Drug Description

Darunavir, also known as Prezista, is an inhibitor of the human immunodeficiency virus (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. Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. [1]

References

[1] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

HIV/AIDS-Related Uses

• Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/ritonavir.
• The use of other active agents with PREZISTA/ritonavir is associated with a greater likelihood of treatment response[1]

References

[1] Prezista Prescribing Information, December 2011. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed 12/22/2011.

Dosing Information

Oral. [1]

Dosage Form

Tablets containing darunavir 75, 150, 400, or 600 mg. [2]

Oral Suspension containing darunavir 100 mg/mL. [3]

DOSAGE AND ADMINISTRATION

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

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

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

Treatment-Experienced Adult Patients
• With no darunavir resistance associated substitutions^*: PREZISTA 800 mg (two 400 mg tablets or 8 mL^†) once daily with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL) once daily and with food.

• With at least one darunavir resistance associated substitution*: PREZISTA 600 mg (e.g. one 600 mg tablet or 6 mL) twice daily with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL) twice daily and with food.

^* V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V
^† An 8 mL dose should be taken as two 4 mL administrations with the included oral dosing syringe

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

Pediatric Patients (age 3 to less than 18 years)
Do not use once daily dosing in pediatric patients.

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

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

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

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

Dosing recommendations for pediatric patients weighing at least 10 kg but less than 15 kg
The weight-based dose in pediatric patients weighing less than 15 kg is PREZISTA 20 mg/kg with ritonavir 3 mg/kg which can be dosed using the following information:

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

Body weight (kg): Dose (twice daily with food)

• Greater than or equal to 10 kg to less than 11 kg: PREZISTA 200 mg (2 mL) with ritonavir 32 mg (0.4 mL) taken twice daily with food
• Greater than or equal to 11 kg to less than 12 kg: PREZISTA 220 mg (2.2 mL) with ritonavir 32 mg (0.4 mL) taken twice daily with food
• Greater than or equal to 12 kg to less than 13 kg: PREZISTA 240 mg (2.4 mL) with ritonavir 40 mg (0.5 mL) taken twice daily with food
• Greater than or equal to 13 kg to less than 14 kg: PREZISTA 260 mg (2.6 mL) with ritonavir 40 mg (0.5 mL) taken twice daily with food
• Greater than or equal to 14 kg to less than 15 kg: PREZISTA 280 mg (2.8 mL) with ritonavir 48 mg (0.6 mL) taken twice daily with food

^*with ritonavir oral solution: 80 mg/mL

Dosing recommendations for pediatric patients weighing at least 15 kg
Pediatric patients who weigh at least 15 kg and are able to swallow tablets can be dosed using the following information:

Recommended Dose for Pediatric Patients with PREZISTA Tablets and Ritonavir Oral Solution or Tablets/Capsules for Pediatric Patients Weighing At Least 15 kg

Body weight (kg): Dose (twice daily with food)

• Greater than or equal to 15 kg to less than 30 kg: PREZISTA 375 mg with ritonavir^* 50 mg (0.6 mL) taken twice daily with food
• Greater than or equal to 30 kg to less than 40 kg: PREZISTA 450 mg with ritonavir^* 60 mg (0.75 mL) taken twice daily with food
• Greater than or equal to 40 kg: PREZISTA 600 mg with ritonavir^†100 mg taken twice daily with food

^*with ritonavir oral solution: 80 mg/mL
^†with ritonavir capsules or tablets: 100 mg

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

Recommended Dose for Pediatric Patients with PREZISTA Oral Suspension (100 mg/mL) and Ritonavir Oral Solution^* for Pediatric Patients Weighing At Least 15 kg

Body weight (kg): Dose (twice daily with food)

• Greater than or equal to 15 kg to less than 30 kg: PREZISTA 375 mg^† (3.8 mL) with ritonavir 50 mg (0.6 mL) taken twice daily with food
• Greater than or equal to 30 kg to less than 40 kg: PREZISTA 450 mg^# (4.6 mL) with ritonavir 60 mg (0.75 mL) taken twice daily with food
• Greater than or equal to 40 kg: PREZISTA 600 mg (6 mL) with ritonavir 100 mg (1.25 mL) taken twice daily with food

^*with ritonavir oral solution: 80 mg/mL
^†The 375 mg dose refers to the dose using darunavir tablets for this weight group, which is rounded off to 3.8 mL for suspension dosing.
^#The 450 mg dose refers to the dose using darunavir tablets for this weight group, which is rounded off to 4.6 mL for suspension dosing.

