Prezista

PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adult and pediatric patients 3 years of age and older

• Testing:
  
  
  • In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with PREZISTA/ritonavir to assess drug susceptibility of the HIV-1 virus (
    
    
    2.1 Testing Prior to Initiation of PREZISTA/ritonavir

    In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus

    [see Microbiology (12.4)].

    Refer to

    Dosage and Administration (2.3), (2.4)and (2.5)

    for dosing recommendations.

    Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with PREZISTA/ritonavir

    [see Warnings and Precautions (5.2)]

    .
    ,
    
    
    12.4 Microbiology

    Mechanism of Action

    Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 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 EC₅₀values 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 EC₅₀values ranging from less than 0.1 to 4.3 nM. The EC₅₀value 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 PIs 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, rilpivirine, efavirenz, etravirine, 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 PREZISTA/ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions 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 substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC₅₀values ranging from 125 nM to 3461 nM.

    Clinical trials of PREZISTA/ritonavir in treatment-experienced subjects

    : In a pooled analysis of the 600/100 mg PREZISTA/ritonavir twice daily arms of trials TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine trials TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M developed most frequently on PREZISTA/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (less than 50 copies/mL). Other substitutions that developed frequently in PREZISTA/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had a greater than 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some PREZISTA/ritonavir virologic failure isolates. In trial TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on PREZISTA/ritonavir.

    In the 96-week as-treated analysis of the Phase 3 trial TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving PREZISTA/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on PREZISTA/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI substitutions on PREZISTA/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes greater than 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V. These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (greater than 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (greater than 10-fold) to lopinavir at baseline.

    In the 48-week analysis of the Phase 3 trial TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving PREZISTA/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving PREZISTA/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on PREZISTA/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on PREZISTA/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the PREZISTA/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the PREZISTA/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60; 12%) and 4 (4/42; 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.

    Clinical trials of PREZISTA/ritonavir in treatment-naïve subjects

    : In the 192-week as-treated analysis censoring those who discontinued before Week 4 of the Phase 3 trial TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving PREZISTA/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the PREZISTA/ritonavir arm, emergent PI resistance-associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43). However, none of the darunavir virologic failures had a decrease in darunavir susceptibility (greater than 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or resistance to emtricitabine, which was included in the fixed background regimen, was identified in 4 virologic failures from the PREZISTA/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm.

    Cross-resistance

    Cross-resistance among PIs has been observed. Darunavir has a less than 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 PIs remain susceptible to darunavir.

    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 PI-resistant viruses showed a fold change in EC₅₀values less than 3 for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In trials TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the PREZISTA/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change greater than 3) achieved less than 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on PREZISTA/ritonavir 600/100 mg twice daily (greater than 7-fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).

    In trial TMC114-C214, the 7 PREZISTA/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos)amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these 7 were resistant to saquinavir and 5 were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline.

    Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors 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/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as-treated analyses using pooled data from the Phase 2b trials (Trials TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine trials TMC125-C206 and TMC125-C216 at Week 24 (n=591).

    Diminished virologic responses were observed in subjects with 5 or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 17).

    Table 17: Response to PREZISTA/ritonavir 600/100 mg Twice Daily by Baseline Number of IAS-Defined Primary PI Resistance-Associated Substitutions: As-treated Analysis of Trials TMC114-C213, TMC114-C202, and TMC114-C215

    # IAS-defined primary PI substitutions	Proportion of subjects with <50 copies/mL at Week 96 N=439
    	Overall	de novo ENF	Re-used/No ENF
    ENF=enfuvirtide
    All	44% (192/439)	54% (61/112)	40% (131/327)
    0 – 4	50% (162/322)	58% (49/85)	48% (113/237)
    5	22% (16/74)	47% (9/19)	13% (7/55)
    ≥6	9% (3/32)	17% (1/6)	8% (2/26)

    IAS Primary PI Substitutions (2008): D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M.

    The presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA/ritonavir. In subjects not taking enfuvirtide

    de novo

    , the proportion of subjects achieving viral load less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0–1, 2 and greater than or equal to 3 of these substitutions, respectively.

    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 18. These baseline phenotype groups are based on the select patient populations in the trials TMC114-C213, TMC114-C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for PREZISTA/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir.

    Table 18: Response (HIV-1 RNA <50 copies/mL at Week 96) to PREZISTA/ritonavir 600/100 mg Twice Daily by Baseline Darunavir Phenotype and by Use of Enfuvirtide: As-treated Analysis of Trials TMC114-C213, TMC114-C202, and TMC114-C215

    Baseline DRV phenotype	Proportion of subjects with <50 copies/mL at Week 96 N=417
    	All	de novo ENF	Re-used/No ENF
    ENF=enfuvirtide
    Overall	175/417 (42%)	61/112 (54%)	131/327 (40%)
    0 – 7	148/270 (55%)	44/65 (68%)	104/205 (51%)
    >7 – 20	16/53 (30%)	7/17 (41%)	9/36 (25%)
    >20	11/94 (12%)	6/23 (26%)	5/71 (7%)
    )
    
    
  • Monitor serum liver chemistry tests before and during therapy with PREZISTA/ritonavir. (
    
    
    2.1 Testing Prior to Initiation of PREZISTA/ritonavir

    In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus

    [see Microbiology (12.4)].

