Darunavir
DRUG DESCRIPTION
PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV) protease.
PREZISTA (darunavir), in the form of darunavir ethanolate, has the following 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 monoethanolate. Its molecular formula is C27H37N3O7S • C2H5OH and its molecular weight is 593.73.
Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.
PREZISTA 300 mg and PREZISTA 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration. PREZISTA 400 mg is available as a light orange, oval-shaped, film-coated tablet for oral administration. Each 300 mg tablet contains darunavir ethanolate equivalent to 300 mg of darunavir. Each 400 mg tablet contains darunavir ethanolate equivalent to 400 mg of darunavir. Each 600 mg tablet contains darunavir ethanolate equivalent to 600 mg of darunavir. During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product quality or performance. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The tablet film coating, OPADRY®Orange, contains FD&C Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
All dosages for PREZISTA are expressed in terms of the free form of darunavir.
INDICATIONS
PREZISTA®, co-administered with 100 mg ritonavir (PREZISTA/rtv), 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 patients.
In treatment-experienced patients, the following points should be considered when initiating therapy with PREZISTA/rtv:
Treatment history and, when available, genotypic or phenotypic testing, should guide the use of PREZISTA/rtv [see CLINICAL PHARMACOLOGY].
The use of other active agents with PREZISTA/rtv is associated with a greater likelihood of treatment response [see CLINICAL PHARMACOLOGYandClinical Studies].
The risks and benefits of PREZISTA/rtv have not been established in pediatric patients.
No clinical studies have demonstrated the effect of PREZISTA/rtv on clinical progression of HIV-1.
DOSAGE AND ADMINISTRATION
Adult Patients
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. The type of food does not affect exposure to darunavir.
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. The type of food does not affect exposure to darunavir.
Pediatric Patients
The safety and efficacy of PREZISTA in pediatric patients has not been established [see Use in Specific Populations and CLINICAL PHARMACOLOGY].
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/rtv when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations and CLINICAL PHARMACOLOGY].
SIDE EFFECTS
The safety assessment is based on all safety data from the Phase 2b studies (Studies TMC 114-C213, TMC 114-C202, TMC 114-C215, and TMC 114-C208) and Phase 3 studies (TMC 114-C211, TMC 114-C214, TMC 114-C209, DUET-1 (TMC 125-C206), and DUET-2 (TMC 125-C216)) reported with PREZISTA/rtv 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 100 mg of ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.
Antiretroviral Treatment-Naïve Adult Subjects
Study TMC 114-C211
The safety assessment is based on all safety data from the Phase 3 trial TMC 114-C211 comparing PREZISTA/rtv 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/rtv 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 54.8 and 53.3 weeks, respectively.
The majority of the adverse drug reactions (ADRs) reported during treatment with PREZISTA/rtv 800/100 mg once daily were mild in severity. The most common ADRs to PREZISTA/rtv 800/100 mg once daily ( ? 5%) of at least moderate intensity ( ? Grade 2) were diarrhea and headache. 2% of subjects in the PREZISTA/rtv arm discontinued treatment due to ADRs.
ADRs to PREZISTA/rtv 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 2.
Table 2: Selected Adverse Drug Reactions to PREZISTA/rtv 800/100 mg Once Daily* of At Least Moderate Intensity ( ? Grade 2) in Antiretroviral Treatment-Naïve HIV-1-Infected Adult SubjectsSystem Organ Class,
Preferred Term,
% Randomized Study
TMC 114-C211
PREZISTA/rtv 800/100 mg once daily
+ TDF/FTC
N = 343 lopinavir/ritonavir 800/200 mg per day
+ TDF/FTC
N = 346
Gastrointestinal Disorders
Abdominal pain 4% 5%
Acute pancreatitis < 1% < 1%
Diarrhea 6% 13%
Dyspepsia < 1% 0%
Flatulence < 1% < 1%
Nausea 3% 3%
Vomiting 2% 3%
General Disorders and Administration Site Conditions
Asthenia < 1% 0%
Fatigue < 1% 2%
Hepatobiliary Disorders
Acute Hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity) < 1% < 1%
Metabolism and Nutrition Disorders
Anorexia 1% < 1%
Diabetes mellitus < 1% < 1%
Musculoskeletal and Connective Tissue Disorders
Myalgia < 1% < 1%
Nervous System Disorders
Headache 5% 4%
Psychiatric Disorders
Abnormal Dreams < 1% < 1%
Skin and Subcutaneous Tissue Disorders
Pruritus < 1% < 1%
Rash 2% 4%
Stevens-Johnson Syndrome < 1% 0%
N=total number of subjects per treatment group
TDF = tenofovir disoproxil fumarate
FTC = emtricitabine
* Excluding laboratory abnormalities reported as ADRs
Laboratory abnormalities
The percentages of antiretroviral treatment-naïve HIV-1-infected adult subjects treated with PREZISTA/rtv 800/100 mg once daily with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 3.
