	Prezista/ritonavir 600/100 mg twice daily + OBR N = 298	lopinavir/ritonavir 400/100 mg twice daily + OBR N = 297
N=total number of subjects per treatment group OBR = optimized background regimen
* Excluding laboratory abnormalities reported as ADRs
Gastrointestinal Disorders
Abdominal distension	2%	< 1%
Abdominal pain	6%	3%
Diarrhea	14%	20%
Dyspepsia	2%	1%
Nausea	7%	6%
Vomiting	5%	3%
General Disorders and Administration Site Conditions
Asthenia	3%	1%
Fatigue	2%	1%
Metabolism and Nutrition Disorders
Anorexia	2%	2%
Diabetes mellitus	2%	< 1%
Nervous System Disorders
Headache	3%	3%
Skin and Subcutaneous Tissue Disorders
Rash	7%	3%

Less Common Adverse Reactions

Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving Prezista/ritonavir 600/100 mg twice daily are listed below by body system:

Gastrointestinal Disorders: acute pancreatitis, flatulence

Musculoskeletal and Connective Tissue Disorders: myalgia

Psychiatric Disorders: abnormal dreams

Skin and Subcutaneous Tissue Disorders: pruritus, urticaria

Laboratory abnormalities:

Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with Prezista/ritonavir 600/100 mg twice daily are presented in Table 8.

Table 8: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects*

		Randomized Study TMC114-C214
Laboratory Parameter Preferred Term, %	Limit	Prezista/ritonavir 600/100 mg twice daily + OBR	lopinavir/ritonavir 400/100 mg twice daily + OBR
N=total number of subjects per treatment group OBR = optimized background regimen
* Grade 4 data not applicable in Division of AIDS grading scale
Biochemistry
Alanine Aminotransferase
Grade 2	> 2.5 to ≤ 5.0 × ULN	7%	5%
Grade 3