    Refer to

    Dosage and Administration (2.3), (2.4)and (2.5)

    for dosing recommendations.

    Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with PREZISTA/ritonavir

    [see Warnings and Precautions (5.2)]

    .
    ,
    
    
    2.2 Monitoring During Treatment with PREZISTA/ritonavir

    Patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases should be monitored for elevation in serum liver biochemistries, especially during the first several months of PREZISTA/ritonavir treatment

    [see Warnings and Precautions (5.2)]

    .
    ,
    
    
    5.2 Hepatotoxicity

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

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

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

    Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/ritonavir should prompt consideration of interruption or discontinuation of treatment.
    )
    
    
• Treatment-naïve adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet) taken with ritonavir 100 mg once daily and with food. (
  
  
  2.3 Recommended Dosage in Adult Patients

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

  Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg per mL PREZISTA oral suspension.

  Treatment-Naïve Adult Patients

  The recommended oral dose of PREZISTA is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet or capsule or 1.25 mL of a 80 mg per mL ritonavir oral solution) once daily and with food. An 8 mL PREZISTA dose should be taken as two 4 mL administrations with the included oral dosing syringe.

  Treatment-Experienced Adult Patients

  The recommended oral dosage for treatment-experienced adult patients is summarized in Table 1.

  Baseline genotypic testing is recommended for dose selection. However, when genotypic testing is not feasible, PREZISTA 600 mg taken with ritonavir 100 mg twice daily is recommended.

  Table 1: Recommended PREZISTA/ritonavir Dosage in Treatment-Experienced Adult Patients

  	Formulation and Recommended Dosing
  Baseline Resistance	PREZISTA tablets with ritonavir tablets or capsule	PREZISTA oral suspension (100 mg/mL) with ritonavir oral solution (80 mg/mL)
  With no darunavir resistance associated substitutionsV11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V	One 800 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food	8 mLAn 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken once daily with food
  With at least one darunavir resistance associated substitutions , or with no baseline resistance information	One 600 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken twice daily with food	6 mL PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken twice daily with food
  )
  
• Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (
  
  
  2.3 Recommended Dosage in Adult Patients

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

  Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg per mL PREZISTA oral suspension.

  Treatment-Naïve Adult Patients

  The recommended oral dose of PREZISTA is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet or capsule or 1.25 mL of a 80 mg per mL ritonavir oral solution) once daily and with food. An 8 mL PREZISTA dose should be taken as two 4 mL administrations with the included oral dosing syringe.

  Treatment-Experienced Adult Patients

  The recommended oral dosage for treatment-experienced adult patients is summarized in Table 1.

  Baseline genotypic testing is recommended for dose selection. However, when genotypic testing is not feasible, PREZISTA 600 mg taken with ritonavir 100 mg twice daily is recommended.

  Table 1: Recommended PREZISTA/ritonavir Dosage in Treatment-Experienced Adult Patients

  	Formulation and Recommended Dosing
  Baseline Resistance	PREZISTA tablets with ritonavir tablets or capsule	PREZISTA oral suspension (100 mg/mL) with ritonavir oral solution (80 mg/mL)
  With no darunavir resistance associated substitutionsV11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V	One 800 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food	8 mLAn 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken once daily with food
  With at least one darunavir resistance associated substitutions , or with no baseline resistance information	One 600 mg PREZISTA tablet with one 100 mg ritonavir tablet/capsule, taken twice daily with food	6 mL PREZISTA oral suspension with 1.25 mL ritonavir oral solution, taken twice daily with food
  )
  
• Pregnant patients: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (
  
  
  2.4 Recommended Dosage During Pregnancy

  The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food.

  PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance.
  )
  
• Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of PREZISTA and ritonavir is based on body weight and should not exceed the adult dose. PREZISTA should be taken with ritonavir and with food. (
  
  
  2.5 Recommended Dosage in Pediatric Patients (age 3 to less than 18 years)

  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 adults.

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

  The recommended dose of PREZISTA/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose. PREZISTA should be taken with ritonavir and with food.

  The recommendations for the PREZISTA/ritonavir dosage regimens were based on pediatric clinical trial data and population pharmacokinetic modeling and simulation

  [see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)].

  Dosing Recommendations for Treatment-Naïve Pediatric Patients or Antiretroviral Treatment-Experienced Pediatric Patients with No Darunavir Resistance Associated Substitutions

  Pediatric Patients Weighing At Least 10 kg but Less than 15 kg

  The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is PREZISTA 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table:

  Table 2: Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutionsdarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

  Body weight (kg)	Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL)
  	Dose: once daily with food
  Greater than or equal to 10 kg to less than 11 kg	PREZISTA 3.6 mLThe 350 mg, 385 mg, 455 mg and 490 mg darunavir dose for the specified weight groups were rounded up for suspension dosing convenience to 3.6 mL, 4 mL, 4.6 mL and 5 mL, respectively.(350 mg) with ritonavir 0.8 mL (64 mg)
  Greater than or equal to 11 kg to less than 12 kg	PREZISTA 4 mL (385 mg) with ritonavir 0.8 mL (64 mg)
  Greater than or equal to 12 kg to less than 13 kg	PREZISTA 4.2 mL (420 mg) with ritonavir 1 mL (80 mg)
  Greater than or equal to 13 kg to less than 14 kg	PREZISTA 4.6 mL (455 mg) with ritonavir 1 mL (80 mg)
  Greater than or equal to 14 kg to less than 15 kg	PREZISTA 5 mL (490 mg) with ritonavir 1.2 mL (96 mg)