Table 3: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects*Laboratory Parameter
Preferred Term,
% Limit Randomized Study
TMC 114-C211
PREZISTA/rtv 800/100 mg once daily
+ TDF/FTC
N = 343 lopinavir/ritonavir 800/200 mg per day
+ TDF/FTC
N = 346
Biochemistry
Alanine Aminotransferase
Grade 2 > 2.5 to ? 5.0 X ULN 5% 5%
Grade 3 > 5.0 to ? 10.0 X ULN 3% 2%
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 3% 2%
Grade 4 > 10.0 X ULN < 1% 2%
Alkaline Phosphatase
Grade 2 > 2.5 to ? 5.0 X ULN 1% < 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% 3%
Grade 3 > 2.5 to ? 5.0 X ULN 0% < 1%
Grade 4 > 5.0 X ULN 0% 0%
Triglycerides
Grade 2 5.65-8.48 mmol/L
500-750 mg/dL 2% 6%
Grade 3 8.49-13.56 mmol/L
751-1200 mg/dL 1% 4%
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 12% 19%
Grade 3 > 7.77 mmol/L
> 300 mg/dL 1% 4%
Low-Density Lipoprotein Cholesterol
Grade 2 4.13-4.90 mmol/L
160-190 mg/dL 11% 6%
Grade 3 ? 4.91 mmol/L
? 191 mg/dL 2% 4%
Elevated Glucose Levels
Grade 2 6.95-13.88 mmol/L
126-250 mg/dL 6% 7%
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 4% 2%
Grade 3 > 2.0 to ? 5.0 X ULN 3% 3%
Grade 4 > 5.0 X ULN 0% < 1%
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.
Antiretroviral Treatment-Experienced Adult Subjects
Study TMC 114-C214
The safety assessment is based on all safety data from the Phase 3 trial TMC 114-C214 comparing PREZISTA/rtv 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/rtv 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 53.5 and 51.5 weeks, respectively.
The majority of the ADRs reported during treatment with PREZISTA/rtv 600/100 mg twice daily were mild in severity. The most common ADRs to PREZISTA/rtv 600/100 mg twice daily ( ? 5%) of at least moderate intensity ( ? Grade 2) were diarrhea, nausea, rash, and abdominal pain. 3.7% of subjects in the PREZISTA/rtv arm discontinued treatment due to ADRs.
ADRs to PREZISTA/rtv 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 4.
Table 4: Selected Adverse Drug Reactions to PREZISTA/rtv 600/100 mg Twice Daily* of At Least Moderate Intensity ( ? Grade 2) in Antiretroviral Treatment-Experienced HIV-1-Infected Adult SubjectsSystem Organ Class,
Preferred Term,
% Randomized Study TMC 114-C214
PREZISTA/rtv 600/100 mg twice daily + OBR
N = 298 lopinavir/ritonavir 400/100 mg twice daily + OBR
N = 297
Gastrointestinal Disorders
Abdominal distension 2% < 1%
Abdominal pain 5% 2%
Diarrhea 12% 18%
Dyspepsia 2% < 1%
Flatulence < 1% 1%
Nausea 7% 6%
Vomiting 4% 3%
General Disorders and Administration Site Conditions
Asthenia 3% 1%
Fatigue 1% 1%
Metabolism and Nutrition Disorders
Anorexia 1% 2%
Diabetes mellitus < 1% 0%
Musculoskeletal and Connective Tissue Disorders
Myalgia 1% < 1%
Nervous System Disorders
Headache 2% 3%
Psychiatric Disorders
Abnormal dreams < 1% 0%
Skin and Subcutaneous Tissue Disorders
Pruritus < 1% 1%
Rash 6% 3%
N=total number of subjects per treatment group
OBR = optimized background regimen
* Excluding laboratory abnormalities reported as ADRs
Laboratory abnormalities
The percentages of antiretroviral treatment-experienced HIV-1-infected adult subjects treated with PREZISTA/rtv 600/100 mg twice daily with Grade 2 to 4 laboratory abnormalities, considered ADRs, are presented in Table 5.
