These highlights do not include all the information needed to use PREZISTA safely and effectively. See Full Prescribing Information for PREZISTA. PREZISTA (darunavir) Tablet, Film Coated for Oral use Initial U.S. Approval – 2006

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 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.

PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of HIV infection in pediatric patients 6 years of age and older [see Use in Specific Populations (8.4) ].

This indication is based on 24-week analyses of plasma HIV RNA levels and CD4+ cell counts from an open-label Phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to < 18 years of age.

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

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.

Treatment-Naïve Adult Patients

The recommended oral dose of PREZISTA tablets is 800 mg (two 400 mg tablets) taken with ritonavir 100 mg once daily and with food.

Treatment-Experienced Adult Patients

The recommended oral dose of PREZISTA tablets is 600 mg (one 600 mg tablet or two 300 mg tablets) taken with ritonavir 100 mg twice daily and with food. Once daily administration of PREZISTA is not recommended in treatment-experienced adult patients.

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 should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA tablets may not be appropriate.

The recommended dose of PREZISTA/ritonavir for pediatric patients (6 to < 18 years of age and weighing at least 44 lbs (20 kg)) is based on body weight (see Table 1) and should not exceed the recommended treatment-experienced adult dose (PREZISTA/ritonavir 600/100 mg b.i.d.). PREZISTA tablets should be taken with ritonavir twice daily and with food.

The safety and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.

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

Table 1: Recommended Dose for Pediatric Patients (6 to < 18 years of age) for PREZISTA Tablets with ritonavir

Body Weight		Dose
(kg)	(lbs)	Â
≥ 20 kg – < 30 kg	≥ 44 lbs – < 66 lbs	375 mg PREZISTA/50 mg ritonavir twice daily
≥ 30 kg – < 40 kg	≥ 66 lbs – < 88 lbs	450 mg PREZISTA/60 mg ritonavir twice daily
≥ 40 kg	≥ 88 lbs	600 mg PREZISTA/100 mg ritonavir twice daily

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) ].

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 (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 (darunavir) 300 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 300 mg of darunavir per tablet. Each tablet is debossed with "300" on one side and "TMC114" on the other side.

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 "400" on one side and "TMC" on the other side.

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 "600" on one side and "TMC" on the other side.

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 2 [also see Drug Interactions (7.3) , Table 7].

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

Table 2: 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 7: 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).

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.

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.

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 (<0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis has been reported. Discontinue PREZISTA/rtv 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/rtv [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/rtv was 0.5%.

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 was similar in subjects with or without a history of sulfonamide allergy.

See Table 2 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 7 for established and other potentially significant drug-drug interactions [see Drug Interactions (7.3) ].

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.

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.

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 eva luation and treatment.

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.

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) ].

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) ]. The safety and efficacy of PREZISTA/ritonavir in pediatric patients 3 to < 6 years of age have not been established.

The safety assessment is based on all safety data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202, TMC114-C215, and TMC114-C208) and Phase 3 studies (TMC114-C211, TMC114-C214, TMC114-C209, DUET-1 (TMC125-C206), and DUET-2 (TMC125-C216)) reported with PREZISTA/ritonavir in a total of 3063 subjects.

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.

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 95.0 and 91.4 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 (≥ 5%) of at least moderate intensity (≥ 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 (≥ Grade 2) in antiretroviral treatment naïve HIV-1-infected adult subjects are presented in Table 3 and subsequent text below the table.

Table 3: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once DailyExcluding laboratory abnormalities reported as ADRs 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
Gastrointestinal Disorders
  Abdominal pain	5%	6%
  Diarrhea	8%	15%
  Nausea	3%	4%
  Vomiting	2%	3%
General Disorders and Administration Site Conditions
  Fatigue	< 1%	3%
Metabolism and Nutrition Disorders
  Anorexia	2%	< 1%
Nervous System Disorders
  Headache	6%	5%
Skin and Subcutaneous Tissue Disorders
  Rash	5%	6%

Less Common Adverse Reactions

Treatment-emergent ADRs of at least moderate intensity (≥ 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

Metabolism and Nutrition Disorders: diabetes mellitus

Musculoskeletal and Connective Tissue Disorders: myalgia

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 4.