  Pediatric Patients Weighing At Least 15 kg

  Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the following table:

  Table 3: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutionsdarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

  Body weight (kg)	Formulation: PREZISTA tablet(s) and ritonavir capsules or tablets (100 mg)	Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL)
  	Dose: once daily with food	Dose: once daily with food
  Greater than or equal to 15 kg to less than 30 kg	PREZISTA 600 mg with ritonavir 100 mg	PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg)
  Greater than or equal to 30 kg to less than 40 kg	PREZISTA 675 mg with ritonavir 100 mg	PREZISTA 6.8 mLThe 675 mg dose using darunavir tablets for this weight group is rounded up to 6.8 mL for suspension dosing convenience.The 6.8 mL and 8 mL darunavir dose should be taken as two (3.4 mL or 4 mL respectively) administrations with the included oral dosing syringe.(675 mg) with ritonavir 1.25 mL (100 mg)
  Greater than or equal to 40 kg	PREZISTA 800 mg with ritonavir 100 mg	PREZISTA 8 mL (800 mg) with ritonavir 1.25 mL (100 mg)

  Dosing Recommendations for Treatment-Experienced Pediatric Patients with At Least One Darunavir Resistance Associated Substitutions

  Pediatric Patients Weighing At Least 10 kg but Less than 15 kg

  The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is PREZISTA 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table:

  Table 4: Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitutiondarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

  Body weight (kg)	Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL)
  	Dose: twice daily with food
  Greater than or equal to 10 kg to less than 11 kg	PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32 mg)
  Greater than or equal to 11 kg to less than 12 kg	PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg)
  Greater than or equal to 12 kg to less than 13 kg	PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg)
  Greater than or equal to 13 kg to less than 14 kg	PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg)
  Greater than or equal to 14 kg to less than 15 kg	PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg)

  Pediatric Patients Weighing At Least 15 kg

  Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or suspension using the following table:

  Table 5: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitutiondarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

  Body weight (kg)	Formulation: PREZISTA tablet(s) and ritonavir tablets, capsules (100 mg) or oral solution (80 mg/mL)	Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL)
  	Dose: twice daily with food	Dose: twice daily with food
  Greater than or equal to 15 kg to less than 30 kg	PREZISTA 375 mg with ritonavir 0.6 mL (48 mg)	PREZISTA 3.8 mL (375 mg)The 375 mg and 450 mg dose using darunavir tablets for this weight group is rounded up to 3.8 mL and 4.6 mL for suspension dosing convenience.with ritonavir 0.6 mL (48 mg)
  Greater than or equal to 30 kg to less than 40 kg	PREZISTA 450 mg with ritonavir 0.75 mL (60 mg)	PREZISTA 4.6 mL (450 mg) with ritonavir 0.75 mL (60 mg)
  Greater than or equal to 40 kg	PREZISTA 600 mg with ritonavir 100 mg	PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg)

  The use of PREZISTA/ritonavir in pediatric patients below 3 years of age is not recommended

  [see Warnings and Precautions (5.10)and Use in Specific Populations (8.4)]

  .
  )
  
• PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment. (
  
  
  2.6 Not Recommended in Patients with Severe Hepatic Impairment

  No dosage 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)]

  .
  )
  

• Oral suspension: 100 mg per mL (
  
  
  3 DOSAGE FORMS AND STRENGTHS

  • Oral suspension: 100 mg per mL
  • Tablets: 75 mg, 150 mg, 600 mg, and 800 mg

  PREZISTA Oral Suspension

  PREZISTA 100 mg per mL is supplied as a white to off-white opaque suspension for oral use, containing 100 mg of darunavir per mL of suspension.

  PREZISTA Tablets

  • 75 mg: white, caplet-shaped, film-coated tablets debossed with "75" on one side and "TMC" on the other side.
  • 150 mg: white, oval-shaped, film-coated tablets debossed with "150" on one side and "TMC" on the other side.
  • 600 mg: orange, oval-shaped, film-coated tablets debossed with "600MG" on one side and "TMC" on the other side.
  • 800 mg: dark red, oval-shaped, film-coated tablets debossed with "800" on one side and "T" on the other side.
  )
  
• Tablets: 75 mg, 150 mg, 600 mg, and 800 mg (
  
  
  3 DOSAGE FORMS AND STRENGTHS

  • Oral suspension: 100 mg per mL
  • Tablets: 75 mg, 150 mg, 600 mg, and 800 mg

  PREZISTA Oral Suspension

  PREZISTA 100 mg per mL is supplied as a white to off-white opaque suspension for oral use, containing 100 mg of darunavir per mL of suspension.

