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FDA Approval of Prezista

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Accession Number
 A00771

Author
 U.S. Food and Drug Administration

Source
 FDA List Serv Announcement

Release Date
 June 26, 2006

Major Descriptors

Topic
 Drugs and Treatment

Text
 Prezista Approval
The Food and Drug Administration today, June 23, 2006, granted accelerated approval for Prezista (darunavir - formerly known as TMC-114), a new drug for treatment experienced adults whose infection with the human immunodeficiency virus (HIV) is not responding to treatment with other antiretroviral drugs. Prezista, a protease inhibitor, is indicated to be co-administered with a low-dose of ritonavir, in combination with other active anti-HIV agents. Ritonavir, which is also a protease inhibitor, slows the metabolism of Prezista, resulting in increased plasma concentrations. The recommended oral dose of Prezista tablets is 600 mg (two 300 mg tablets) twice daily taken with ritonavir 100 mg twice daily and with food. The type of food does not affect exposure to darunavir.
The accelerated approval is based on evidence from two randomized, controlled studies comparing the safety and effectiveness of a Prezista-ritonavir combination with other ritonavir-boosted protease inhibitor combinations. Patients in both arms of these trials also used other anti-HIV agents (nucleoside reverse transcriptase inhibitors) with or without enfuvirtide, a fusion inhibitor that inhibits the virus from entering the cell. In these studies, patients on a Prezista-ritonavir combination experienced higher rates of reduction of their HIV viral load than patients on other ritonavir-boosted protease inhibitor combinations. Seventy percent of treatment-experienced patients achieved a virologic response with PREZISTA/ritonavir in combination therapy compared to 21 percent in control group at week 24.
The most common side effects reported by patients on the Prezista-ritonavir regimen included diarrhea, nausea, and headache. About seven percent of patients on this combination therapy experienced skin rashes ranging from mild to serious.
The risks and benefits of Prezista have not been established for adults who have not been previously treated for HIV, or for children. As a condition of the accelerated approval, the manufacturer is required to conduct post-marketing trials to verify and describe the clinical benefits of Prezista. In addition, the manufacturer has committed to conducting other postmarketing studies that include studies in pediatric populations, studies to better define certain drug-drug interactions, and to evaluate the drug in patients with varying degrees of liver impairment to identify appropriate dosing for this patient population. Prezista is manufactured for Tibotec, Inc., Division of Ortho Biotech Products, L.P., Raritan, N.J., by JOLL, Gurabo, Puerto Rico. A pdf version of the approved labeling is attached. <> Richard Klein Office of Special Health Issues Food and Drug Administration Jeffrey Murray Division of Antiviral Products Food and Drug Administration An archive of past list serve announcements is available on the FDA web site at http://www.fda.gov/oashi/aids/listserve/archive.html This release was provided by the FDA and posted on AIDSinfo Web site (http://AIDSinfo.nih.gov).
PREZISTA* (Tibotec, Inc.) (darunavir) Tablets DESCRIPTION PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV) protease.
Tablets 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 has the following structural formula:
Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C. PREZISTA is available as an orange, oval-shaped, film-coated tablet for oral administration. Each tablet contains darunavir ethanolate equivalent to 300 mg of darunavir. 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.
MICROBIOLOGY Mechanism of Action Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles. Antiviral Activity Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G), and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, efavirenz, or nevirapine, and the fusion inhibitor enfuvirtide. Resistance Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wildtype HIV had 6- to 21-fold decreased susceptibility to darunavir and harbored 3 to 6 of the following amino acidsubstitutions S37N/D, R41E/S/T, K55Q, K70E, A71T, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple protease inhibitor resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, including L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease mutations and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.