Do not use PREZISTA/ritonavir in pediatric patients below 3 years of age. [4]


Patients with hepatic impairment:

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available regarding the use of darunavir/ritonavir when coadministered to subjects with severe hepatic impairment; therefore, darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment. [5]

Storage

Store darunavir tablets at 25°C (77°F); excursions permitted at 15°C to 30°C (59°F to 86°F). [6]

Store PREZISTA Oral Suspension at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate or freeze. Avoid exposure to excessive heat. Store in the original container. Shake well before each usage. [7]

References

[1] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[2] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[3] Prezista Prescribing Information, December 2011. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed 12/22/2011.

[4] Prezista Prescribing Information, December 2011. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed 12/22/2011.

[5] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[6] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[7] Prezista Prescribing Information, December 2011. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed 12/22/2011.

Pharmacology

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. [1]

The evidence of efficacy of darunavir/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1 infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data is included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects. [2]

Study TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC). HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA ≥ 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA < 100,000 copies/mL or ≥ 100,000 copies/mL) and screening CD4+ cell count (< 200 cells/mm³ or ≥ 200 cells/mm³). Virologic response was defined as a confirmed plasma HIV-1 RNA viral load < 50 copies/mL. Analyses included 689 subjects in Study TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier. Demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the lopinavir/ritonavir arm. [3]

In Study TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm³ in the darunavir/ritonavir 800/100 mg once daily arm and 263 cells/mm³ in the lopinavir/ritonavir 800/200 mg per day arm. Of the darunavir/ritonavir subjects with a confirmed virologic response of < 50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the darunavir/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations. [4]

Study TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs). HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA > 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load < 400 copies/mL. Analyses included 595 subjects in Study TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier. At 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm3 in the darunavir/ritonavir 600/100 mg twice daily arm and 93 cells/mm³ in the lopinavir/ritonavir 400/100 mg twice daily arm. Virologic success and virologic failure (includes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are ≥ 50 copies in the 96 week window and patients who had a change in their OBR that was not permitted by the protocol) were 58% versus 52% and 26% versus 33%, respectively in the darunavir/ritonavir arm versus the lopinavir/ritonavir arm. [5]

Studies TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to darunavir/ritonavir received the recommended dose of 600/100 mg twice daily. 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. The virologic response rate was evaluated in subjects receiving darunavir/ritonavir plus an 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 in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of 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 log10 versus baseline. In the pooled Studies TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA < 400 copies/mL in the arm receiving darunavir/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log10 copies/mL in the arm receiving darunavir/ritonavir 600/100 mg twice daily and –0.37 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving darunavir/ritonavir 600/100 mg twice daily (103 cells/mm³) than in the comparator PI arm (17 cells/mm³). [6]
.
The absolute oral bioavailability of a single 600-mg dose of darunavir alone and after coadministration with ritonavir 100 mg twice daily was 37% and 82%, respectively. Darunavir coadministered with ritonavir 100 mg twice daily was absorbed following oral administration with a time to peak plasma concentration (Tmax) of approximately 2.5 to 4 hours. When administered with food, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of darunavir, coadministered with ritonavir, is approximately 30% greater than in the fasting state. Therefore, darunavir, coadministered with ritonavir, should always be taken with food. Within the range of meals studied, darunavir exposure is similar. [7]

Darunavir binds primarily to plasma alpha 1-acid glycoprotein. Darunavir is approximately 95% bound to plasma proteins. In vitro experiments with human liver microsomes indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by cytochrome P450 (CYP) enzymes, primarily by CYP3A. At least three 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. A mass-balance study in healthy volunteers showed that, after single-dose administration of 14-C-darunavir 400 mg coadministered with ritonavir 100 mg, the majority of the radioactivity in plasma resulted from darunavir. [13] In the same mass-balance study, approximately 79.5% and 13.9% of the administered dose of 14-C darunavir was recovered in the feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when darunavir was taken with ritonavir. After IV administration, the clearance of darunavir, administered alone and coadministered twice daily with ritonavir 100 mg, was 32.8 L/h and 5.9 L/h, respectively. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely they will be significantly removed by hemodialysis or peritoneal dialysis. [8]

Darunavir is in FDA Pregnancy Category C. There are no adequate and well-controlled studies conducted in pregnant women. Reproduction studies conducted with darunavir have shown no embryotoxicity or teratogenicity in mice, rats, or rabbits.  However, due to limited bioavailability and/or dosing limitations, animal exposures (based on AUC) were only 50% (mice and rats) and 5% (rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir. In a 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 because of exposure of the pups to drug substances via mother's milk. Sexual development, fertility, and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir. In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels.  To monitor maternal-fetal outcomes of pregnant women exposed to antiretrovirals such as darunavir, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether darunavir is excreted in human milk; it is excreted in the milk of lactating rats. Because of the potential for HIV transmission and for serious adverse effects from darunavir to the breastfed infant, women should be instructed not to breastfeed while taking darunavir. [9]