  PREZISTA Tablets

  • 75 mg: white, caplet-shaped, film-coated tablets debossed with "75" on one side and "TMC" on the other side.
  • 150 mg: white, oval-shaped, film-coated tablets debossed with "150" on one side and "TMC" on the other side.
  • 600 mg: orange, oval-shaped, film-coated tablets debossed with "600MG" on one side and "TMC" on the other side.
  • 800 mg: dark red, oval-shaped, film-coated tablets debossed with "800" on one side and "T" on the other side.
  )
  

• Pregnancy: Total darunavir exposures were generally lower during pregnancy compared to postpartum period. The reduction in darunavir exposures during pregnancy were greater for once daily dosing compared to the twice daily dosing regimen. (
  
  
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREZISTA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.

  Risk Summary

  Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Available limited data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP

  )

  [see Data]

  .

  The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

  Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose

  [see Data]

  .

  Clinical Considerations

  The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food.

  PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance

  [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

  .

  Data

  Human Data

  PREZISTA/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial through the postpartum period (6–12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.

  The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6–12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen

  [see Clinical Pharmacology (12.3)].

  Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for 11% (2/18) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).

  PREZISTA/ritonavir was well tolerated during pregnancy and postpartum. There were no new clinically relevant safety findings compared with the known safety profile of PREZISTA/ritonavir in HIV-1-infected adults.

  Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine.

  Based on prospective reports to the APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6.% (95% CI: 2.3% to 5.3.%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens.

  Animal Data

  Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.
  ,
  
  
  12.3 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), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 11 displays the population pharmacokinetic estimates of darunavir after oral administration of PREZISTA/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in trial TMC114-C214, 278 patients in trial TMC114-C229 and 119 patients [integrated data] from trials TMC114-C202 and TMC114-C213) and PREZISTA/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in trial TMC114-C211 and 280 patients in trial TMC114-C229) to HIV-1-infected patients.

  Table 11: Population Pharmacokinetic Estimates of Darunavir at PREZISTA/ritonavir 800/100 mg Once Daily (Trial TMC114-C211, 48-Week Analysis and Trial TMC114-C229, 48-Week Analysis) and PREZISTA/ritonavir 600/100 mg Twice Daily (Trial TMC114-C214, 48-Week Analysis, Trial TMC114-C229, 48-Week Analysis and Integrated Data from Trials TMC114-C213 and TMC114-C202, Primary 24-Week Analysis)

  	PREZISTA/ritonavir 800/100 mg once daily		PREZISTA/ritonavir 600/100 mg twice daily
  Parameter	TMC114-C211 N=335	TMC114-C229 N=280	TMC114-C214 N=285	TMC114-C229 N=278	TMC114-C213 + TMC114-C202 (integrated data) N=119
  N=number of subjects with data
  AUC24h(ng.h/mL)AUC 24h is calculated as AUC 12h*2.
  Mean ± Standard Deviation	93026 ± 27050	93334 ± 28626	116796 ± 33594	114302 ± 32681	124698 ± 32286
  Median (Range)	87854 (45000–219240)	87788 (45456–236920)	111632 (64874–355360)	109401 (48934–323820)	123336 (67714–212980)
  C0h(ng/mL)
  Mean ± Standard Deviation	2282 ± 1168	2160 ± 1201	3490 ± 1401	3386 ± 1372	3578 ± 1151
  Median (Range)	2041 (368–7242)	1896 (184–7881)	3307 (1517–13198)	3197 (250–11865)	3539 (1255–7368)

  Absorption and Bioavailability

  Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a T_maxof 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 suggest that PREZISTA/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.

  Effects of Food on Oral Absorption

  When PREZISTA tablets were administered with food, the C_maxand AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. 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 mg¹⁴C-darunavir, co-administered 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-1.

  Elimination

  A mass balance study in healthy volunteers showed that after single dose administration of 400 mg¹⁴C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of¹⁴C-darunavir 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 co-administered 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 is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated

  [see Dosage and Administration (2.6)and Use in Specific Populations (8.6)]

  .

  Hepatitis B or Hepatitis C Virus Co-infection

  The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in 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 with¹⁴C-PREZISTA/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-1-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 Use in Specific Populations (8.7)]

  .

  Gender

  Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.

  Race

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

  Geriatric Patients

  Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65)

  [see Use in Specific Populations (8.5)]

  .

  Pediatric Patients

  PREZISTA/ritonavir administered twice daily

  The pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving PREZISTA/ritonavir 600/100 mg twice daily

  [see Dosage and Administration (2.5)]

  .

  PREZISTA/ritonavir administered once daily

  The pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving PREZISTA/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naïve adults receiving PREZISTA/ritonavir 800/100 mg once daily

  [see Dosage and Administration (2.5)]

  .

  Based on population pharmacokinetic modeling and simulation, the proposed PREZISTA/ritonavir once daily dosing regimens for pediatric patients 3 to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-naïve adults receiving PREZISTA/ritonavir 800/100 mg once daily

  [see Dosage and Administration (2.5)]

  .