Clinical studies of darunavir/ritonavir in treatment-experienced subjects In the Phase 2b Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, multiple protease inhibitor-resistant HIV-1 isolates from highly treatment-experienced subjects who received PREZISTA/rtv 600/100 mg b.i.d. and experienced virologic failure, either by rebound, or by never being suppressed, developed amino acid substitutions that were associated with a decrease in susceptibility to darunavir. The amino acid substitution V32I developed on PREZISTA/rtv 600/100 mg b.i.d. in greater than 30% of virologic failure isolates and substitutions at amino acid position I54 developed in greater than 20% of virologic failure isolates. Other substitutions that developed in 10% to 20% of PREZISTA/rtv virologic failure isolates occurred at amino acid positions I15, L33, I47, G73 and L89. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 21-fold at baseline and 94-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites of some darunavir virologic failure isolates. The resistance profile in treatment-naïve subjects has not been characterized.
Cross-resistance Cross-resistance among protease inhibitors has been observed. Darunavir has a < 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these protease inhibitors remain susceptible to darunavir. In Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, 60% (88/147) of subjects on darunavir/rtv whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change > 3) demonstrated a decrease of . 1 log10 in viral load at week 24, and 36% (53/147) achieved < 50 copies/mL plasma HIV RNA levels. Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from protease inhibitor-resistant viruses showed a fold change in EC50 values < 3 for tipranavir, indicative of limited crossresistance between darunavir and tipranavir. Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg b.i.d., greater than 50% were still susceptible to tipranavir while less than 5% were susceptible to other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir). Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the nonnucleoside reverse transcriptase inhibitors or the fusion inhibitor is unlikely because the viral targets are different.
Baseline Genotype/Phenotype and Virologic Outcome Analyses Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of PREZISTA/rtv 600/100 mg b.i.d. therapy. Analyses were conducted to evaluate the impact of specific baseline protease inhibitor resistance-associated mutations and the number of protease inhibitor resistanceassociated mutations at baseline on virologic response. Both specific mutations and the number of baseline mutations, as well as susceptible drugs in the optimized background regimen and enfuvirtide use, affected PREZISTA/rtv response rates in Phase 2b Studies TMC114-C213 and TMC114-C202. The presence at baseline of the mutations V32I, I47V, or I54L or M, was associated with a decreased virologicresponse to darunavir and decreased susceptibility to darunavir. In addition, a diminished virologic response was observed in subjects with . 7 protease inhibitor resistance-associated mutations (any change at amino acid positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88, or 90) at baseline (see Table 1). In a supportive analysis of Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, the presence at baseline of three or more of the mutations V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA/rtv (the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at week 24 was 50%, 22% and 10% when the baseline genotype had 0-2, 3 and .4 of these mutations, respectively). Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data. Table 1
Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 2. These baseline phenotype groups are based on the select subject populations in the Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, and are not meant to represent definitive clinical susceptibility breakpoints for PREZISTA/rtv. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir in protease inhibitor-experienced patients. Table 2
CLINICAL PHARMACOLOGY Pharmacokinetics in Adults The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg twice daily), have been evaluated in healthy adult volunteers and in HIV-1 infected subjects. Table 3 displays the population pharmacokinetic estimates of darunavir from an analysis of integrated data from Studies TMC114-C213 and TMC114-C202 of 119 subjects administered the darunavir/ritonavir 600/100 mg b.i.d. dose. Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of 600 mg darunavir was given orally in combination with 100 mg ritonavir b.i.d., 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. Table 3
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. 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, coadministered 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). Metabolism: In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg 14C-darunavir, coadministered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV. Elimination: A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14Cdarunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14Cdarunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.
Special Populations Hepatic Impairment: Darunavir primarily undergoes hepatic metabolism. PREZISTA has not been studied in patients with varying degrees of hepatic impairment (see PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION). Hepatitis B or Hepatitis C Virus Co-infection: The primary 24-week analysis of the data from Study TMC114-C213 in 31 HIV-1 infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir. Renal Impairment: Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease. (see PRECAUTIONS, Patients with co-existing conditions, Renal Impairment, and DOSAGE AND ADMINISTRATION). Gender: Population pharmacokinetic analysis showed higher mean darunavir exposure (16.8%) in HIV infected females (n=68) compared to males. This difference is not clinically relevant. Race: Population pharmacokinetic analysis of darunavir in HIV infected subjects indicated that race had no apparent effect on the exposure to darunavir. Geriatric Patients: Population pharmacokinetic analysis in HIV infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected subjects (n=12, age . 65) (see PRECAUTIONS, Geriatric Use). Pediatric Patients: The pharmacokinetics of darunavir in combination with ritonavir in pediatric patients has not been established. There are insufficient data at this time to recommend a dose. Drug Interactions: See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions. Darunavir and ritonavir are both inhibitors of CYP3A. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see sections CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions). 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, Cmax, and Cmin values are summarized in Table 4 (effect of other drugs on darunavir) and Table 5 (effect of darunavir on other drugs). For information regarding clinical recommendations, see PRECAUTIONS, Drug Interactions.