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 (PBMCs), and human monocytes/macrophages with median effective concentration (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 groups M and group O primary isolates with EC50 values ranging from less than 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. [10]

HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from people treated with darunavir/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 in protease: S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V. 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 8 protease mutations and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM. [11]

In a pooled analysis of the 600/100 mg darunavir/ritonavir twice daily arms of Studies TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine studies TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M developed most frequently on darunavir/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (< 50 copies/mL). Other substitutions that developed frequently in darunavir/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 > 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 darunavir/ritonavir virologic failure isolates. In Study TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on darunavir/ritonavir. [12]

In the 96-week as-treated analysis of the Phase 3 Study 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 darunavir/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 darunavir/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes > 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 (> 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 (> 10-fold) to lopinavir at baseline. [13]

In the 48-week analysis of the Phase 3 Study 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 darunavir/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving darunavir/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on darunavir/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 darunavir/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 darunavir/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 darunavir/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the darunavir/ritonavir 800/100 mg once daily and darunavir/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. [14]

Clinical studies of darunavir/ritonavir in treatment-naive subjects: In the 192-week as-treated analysis censoring those who discontinued before Week 4 of the Phase 3 Study 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 darunavir/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the darunavir/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 (> 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 (> 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 darunavir/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm. [15]

Cross-resistance among PIs 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 PIs remain susceptible to darunavir. [16]

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 EC50 values < 3 for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In Studies TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change > 3) achieved < 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily (> 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). [17]

In Study TMC114-C214, the 7 darunavir/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. [18]

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. [19]

Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of darunavir/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 studies (Studies 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 Studies TMC125-C206 and TMC125C216 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). 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 darunavir/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load < 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, 2 and ≥ 3 of these substitutions, respectively. [20]

References

[1] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[2] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[3] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[4] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[5] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[6] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[7] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[8] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[9] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[10] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[11] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[12] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[13] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[14] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[15] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[16] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[17] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[18] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[19] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[20] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

Adverse Events/Toxicity

Clinical Trials Experience: Treatment-Naïve Adults
Study TMC114-C211: The majority of the adverse drug reactions (ADRs) reported during treatment with darunavir/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to darunavir/ritonavir 800/100 mg once daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the darunavir/ritonavir arm discontinued treatment due to ADRs. [1]

Clinical Trials Experience: Treatment-Experienced Adults
Study TMC114-C214: The majority of the ADRs reported during treatment with darunavir/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to darunavir/ritonavir 600/100 mg twice daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the darunavir/ritonavir arm discontinued treatment due to ADRs. [2]

The following serious ADRs of at least moderate intensity (≥ Grade 2) occurred in the Phase 2b studies and Phase 3 studies with darunavir/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting. [3]

Clinical Trials Experience: Pediatric Patients
PREZISTA/ritonavir has been studied in combination with other antiretroviral agents in 2 Phase II trials. TMC114-C212, in which 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 20 kg were included and TMC114-C228, in which 21 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 3 to less than 6 years of age and weighing at least 10 kg were included.

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

Study TMC114-C212: ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), excluding laboratory abnormalities reported as ADRs, were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%). Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).

Study TMC114-C228: ADRs to PREZISTA/ritonavir (all grades, greater than or equal to 3%), excluding laboratory abnormalities, were diarrhea (19%), vomiting (14%) and rash (10%). There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study. [4]

Hepatotoxicity: Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with darunavir/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 darunavir/ritonavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/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 darunavir/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 darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment. [5]

Severe skin reactions: During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (<0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis has been reported. Discontinue darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with darunavir/ritonavir. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using darunavir/ritonavir was 0.5%. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir + raltegravir compared to subjects receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash. [6]

Sulfa allergy: Darunavir contains a sulfonamide moiety. Darunavir should be used with caution in patients with a known sulfonamide allergy. In clinical studies with darunavir/ritonavir, the incidence and severity of rash was similar in subjects with or without a history of sulfonamide allergy. [7]

Diabetes mellitus / hyperglycemia: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established. [8]

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. [9]

Immune reconstitution syndrome: During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium complex infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, or tuberculosis. Symptoms of immune reconstitution syndrome necessitate further evaluation and treatment. [10]

Hemophilia: There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established. [11]

Pediatric Patients: Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age. [12]

The following events have been identified during postmarketing use of darunavir: redistribution of body fat, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and darunavir/ritonavir), and toxic epidermal necrolysis. [13]

References

[1] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[2] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[3] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[4] Prezista Prescribing Information, December 2011. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed 12/22/2011.

[5] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[6] FDA Prezista Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021976s018lbl.pdf. Accessed 11/02/2011.