  The population pharmacokinetic parameters in pediatric subjects with PREZISTA/ritonavir administered once or twice daily are summarized in the table below:

  Table 12: Population Pharmacokinetic Estimates of Darunavir Exposure (Trials TMC114-C230, TMC114-C212 and TMC114-C228) Following Administration of Doses in Tables 2 and 3

  	PREZISTA/ritonavir once daily	PREZISTA/ritonavir twice daily
  			TMC114-C228Subjects may have contributed pharmacokinetic data to both the 10 kg to less than 15 kg weight group and the 15 kg to less than 20 kg weight group.
  Parameter	TMC114-C230Summary statistics for population pharmacokinetic parameter estimates for DRV after administration of DRV/rtv at 800/100 mg once daily in treatment-naïve HIV-1 infected subjects from 12 to <18 years of age – Week-48 Analyses. N=12	TMC114-C212 N=74
  			10 to less than 15 kgCalculated from individual pharmacokinetic parameters estimated for Week 2 and Week 4, based on the Week 48 analysis that evaluated a darunavir dose of 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily. N=10	15 to less than 20 kgThe 15 kg to less than 20 kg weight group received 380 mg (3.8 mL) PREZISTA oral suspension twice daily with 48 mg (0.6 mL) ritonavir oral solution twice daily in TMC114-C228. Calculated from individual pharmacokinetic parameters estimated for Week 2 post-dose adjustment visit; Week 24 and Week 48 based on the – Week 48 analysis that evaluated a darunavir dose of 380 mg twice daily. N=13
  N=number of subjects with data.
  AUC24h(ng∙h/mL)AUC 24h is calculated as AUC 12h*2.)
  Mean ± Standard Deviation	84390 ± 23587	126377 ± 34356	137896 ± 51420	157760 ± 54080
  Median (Range)	86741 (35527–123325)	127340 (67054–230720)	124044 (89688–261090)	132698 (112310–294840)
  C0h(ng/mL)
  Mean ± Standard Deviation	2141 ± 865	3948 ± 1363	4510 ± 2031	4848 ± 2143
  Median (Range)	2234 (542–3776)	3888 (1836–7821)	4126 (2456–9361)	3927 (3046–10292)

  Pregnancy and Postpartum

  The exposure to total darunavir and ritonavir after intake of PREZISTA/ritonavir 600/100 mg twice daily and PREZISTA/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Table 13, Table 14and Figure 1).

  Table 13: Pharmacokinetic Results of Total Darunavir After Administration of PREZISTA/ritonavir at 600/100 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy and Postpartum

  Pharmacokinetics of total darunavir (mean ± standard deviation)	2ndTrimester of pregnancy (n=12)n=11 for AUC 24h	3rdTrimester of pregnancy (n=12)	Postpartum (6–12 Weeks) (n=12)
  Cmax, ng/mL	4668 ± 1097	5328 ± 1631	6659 ± 2364
  AUC24h, ng.h/mLAUC 24h is calculated as AUC 12h*2.	78740 ± 19194	91760 ± 34720	113780 ± 52680
  Cmin, ng/mL	1922 ± 825	2661 ± 1269	2851 ± 2216

  Table 14: Pharmacokinetic Results of Total Darunavir After Administration of PREZISTA/ritonavir at 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy and Postpartum

  Pharmacokinetics of total darunavir (mean ± standard deviation)	2ndTrimester of pregnancy (n=17)	3rdTrimester of pregnancy (n=15)	Postpartum (6–12 Weeks) (n=16)
  Cmax, ng/mL	4964 ± 1505	5132 ± 1198	7310 ± 1704
  AUC24h, ng.h/mL	62289 ± 16234	61112 ± 13790	92116 ± 29241
  Cmin, ng/mL	1248 ± 542	1075 ± 594	1473 ± 1141

  Due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum, unbound darunavir exposures were less reduced during pregnancy as compared to postpartum. Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen (see Figure 1).

  Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir After Administration of PREZISTA/ritonavir at 600/100 mg Twice Daily or 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2^ndand 3^rdTrimester of Pregnancy Compared to Postpartum

  Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio. Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

  

  Drug Interactions

  [

  See also

  Contraindications (4)

  ,

  Warnings and Precautions (5.5)and Drug Interactions (7)

  .

  ]

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

  Darunavir and ritonavir are metabolized by CYP3A.

  In vitro

  data indicate that darunavir may be a P-gp substrate. 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 or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.

  Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, C_max, and C_minvalues are summarized in Table 15 (effect of other drugs on darunavir) and Table 16 (effect of darunavir on other drugs). For information regarding clinical recommendations,

  see Drug Interactions (7)

  .

  Several interaction studies have been performed with a dose other than the recommended dose of the co-administered drug or darunavir; however, the results are applicable to the recommended dose of the co-administered drug and/or darunavir.