Table 4
Table 5
INDICATIONS AND USAGE PREZISTA, co-administered with 100 mg ritonavir (PREZISTA/rtv), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatmentexperienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor. This indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from 2 controlled trials of PREZISTA/rtv in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. 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 MICROBIOLOGY). *The use of other active agents with PREZISTA/rtv is associated with a greater likelihood of treatment response (see MICROBIOLOGY and INDICATIONS AND USAGE, Description of Clinical Studies). *The risks and benefits of PREZISTA/rtv have not been established in treatment-naïve adult patients or pediatric patients.
Description of Clinical Studies The evidence of efficacy of PREZISTA/rtv is based on the analyses of 24-week data from 2 ongoing, randomized, controlled trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1 infected adult subjects. These efficacy results were supported by the 24-week pooled analysis of the open label trials TMC114- C215 and TMC114-C208 of subjects who initiated PREZISTA/rtv at the recommended dose. Treatment-Experienced Subjects: Studies TMC114-C213 and TMC114-C202: These are ongoing randomized, controlled, Phase 2b trials consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to PREZISTA/rtv received the recommended dose of 600/100 mg b.i.d. HIV-1 infected subjects 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, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide. Analyses included 318 subjects in Study TMC114-C213 and 319 subjects in Study TMC114-C202 who had completed 24 weeks of treatment or discontinued earlier. At 24 weeks, the virologic response rate was evaluated in subjects receiving PREZISTA/rtv plus an optimized background regimen (OBR) versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir/ritonavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 23% of the control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus baseline. In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/rtv arm and the comparator PI arm. Table 6 compares the demographic characteristics between subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and subjects in the comparator PI arm.
Table 6
Table 7 Table 7 compares the baseline characteristics between subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and subjects in the comparator PI arm.
Table 8
Through 24 weeks of treatment, the proportion of subjects with HIV-1 RNA < 400 copies/mL in the arm receiving PREZISTA/rtv 600/100 mg b.i.d. compared to the comparator PI arm was 63% and 19%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were -1.89 log10 copies/mL in the arm receiving PREZISTA/rtv 600/100 mg b.i.d. and -0.48 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving PREZISTA/rtv 600/100 mg b.i.d. (92 cells/mm3) than in the comparator PI arm (17 cells/mm3). The TMC114-C215/C208 analysis: Additional data on the efficacy of PREZISTA/rtv 600/100 mg b.i.d. have been obtained in treatment-experienced subjects participating in the non-randomized trials TMC114-C215 and TMC114- C208. The 246 subjects from these trials included in the TMC114-C215/C208 24-week efficacy analysis initiated therapy with PREZISTA/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 the TMC114-C215/C208 analysis were the same as those for Studies TMC114-C213 and TMC114-C202. Baseline characteristics of the subjects included in the TMC114-C215/C208 analysis were comparable to those subjects in Studies TMC114-C213 and TMC114-C202. The TMC114-C215/C208 24-week efficacy analysis supported the viral load reduction and CD4+ cell count increases observed in the Studies TMC114-C213 and TMC114-C202. Of the 246 subjects at Week 24, 65% had a virologic response defined as a decrease of at least 1.0 log10 in plasma viral load versus baseline and 40% of the subjects reached less than 50 HIV-1 RNA copies/mL. The mean increase in CD4+ cell count versus baseline was 80 cells/mm3 at Week 20. At Week 24, 57% of the subjects reached less than 400 HIV-1 RNA copies/mL, and the mean changes in plasma HIV-1 RNA from baseline were -1.65 log10 copies/mL.