Table 5: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects*Laboratory Parameter
Preferred Term,
% Limit Randomized Study
TMC 114-C214
PREZISTA/rtv
600/100 mg
twice daily + OBR
N = 298 lopinavir/ritonavir
400/100 mg
twice daily + OBR
N = 297
Biochemistry
Alanine Aminotransferase
Grade 2 > 2.5 to ? 5.0 X ULN 6% 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 4% 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 0% 1%
Grade 3 > 2.5 to ? 5.0 X ULN < 1% 0%
Grade 4 > 5.0 X ULN < 1% 0%
Triglycerides
Grade 2 5.65-8.48 mmol/L
500-750 mg/dL 11% 11%
Grade 3 8.49-13.56 mmol/L
751-1200 mg/dL 7% 9%
Grade 4 > 13.56 mmol/L
> 1200 mg/dL 2% 5%
Total Cholesterol
Grade 2 6.20-7.77 mmol/L
240-300 mg/dL 24% 19%
Grade 3 > 7.77 mmol/L
> 300 mg/dL 8% 11%
Low-Density Lipoprotein Cholesterol
Grade 2 4.13-4.90 mmol/L
160-190 mg/dL 13% 11%
Grade 3 ? 4.91 mmol/L
? 191 mg/dL 7% 8%
Elevated Glucose Levels
Grade 2 6.95-13.88 mmol/L
126-250 mg/dL 8% 9%
Grade 3 13.89-27.75 mmol/L
251-500 mg/dL < 1% < 1%
Grade 4 > 27.75 mmol/L
> 500 mg/dL < 1% 0%
Pancreatic Lipase
Grade 2 > 1.5 to ? 3.0 X ULN 2% 4%
Grade 3 > 3.0 to ? 5.0 X ULN 2% < 1%
Grade 4 > 5.0 X ULN < 1% 0%
Pancreatic Amylase
Grade 2 > 1.5 to ? 2.0 X ULN 6% 6%
Grade 3 > 2.0 to ? 5.0 X ULN 6% 3%
Grade 4 > 5.0 X ULN 0% 0%
N=total number of subjects per treatment group
OBR = optimized background regimen
* Grade 4 data not applicable in Division of AIDS grading scale.
Serious ADRs
The following serious ADRs of at least moderate intensity ( ? Grade 2) occurred in the Phase 2b studies (Studies TMC 114-C213, TMC 114-C202, TMC 114-C215, and TMC 114-C208) and Phase 3 studies (TMC 114-C211, TMC 114-C214, TMC 114-C209, DUET-1 (TMC 125-C206), and DUET-2 (TMC 125-C216)) with PREZISTA/rtv: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.
Additional ADRs to PREZISTA/rtv identified in other clinical trials
In Studies TMC 114-C213, TMC 114-C202, TMC 114-C215, TMC 114-C208, TMC 114-C209, DUET-1, and DUET-2, the only additional ADR of interest identified was lipodystrophy.
Patients co-infected with hepatitis B and/or hepatitis C virus
In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes [see WARNINGS AND PRECAUTIONS]. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.
Postmarketing Experience
The following events have been identified during postmarketing use of PREZISTA. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Rarely, events of hypersensitivity (including facial edema), and rhabdomyolysis (assoicated with co-administration with HMG-CoA reductase inhibitors and PREZISTA) have been reported.
DRUG INTERACTIONS
See also CONTRAINDICATIONS and CLINICAL PHARMACOLOGY.
Potential for PREZISTA/rtv to Affect Other Drugs
PREZISTA co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 6).
Potential for Other Drugs to Affect Darunavir
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 (see Table 6).