  Table 15: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-Administered Drugs

  Co-administered drug	Dose/Schedule		N	PK	LS Mean ratio (90% CI) of darunavir Pharmacokinetic parameters with/without co-administered drug no effect =1.00
  	Co-administered Drug	Darunavir/ritonavir			Cmax	AUC	Cmin
  N = number of subjects with data
  Co-administration with other HIV protease inhibitors
  Atazanavir	300 mg q.d.q.d. = once daily	400/100 mg b.i.d.b.i.d. = twice daily	13	↔	1.02 (0.96–1.09)	1.03 (0.94–1.12)	1.01 (0.88–1.16)
  Indinavir	800 mg b.i.d.	400/100 mg b.i.d.	9	↑	1.11 (0.98–1.26)	1.24 (1.09–1.42)	1.44 (1.13–1.82)
  Lopinavir/ritonavir	400/100 mg b.i.d.	1200/100 mg b.i.d.The pharmacokinetic parameters of darunavir in this study were compared with the pharmacokinetic parameters following administration of PREZISTA/ritonavir 600/100 mg twice daily.	14	↓	0.79 (0.67–0.92)	0.62 (0.53–0.73)	0.49 (0.39–0.63)
  	533/133.3 mg b.i.d.	1200 mg b.i.d.	15	↓	0.79 (0.64–0.97)	0.59 (0.50–0.70)	0.45 (0.38–0.52)
  Saquinavir hard gel capsule	1000 mg b.i.d.	400/100 mg b.i.d.	14	↓	0.83 (0.75–0.92)	0.74 (0.63–0.86)	0.58 (0.47–0.72)
  Co-administration with other HIV antiretrovirals
  Didanosine	400 mg q.d.	600/100 mg b.i.d.	17	↔	0.93 (0.86–1.00)	1.01 (0.95–1.07)	1.07 (0.95–1.21)
  Efavirenz	600 mg q.d.	300/100 mg b.i.d.	12	↓	0.85 (0.72–1.00)	0.87 (0.75–1.01)	0.69 (0.54–0.87)
  Etravirine	200 mg b.i.d.	600/100 mg b.i.d.	15	↔	1.11 (1.01–1.22)	1.15 (1.05–1.26)	1.02 (0.90–1.17)
  Nevirapine	200 mg b.i.d.	400/100 mg b.i.d.	8	↑	1.40Ratio based on between-study comparison. (1.14–1.73)	1.24 (0.97–1.57)	1.02 (0.79–1.32)
  Rilpivirine	150 mg q.d.	800/100 mg q.d.	15	↔	0.90 (0.81–1.00)	0.89 (0.81–0.99)	0.89 (0.68–1.16)
  Tenofovir disoproxil fumarate	300 mg q.d.	300/100 mg b.i.d.	12	↑	1.16 (0.94–1.42)	1.21 (0.95–1.54)	1.24 (0.90–1.69)
  Co-administration with other drugs
  Artemether/lumefantrine	80/480 mg (6 doses at 0, 8, 24, 36, 48, and 60 hours)	600/100 mg b.i.d.	14	↔	1.00 (0.93–1.07)	0.96 (0.90–1.03)	0.87 (0.77–0.98)
  Carbamazepine	200 mg b.i.d.	600/100 mg b.i.d.	16	↔	1.04 (0.93–1.16)	0.99 (0.90–1.08)	0.85 (0.73–1.00)
  Clarithromycin	500 mg b.i.d.	400/100 mg b.i.d.	17	↔	0.83 (0.72–0.96)	0.87 (0.75–1.01)	1.01 (0.81–1.26)
  Ketoconazole	200 mg b.i.d.	400/100 mg b.i.d.	14	↑	1.21 (1.04–1.40)	1.42 (1.23–1.65)	1.73 (1.39–2.14)
  Omeprazole	20 mg q.d.	400/100 mg b.i.d.	16	↔	1.02 (0.95–1.09)	1.04 (0.96–1.13)	1.08 (0.93–1.25)
  Paroxetine	20 mg q.d.	400/100 mg b.i.d.	16	↔	0.97 (0.92–1.02)	1.02 (0.95–1.10)	1.07 (0.96–1.19)
  Pitavastatin	4 mg q.d.	800/100 mg q.d.	27	↔	1.06 (1.00–1.12)	1.03 (0.95–1.12)	NA
  Ranitidine	150 mg b.i.d.	400/100 mg b.i.d.	16	↔	0.96 (0.89–1.05)	0.95 (0.90–1.01)	0.94 (0.90–0.99)
  Rifabutin	150 mg q.o.d.q.o.d. = every other day	600/100 mg b.i.d.	11	↑	1.42 (1.21–1.67)	1.57 (1.28–1.93)	1.75 (1.28–2.37)
  Sertraline	50 mg q.d.	400/100 mg b.i.d.	13	↔	1.01 (0.89–1.14)	0.98 (0.84–1.14)	0.94 (0.76–1.16)

  Table 16: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of PREZISTA/ritonavir