CONTRAINDICATIONS PREZISTA is contraindicated in patients with known hypersensitivity to any of the ingredients of the product. 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 are listed in Table 9 (also see PRECAUTIONS, Drug Interactions, Table 10).
Table 9
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. WARNINGS ALERT: Find out about medicines that should not be taken with PREZISTA/rtv. This statement is included onthe product¿s bottle label. General PREZISTA (darunavir) must be co-administered with ritonavir and food to exert its therapeutic effect (see DOSAGE and ADMINISTRATION). Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect. Please refer to ritonavir prescribing information for additional information on precautionary measures. Skin Rash During the clinical development program, severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in 7% of subjects treated with PREZISTA; the discontinuation rate due to rash was 0.3%. Rashes were generally mild-to-moderate, self-limited maculopapular skin eruptions. Treatment with PREZISTA should be discontinued if severe rash develops. Sulfa Allergy Darunavir contains a sulfonamide moiety. PREZISTA (darunavir) should be used with caution in patients with a known sulfonamide allergy. Drug Interactions PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA/rtv with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see sections CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions). 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 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 protease inhibitor 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 protease inhibitor therapy and these events have not been established.
PRECAUTIONS Patients with co-existing conditions Hepatic Impairment: Darunavir is primarily metabolized by the liver, hence, caution should be exercised when PREZISTA/rtv is given to patients with hepatic impairment, because increased plasma concentrations are expected in patients with hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA/rtv should be used with caution in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE AND ADMINISTRATION). Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening of liver disease in such patients, interruption or discontinuation of treatment must be considered. 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). 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 CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION). Hemophilia: 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 if treatment had been discontinued. A causal relationship between protease inhibitor therapy and these episodes has 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. Resistance/Cross-Resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in PREZISTA/rtv treated patients, it is unknown what effect therapy with PREZISTA will have on the activity of subsequently administered protease inhibitors. Information for Patients
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. 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. 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. If a patient misses a dose of PREZISTA or ritonavir (NORVIR®) by more than 6 hours, the patient should be told to wait and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If the patient misses a dose of PREZISTA or ritonavir (NORVIR®) by less than 6 hours, the patient should be told to take PREZISTA and ritonavir (NORVIR®) immediately, and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If a dose of PREZISTA 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 or ritonavir (NORVIR®) at any one time. 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. 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. Drug Interactions PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Tables 10 and 11). Drugs that are contraindicated and not recommended for co-administration with PREZISTA/rtv are included in Table 10. 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 10
Table 11
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 PREZISTA/rtv. Other protease inhibitors: 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. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis: Long-term carcinogenicity studies of darunavir in rodents have not been completed. Darunavir, however, was tested negative in the in vitro Ames reverse mutation assay and in vitro chromosomal aberration assay in human lymphocytes, both tested in the absence and presence of metabolic activation system. Darunavir does not induce chromosomal damage in the in vivo micronucleus test in mice. Impairment of Fertility: There were no effects on fertility and early embryonic development with darunavir in rats and darunavir has shown no teratogenic potential in mice (in the presence or absence of ritonavir), rats and rabbits. Pregnancy Pregnancy Category B: Reproduction studies conducted with darunavir have shown no embryotoxicity or teratogenicity in mice, rats and rabbits. Because of limited bioavailability of darunavir in animals and/or dosing limitations, the plasma exposures (AUC values) were approximately 50% in mice and rats and 5% in the 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 or mating performance of offspring was 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. There are, however, no adequate and well-controlled studies in pregnant women. PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. 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 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. 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.