Established and Other Potentially Significant Drug Interactions
Table 6 provides dosing recommendations as a result of drug interactions with PREZISTA/rtv. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see CLINICAL PHARMACOLOGY for Magnitude of Interaction, Tables 8 and 9]
In addition to the drugs included in Table 6, the interaction between PREZISTA/rtv and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see CLINICAL PHARMACOLOGY]: atazanavir, efavirenz, etravirine, nevirapine, omeprazole, ranitidine, and tenofovir disoproxil fumarate.
Other nucleoside reverse transcriptase inhibitors (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 PREZISTA/rtv.
Other PIs
The co-administration of PREZISTA/rtv and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.
WARNINGS
Included as part of the PRECAUTIONS section.
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/rtv. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. 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/rtv therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv 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/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, hepatomegaly) in patients on PREZISTA/rtv should prompt consideration of interruption or discontinuation of treatment.
Skin Rash
In clinical trials (n=3063), rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA [also see 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 subjects using PREZISTA/rtv was 0.5%.
Severe skin rash, accompanied by fever and/or elevations of transaminases in some cases, has been reported in 0.4% of subjects. Stevens-Johnson Syndrome has been rarely ( < 0.1%) reported. Treatment with PREZISTA should be discontinued if severe rash develops.
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/rtv, the incidence and severity of rash was similar in subjects with or without a history of sulfonamide allergy.
Drug Interactions
See below for a listing of drugs that are contraindicated for use with PREZISTA/rtv due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to PREZISTA [see CONTRAINDICATIONS].
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 DARUNAVIR/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 DARUNAVIR/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.
Antimycobacterial Rifampin Rifampin is a potent inducer of CYP450 metabolism. DARUNAVIR/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 DARUNAVIR.
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 DARUNAVIR/ritonavir. There is an increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
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 jeroveci 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/rtv treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is unknown.
Patient Counseling Information
[See FDA-Approved Patient Labeling]
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with PREZISTA. A Patient Package Insert for PREZISTA is available for patient information.
General
Patients should be informed that PREZISTA is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of PREZISTA are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with PREZISTA can reduce the risk of transmitting HIV to others.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using PREZISTA.
Instructions for Use
General
Patients should be advised to take PREZISTA and ritonavir (NORVIR®) with food every day as prescribed. The type of food does not affect exposure to PREZISTA. Patients should be instructed to swallow whole tablets with a drink such as water or milk. PREZISTA must always be used with 100 mg of ritonavir (NORVIR®) in combination with other antiretroviral drugs. Patients should not alter the dose of either PREZISTA or ritonavir (NORVIR®), discontinue ritonavir (NORVIR®), or discontinue therapy with PREZISTA without consulting their physician.
Patients Taking 800 mg of PREZISTA Once Daily
If a patient misses a dose of PREZISTA (two 400 mg tablets) or ritonavir (NORVIR®) by more than 12 hours, the patient should be told to wait and then take the next dose of PREZISTA (two 400 mg tablets) and ritonavir (NORVIR®) at the regularly scheduled time. If the patient misses a dose of PREZISTA (two 400 mg tablets) or ritonavir (NORVIR®) by less than 12 hours, the patient should be told to take PREZISTA (two 400 mg tablets) and ritonavir (NORVIR®) immediately, and then take the next dose of PREZISTA (two 400 mg tablets) and ritonavir (NORVIR®) at the regularly scheduled time. If a dose of PREZISTA (two 400 mg tablets) or ritonavir (NORVIR®) is skipped, the patient should not double the next dose. Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA (two 400 mg tablets) or ritonavir (NORVIR®) at any one time.
Patients Taking 600 mg of PREZISTA Twice Daily
If a patient misses a dose of PREZISTA (one 600 mg tablet or two 300 mg tablets) or ritonavir (NORVIR®) by more than 6 hours, the patient should be told to wait and then take the next dose of PREZISTA (one 600 mg tablet or two 300 mg tablets) and ritonavir (NORVIR®) at the regularly scheduled time. If the patient misses a dose of PREZISTA (one 600 mg tablet or two 300 mg tablets) or ritonavir (NORVIR®) by less than 6 hours, the patient should be told to take PREZISTA (one 600 mg tablet or two 300 mg tablets) and ritonavir (NORVIR®) immediately, and then take the next dose of PREZISTA (one 600 mg tablet or two 300 mg tablets) and ritonavir (NORVIR®) at the regularly scheduled time. If a dose of PREZISTA (one 600 mg tablet or two 300 mg tablets) or ritonavir (NORVIR®) is skipped, the patient should not double the next dose. Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA (one 600 mg tablet or two 300 mg tablets) or ritonavir (NORVIR®) at any one time.