  Co-administered drug	Dose/Schedule		N	PK	LS Mean ratio (90% CI) of co-administered drug pharmacokinetic parameters with/without darunavir no effect =1.00
  	Co-administered drug	Darunavir/ritonavir			Cmax	AUC	Cmin
  N = number of subjects with data;- = no information available
  Co-administration with other HIV protease inhibitors
  Atazanavir	300 mg q.d.q.d. = once daily/100 mg ritonavir q.d. when administered alone	400/100 mg b.i.d.b.i.d. = twice daily	13	↔	0.89 (0.78–1.01)	1.08 (0.94–1.24)	1.52 (0.99–2.34)
  	300 mg q.d. when administered with darunavir/ritonavir
  Indinavir	800 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone	400/100 mg b.i.d.	9	↑	1.08 (0.95–1.22)	1.23 (1.06–1.42)	2.25 (1.63–3.10)
  	800 mg b.i.d. when administered with darunavir/ ritonavir
  Lopinavir/ritonavir	400/100 mg b.i.d.The pharmacokinetic parameters of lopinavir in this study were compared with the pharmacokinetic parameters following administration of lopinavir/ritonavir 400/100 mg twice daily.	1200/100 mg b.i.d.	14	↔	0.98 (0.78–1.22)	1.09 (0.86–1.37)	1.23 (0.90–1.69)
  	533/133.3 mg b.i.d..	1200 mg b.i.d.	15	↔	1.11 (0.96–1.30)	1.09 (0.96–1.24)	1.13 (0.90–1.42)
  Saquinavir hard gel capsule	1000 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone	400/100 mg b.i.d.	12	↔	0.94 (0.78–1.13)	0.94 (0.76–1.17)	0.82 (0.52–1.30)
  	1000 mg b.i.d. when administered with darunavir/ritonavir
  Co-administration with other HIV antiretrovirals
  Didanosine	400 mg q.d.	600/100 mg b.i.d.	17	↔	0.84 (0.59–1.20)	0.91 (0.75–1.10)	-
  Dolutegravir	30 mg q.d	600/100 mg b.i.d.	15	↓	0.89 (0.83–0.97)	0.78 (0.72–0.85)	0.62Noted as C τ or C 24 in the dolutegravir U.S. prescribing information (0.56–0.69)
  Dolutegravir	50 mg q.d.	600/100 mg b.i.d. with 200 mg b.i.d. etravirine	9	↓	0.88 (0.78–1.00)	0.75 (0.69–0.81)	0.63 (0.52–0.76)
  Efavirenz	600 mg q.d.	300/100 mg b.i.d.	12	↑	1.15 (0.97–1.35)	1.21 (1.08–1.36)	1.17 (1.01–1.36)
  Etravirine	100 mg b.i.d.	600/100 mg b.i.d.	14	↓	0.68 (0.57–0.82)	0.63 (0.54–0.73)	0.51 (0.44–0.61)
  Nevirapine	200 mg b.i.d.	400/100 mg b.i.d.	8	↑	1.18 (1.02–1.37)	1.27 (1.12–1.44)	1.47 (1.20–1.82)
  Rilpivirine	150 mg q.d.	800/100 mg q.d.	14	↑	1.79 (1.56–2.06)	2.30 (1.98–2.67)	2.78 (2.39–3.24)
  Tenofovir disoproxil fumarate	300 mg q.d.	300/100 mg b.i.d.	12	↑	1.24 (1.08–1.42)	1.22 (1.10–1.35)	1.37 (1.19–1.57)
  Maraviroc	150 mg b.i.d.	600/100 mg b.i.d.	12	↑	2.29 (1.46–3.59)	4.05 (2.94–5.59)	8.00 (6.35–10.1)
  		600/100 mg b.i.d. with 200 mg b.i.d. etravirine	10	↑	1.77 (1.20–2.60)	3.10 (2.57–3.74)	5.27 (4.51–6.15)
  Co-administration with other drugs
  Atorvastatin	40 mg q.d. when administered alone	300/100 mg b.i.d.	15	↑	0.56 (0.48–0.67)	0.85 (0.76–0.97)	1.81 (1.37–2.40)
  	10 mg q.d. when administered with darunavir/ritonavir
  Artemether	80 mg single dose	600/100 mg b.i.d.	15	↓	0.85 (0.68–1.05)	0.91 (0.78–1.06)	-
  Dihydroartemisinin			15	↑	1.06 (0.82–1.39)	1.12 (0.96–1.30)	-
  Artemether	artemether/lumefantrine 80/480 mg (6 doses at 0, 8, 24, 36, 48, and 60 hours)	600/100 mg b.i.d.	15	↓	0.82 (0.61–1.11)	0.84 (0.69–1.02)	0.97 (0.90–1.05)
  Dihydroartemisinin			15	↓	0.82 (0.66–1.01)	0.82 (0.74–0.91)	1.00 (0.82–1.22)
  Lumefantrine			15	↑	1.65 (1.49–1.83)	2.75 (2.46–3.08)	2.26 (1.92–2.67)
  Buprenorphine/Naloxone	8/2 mg to 16/4 mg q.d.	600/100 mg b.i.d.	17	↔	0.92Ratio is for buprenorphine; mean C max and AUC 24 for naloxone were comparable when buprenorphine/naloxone was administered with or without PREZISTA/ritonavir (0.79–1.08)	0.89 (0.78–1.02)	0.98 (0.82–1.16)
  Norbuprenorphine			17	↑	1.36 (1.06–1.74)	1.46 (1.15–1.85)	1.71 (1.29–2.27)
  Carbamazepine	200 mg b.i.d.	600/100 mg b.i.d.	16	↑	1.43 (1.34–1.53)	1.45 (1.35–1.57)	1.54 (1.41–1.68)
  Carbamazepine epoxide			16	↓	0.46 (0.43–0.49)	0.46 (0.44–0.49)	0.48 (0.45–0.51)
  Clarithromycin	500 mg b.i.d.	400/100 mg b.i.d.	17	↑	1.26 (1.03–1.54)	1.57 (1.35–1.84)	2.74 (2.30–3.26)
  Dabigatran etexilate	150 mg	800/100 mg single dose	14	↑	1.64 (1.21–2.23)	1.72 (1.33–2.23)	-
  		800/100 mg q.d.800/100 mg q.d. for 14 days before co-administered with dabigatran etexilate.	13	↑	1.22 (0.89–1.67)	1.18 (0.90–1.53)	-
  Dextromethorphan	30 mg	600/100 mg b.i.d.	12	↑	2.27 (1.59–3.26)	2.70 (1.80–4.05)	-
  Dextrorphan				↓	0.87 (0.77–0.98)	0.96 (0.90–1.03)	-
  Digoxin	0.4 mg	600/100 mg b.i.d.	8	↑	1.15 (0.89–1.48)	1.36 (0.81–2.27)	-
  Ethinyl estradiol (EE)	Ortho-Novum 1/35 (35 µg EE /1 mg NE)	600/100 mg b.i.d.	11	↓	0.68 (0.61–0.74)	0.56 (0.50–0.63)	0.38 (0.27–0.54)
  Norethindrone (NE)			11	↓	0.90 (0.83–0.97)	0.86 (0.75–0.98)	0.70 (0.51–0.97)
  Ketoconazole	200 mg b.i.d.	400/100 mg b.i.d.	15	↑	2.11 (1.81–2.44)	3.12 (2.65–3.68)	9.68 (6.44–14.55)
  R-Methadone	55–150 mg q.d.	600/100 mg b.i.d.	16	↓	0.76 (0.71–0.81)	0.84 (0.78–0.91)	0.85 (0.77–0.94)
  Omeprazole	40 mg single dose	600/100 mg b.i.d.	12	↓	0.66 (0.48–0.90)	0.58 (0.50–0.66)	-
  5-hydroxy omeprazole				↓	0.93 (0.71–1.21)	0.84 (0.77–0.92)	-
  Paroxetine	20 mg q.d.	400/100 mg b.i.d.	16	↓	0.64 (0.59–0.71)	0.61 (0.56–0.66)	0.63 (0.55–0.73)
  Pitavastatin	4 mg q.d.	800/100 mg q.d.	27	↓	0.96 (0.84–1.09)	0.74 (0.69–0.80)	NA
  Pravastatin	40 mg single dose	600/100 mg b.i.d.	14	↑	1.63 (0.95–2.82)	1.81 (1.23–2.66)	-
  Rifabutin	150 mg q.o.d.q.o.d. = every other daywhen administered with PREZISTA/ritonavir	600/100 mg b.i.d.In comparison to rifabutin 300 mg once daily.	11	↑	0.72 (0.55–0.93)	0.93 (0.80–1.09)	1.64 (1.48–1.81)
  25- O -desacetyl-rifabutin	300 mg q.d. when administered alone		11	↑	4.77 (4.04–5.63)	9.81 (8.09–11.9)	27.1 (22.2–33.2)
  Sertraline	50 mg q.d.	400/100 mg b.i.d.	13	↓	0.56 (0.49–0.63)	0.51 (0.46–0.58)	0.51 (0.45–0.57)
  Sildenafil	100 mg (single dose) administered alone	400/100 mg b.i.d.	16	↑	0.62 (0.55–0.70)	0.97 (0.86–1.09)	-
  	25 mg (single dose)when administered with darunavir/ritonavir
  S-warfarin	10 mg single dose	600/100 mg b.i.d.	12	↓	0.92 (0.86–0.97)	0.79 (0.73–0.85)	-
  7-OH-S-warfarin			12	↑	1.42 (1.24–1.63)	1.23 (0.97–1.57)	-
  )
  
• Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (
  
  
  8.2 Lactation

  Risk Summary

  The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

  There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is present in the milk of lactating rats

  [see Data]

  . Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving PREZISTA

  [see Use in Specific Populations (8.4)]

  .

  Data

  Animal Data

  Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir.
  )
  
• Pediatrics: Not recommended for patients less than 3 years of age. (
  
  
  8.4 Pediatric Use

  PREZISTA/ritonavir is not recommended in pediatric patients below 3 years of age because 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 Warnings and Precautions (5.10)

  ,

  Use in Specific Populations (8.1)and Clinical Pharmacology (12.3)]

  .

  The safety, pharmacokinetic profile, and virologic and immunologic responses of PREZISTA/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age)

  [see Adverse Reactions (6.1)

  ,

  Clinical Pharmacology (12.3)and Clinical Studies (14.4)]

  . Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults

  [see Adverse Reactions (6.1)]

  . Refer to

  Dosage and Administration (2.5)

  for twice-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg.

  In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of PREZISTA/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects)

  [see Adverse Reactions (6.1)

  ,

  Clinical Pharmacology (12.3)and Clinical Studies (14.4)]

  . Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults

  [see Adverse Reactions (6.1)]

  . Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although a PREZISTA/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted PREZISTA exposures for the dosing recommendations in this age group

  [see Clinical Pharmacology (12.3)]

  . Please see

  Dosage and Administration (2.5)

  for once-daily dosing recommendations for pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg.

  Juvenile Animal Data

  In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 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) 2 times the human plasma exposure levels.
  )