ADVERSE REACTIONS The safety assessment is based on all safety data from the Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis reported with the recommended dose PREZISTA/rtv 600/100 mg b.i.d. in the 458 subjects who initiated treatment with the recommended dose (de novo subjects). In Studies TMC114-C213 and TMC114-C202, the mean exposure in weeks for subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and comparator PI arm was 63.5 and 31.5, respectively. The mean exposure in weeks for subjects in the TMC114-C215/C208 analysis was 23.9. The most common treatment-emergent adverse events (> 10%) reported in the de novo subjects, regardless of causality or frequency, were diarrhea, nausea, headache, and nasopharyngitis. For subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and the comparator PI arm in the pooled analysis for Studies TMC114-C213 and TMC114-C202, diarrhea was reported in 19.8% and 28.2%, nausea in 18.3% and 12.9%, headache in 15.3% and 20.2%, and nasopharyngitis in 13.7% and 10.5%, of subjects, respectively. In the randomized trials, rates of discontinuation of therapy due to adverse events were 9% in subjects receiving PREZISTA/rtv and in 5% of subjects in the comparator PI arm. 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. Drug-related clinical adverse events of moderate or severe intensity (. Grade 2) occurring in . 2% of subjects treated with PREZISTA/rtv for 1 to 96 weeks are presented in Table 12.
Table 12
Treatment-emergent adverse events occurring in less than 2% of de novo subjects (n=458) receiving PREZISTA/rtv, considered at least possibly related to treatment and of at least moderate intensity are listed below by body system: Body as a Whole: folliculitis, asthenia, pyrexia, fatigue, rigors, hyperthermia, peripheral edema Cardiovascular System: myocardial infarction, tachycardia, hypertension Digestive System: flatulence, abdominal distension, dry mouth, dyspepsia, abdominal pain, nausea, constipation Metabolic and Nutritional Disorders: anorexia, hypercholesterolemia, hyperlipidemia, diabetes mellitus, decreased appetite, obesity, fat redistribution, hyponatremia, polydipsia Musculoskeletal System: arthralgia, pain in extremity, myalgia, osteopenia, osteoporosis Nervous System: peripheral neuropathy, hypoesthesia, memory impairment, paresthesia, somnolence, transient ischemic attack, confusional state, disorientation, irritability, altered mood, nightmare, anxiety, headache Respiratory System: dyspnea, cough, hiccups Skin and Appendages: lipoatrophy, night sweats, allergic dermatitis, eczema, toxic skin eruption, alopecia, dermatitis medicamentosa, hyperhidrosis, skin inflammation, maculopapular rash, erythema multiforme, Stevens-Johnson Syndrome (reported in another ongoing clinical study) Special Senses: vertigo Urogenital System: acute renal failure, renal insufficiency, nephrolothiasis, polyuria, gynecomastia Laboratory abnormalities: The percentages of adult subjects treated with PREZISTA/rtv 600/100 mg b.i.d. with treatment-emergent Grade 2 to 4 laboratory abnormalities are presented in Table 13.
Table 13
Patients co-infected with hepatitis B and/or hepatitis C virus: Subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, did not experience higher incidence of adverse events or clinical chemistry abnormalities than subjects receiving PREZISTA/rtv who were not co-infected. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection. Standard clinical monitoring of patients with chronic hepatitis B and/or C is considered adequate.
OVERDOSAGE 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. There is no specific antidote 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.
DOSAGE AND ADMINISTRATION Adults: The recommended oral dose of PREZISTA tablets is 600 mg (two 300 mg tablets) twice daily 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 CLINICAL PHARMACOLOGY, Special Populations, Pediatric Patients). Hepatic Impairment: There are no data regarding the use of PREZISTA/rtv when co-administered to patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA/rtv should be used with caution in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS, Patients with coexisting conditions, Hepatic Impairment). Renal Impairment: No dose adjustment is required in 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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Renal Impairment and PRECAUTIONS, Patients with co-existing conditions, Renal Impairment).
HOW SUPPLIED PREZISTA (darunavir) 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 tablets are packaged in bottles in the following configuration: 300 mg tablets/bottles of 120 (NDC 59676-560-01) Storage: Store PREZISTA tablets at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F). Manufactured for Tibotec, Inc. by: JOLLC, Gurabo, Puerto Rico Distributed by: Tibotec Therapeutics, Division of Ortho Biotech Products, L.P., Raritan NJ 08869 Issued: June 2006 Patent Numbers: 5,843,946; 6,248,775; 6,335,460 and other US patents pending 10101700