Drug Interactions
PREZISTA/rtv may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
Patients receiving estrogen-based contraceptives should be instructed to use alternate contraceptive measures during therapy with PREZISTA/rtv because hormonal levels may decrease.
Fat Redistribution
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZISTA/rtv, and that the cause and long-term health effects of these conditions are not known at this time.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis and Mutagenesis
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
Impairment of Fertility
No effects on fertility or early embryonic development were observed with darunavir in rats and darunavir has shown no teratogenic potential in mice (in the presence or absence of ritonavir), rats and rabbits.
Use In Specific Populations
Pregnancy
Pregnancy Category C: PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk.
No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice, rats and rabbits. 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.
In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.
In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels.
Antiretroviral Pregnancy Registry:To monitor maternal-fetal outcomes of pregnant women exposed to PREZISTA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
PREZISTA/rtv should not be used 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,CLINICAL PHARMACOLOGY and Nonclinical Toxicology].
Geriatric Use
Clinical studies of PREZISTA 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 PREZISTA in elderly patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY].
Hepatic Impairment
No dose adjustment of PREZISTA/rtv is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of PREZISTA/rtv in subjects with severe hepatic impairment, therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Renal Impairment
Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis [see CLINICAL PHARMACOLOGY].
OVERDOSE
Human experience of acute overdose with PREZISTA/rtv is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
No specific antidote is available for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
CONTRAINDICATIONS
Co-administration of PREZISTA/rtv 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 1 [also see DRUG INTERACTIONS, Table 6].
Due to the need for co-administration of PREZISTA with 100 mg of ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.
CLINICAL PHARMACOLOGY
Mechanism of Action
Darunavir is an HIV antiviral drug.
Pharmacodynamics
In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were administered supratherapeutic doses of darunavir/ritonavir 1600/100 mg once daily and 800/100 mg twice daily for seven days.
At the mean maximum darunavir concentration of 6599 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 2-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.
Pharmacokinetics
Pharmacokinetics in Adults
General
Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of PREZISTA 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.
The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), have been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 7 displays the population pharmacokinetic estimates of darunavir after oral administration of PREZISTA/rtv 600/100 mg twice daily [based on sparse sampling in 285 patients in study TMC 114-C214 and 119 patients (integrated data) from Studies TMC 114-C202 and TMC 114-C213] and PREZISTA/rtv 800/100 mg once daily [based on sparse sampling in 335 patients in Study TMC 114-C211] to HIV-1-infected patients.
Table 7: Population Pharmacokinetic Estimates of Darunavir at the PREZISTA/rtv 800/100 mg once daily (Study TMC 114-C211, 48 Week Analysis) and PREZISTA/rtv 600/100 mg twice daily (Study TMC 114-C214, 48 Week Analysis and Integrated data from Studies TMC 114-C213 and TMC 114-C202, Primary 24-Week Analysis)Parameter Study
TMC 114-C211
PREZISTA/rtv
800/100 mg
once daily
N = 335 Study
TMC 114-C214
PREZISTA/rtv
600/100 mg
twice daily
N = 285 Studies
TMC 114-C213
and TMC 114-C202
(integrated data)
PREZISTA/rtv
600/100 mg
twice daily
N =119
AUC24h (ng•h/mL)*
Mean ± Standard Deviation 93026 ± 27050 116796 ± 33594 124698 ± 32286
Median (Range) 87854
(45000-219240) 111632
(64874-355360) 123336
(67714-212980)
C0h (ng/mL)
Mean ± Standard Deviation 2282 ± 1168 3490 ± 1401 3578 ± 1151
Median (Range) 2041
(368-7242) 3307
(1517-13198) 3539
(1255-7368)
N = number of subjects with data.
*AUC24h is calculated as AUC12h*2
Absorption and Bioavailability
Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5-4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters.
Effects of Food on Oral Absorption
When administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 30% higher relative to the fasting state. Therefore, PREZISTA tablets, co-administered with ritonavir, should always be taken with food. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).
Distribution
Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).