Table 4: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult SubjectsGrade 4 data not applicable in Division of AIDS grading scale.

		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
Biochemistry
Alanine Aminotransferase
  Grade 2	> 2.5 to ≤ 5.0 X ULN	7%	6%
  Grade 3	> 5.0 to ≤ 10.0 X ULN	3%	3%
  Grade 4	> 10.0 X ULN	< 1%	3%
Aspartate Aminotransferase
  Grade 2	> 2.5 to ≤ 5.0 X ULN	6%	6%
  Grade 3	> 5.0 to ≤ 10.0 X ULN	4%	2%
  Grade 4	> 10.0 X ULN	1%	2%
Alkaline Phosphatase
  Grade 2	> 2.5 to ≤ 5.0 X ULN	2%	1%
  Grade 3	> 5.0 to ≤ 10.0 X ULN	0%	< 1%
  Grade 4	> 10.0 X ULN	0%	0%
Hyperbilirubinemia
  Grade 2	> 1.5 to ≤ 2.5 X ULN	< 1%	4%
  Grade 3	> 2.5 to ≤ 5.0 X ULN	< 1%	< 1%
  Grade 4	> 5.0 X ULN	0%	0%
Triglycerides
  Grade 2	5.65-8.48 mmol/L 500-750 mg/dL	3%	8%
  Grade 3	8.49-13.56 mmol/L 751-1200 mg/dL	1%	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	16%	23%
  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%	10%
  Grade 3	≥ 4.91 mmol/L ≥ 191 mg/dL	5%	5%
Elevated Glucose Levels
  Grade 2	6.95-13.88 mmol/L 126-250 mg/dL	7%	8%
  Grade 3	13.89-27.75 mmol/L 251-500 mg/dL	< 1%	0%
  Grade 4	> 27.75 mmol/L > 500 mg/dL	0%	0%
Pancreatic Lipase
  Grade 2	> 1.5 to ≤ 3.0 X ULN	2%	1%
  Grade 3	> 3.0 to ≤ 5.0 X ULN	< 1%	< 1%
  Grade 4	> 5.0 X ULN	0%	< 1%
Pancreatic Amylase
  Grade 2	> 1.5 to ≤ 2.0 X ULN	5%	2%
  Grade 3	> 2.0 to ≤ 5.0 X ULN	3%	3%
  Grade 4	> 5.0 X ULN	0%	< 1%

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 (≥ 5%) of at least moderate intensity (≥ 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 (≥ Grade 2) in antiretroviral treatment-experienced 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 600/100 mg Twice DailyExcluding laboratory abnormalities reported as ADRs 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
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 (≥ 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 6.

Table 6: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult SubjectsGrade 4 data not applicable in Division of AIDS grading scale.  

		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
Biochemistry
Alanine Aminotransferase
  Grade 2	> 2.5 to ≤ 5.0 X ULN	7%	5%
  Grade 3	> 5.0 to ≤ 10.0 X ULN	2%	2%
  Grade 4	> 10.0 X ULN	1%	2%
Aspartate Aminotransferase
  Grade 2	> 2.5 to ≤ 5.0 X ULN	6%	6%
  Grade 3	> 5.0 to ≤ 10.0 X ULN	2%	2%
  Grade 4	> 10.0 X ULN	< 1%	2%
Alkaline Phosphatase
  Grade 2	> 2.5 to ≤ 5.0 X ULN	< 1%	0%
  Grade 3	> 5.0 to ≤ 10.0 X ULN	< 1%	< 1%
  Grade 4	> 10.0 X ULN	0%	0%
Hyperbilirubinemia
  Grade 2	> 1.5 to ≤ 2.5 X ULN	< 1%	2%
  Grade 3	> 2.5 to ≤ 5.0 X ULN	< 1%	< 1%
  Grade 4	> 5.0 X ULN	< 1%	0%
Triglycerides
  Grade 2	5.65-8.48 mmol/L 500-750 mg/dL	10%	11%
  Grade 3	8.49-13.56 mmol/L 751-1200 mg/dL	7%	10%
  Grade 4	> 13.56 mmol/L > 1200 mg/dL	3%	6%
Total Cholesterol
  Grade 2	·