[7] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[8] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[9] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[10] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[11] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[12] Prezista Prescribing Information, December 2011. Available at: http://www.prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed 12/22/2011.

[13] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

Drug and Food Interactions

Darunavir must be coadministered with ritonavir and food to achieve the desired antiviral effect. Failure to administer darunavir with ritonavir and food may result in a loss of efficacy of darunavir. [1]

Coadministration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). [2]

Drugs that are contraindicated with darunavir/ritonavir:

• Alfuzosin: Potential for serious and/or life-threatening reactions such as hypotension.
• Ergot Derivatives (Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine): Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
• Cisapride: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Pimozide: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Midazolam (orally administered), Triazolam: Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with darunavir/ritonavir may cause large increases in the concentrations of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
• St. John’s Wort (Hypericum perforatum): Patients taking darunavir/ritonavir should not use products containing St. John’s wort because coadministration may result in reduced plasma concentrations of darunavir. This may result in loss of therapeutic effect and development of resistance.
• HMG CoA Reductase Inhibitors (Lovastatin, Simvastatin): Potential for serious reactions such as myopathy including rhabdomyolysis. For dosing recommendation regarding atorvastatin and pravastatin, see Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.
• Rifampin: Rifampin is a potent inducer of CYP450 metabolism. Darunavir/ritonavir should not be used in combination with rifampin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to darunavir.
• Sildenafil (for treatment of pulmonary arterial hypertension): A safe and effective dose for the treatment of pulmonary arterial hypertension has not been established with darunavir/ritonavir. There is an increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). [3] [4]

Darunavir coadministered with ritonavir is an inhibitor of CYP3A and CYP2D6. Coadministration of darunaivr and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events. [5]

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. Coadministration 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. [6]

Established and other potentially significant drug interactions (alterations in dose or regimen may be recommended based on drug interaction studies or predicted interaction):

Didanosine: Didanosine should be administered one hour before or two hours after darunavir/ritonavir (which are administered with food).

Indinavir (the reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily): The appropriate dose of indinavir in combination with darunavir has not been established.

Lopinavir/ritonavir: Appropriate doses of the combination have not been established. Hence, it is not recommended to coadminister lopinavir/ritonavir and darunavir, with or without ritonavir.

Saquinavir: Appropriate doses of the combination have not been established. Hence, it is not recommended to coadminister saquinavir and darunavir, with or without ritonavir.

Maraviroc: Maraviroc concentrations are increased when coadministered with darunavir/ritonavir. When used in combination with darunavir/ritonavir, the dose of maraviroc should be 150 mg twice daily.

Antiarrhythmics (bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone): Concentrations of these drugs may be increased when coadministered with darunavir/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with darunavir/ritonavir.

Antiarrhythmic (digoxin): The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.

Warfarin: Warfarin concentrations are decreased when coadministered with darunavir/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with darunavir/ritonavir.

Carbamazepine: The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating coadministration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.

Anticonvulsant (phenobarbital, phenytoin): Coadministration of darunavir/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when coadministering with darunavir/ritonavir.

Antidepressant (trazodone, desipramine): Concomitant use of trazodone or desipramine and darunavir/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with darunavir/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.

Clarithromycin: No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: for subjects with CLcr of 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%; For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.

Antifungals (ketoconazole, itraconazole, voriconazole): Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When coadministration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.

Colchicine: Treatment of gout-flares – coadministration of colchicine in patients on darunavir/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on darunavir/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine in patients on darunavir/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with darunavir/ritonavir.

Rifabutin (the reference regimen for rifabutin was 300 mg once daily): Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.

Beta-Blockers (metoprolol, timolol): Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when coadministered with darunavir/ritonavir.

Midazolam (parenterally administered): Concomitant use of parenteral midazolam with darunavir/ritonavir may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with darunavir/ritonavir is contraindicated.

Calcium channel blockers (felodipine, nifedipine, nicardipine): Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when darunavir/ritonavir are coadministered. Caution is warranted and clinical monitoring of patients is recommended.

Dexamethasone: Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to darunavir.

Fluticasone (inhaled/nasal): Concomitant use of inhaled fluticasone and darunavir/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use.

Bosentan: Coadministration of bosentan in patients on darunavir/ritonavir: In patients who have been receiving darunavir/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of darunavir/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of darunavir/ritonavir. After at least 10 days following the initiation of darunavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

HMG-CoA reductase inhibitors (pravastatin, atorvastatin, rosuvastatin): Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.

Immunosuppressants (cyclosporine, tacrolimus, sirolimus): Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when coadministered with darunavir/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when coadministered with darunavir/ritonavir.

Salmeterol: Concurrent administration of salmeterol and darunavir/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Narcotic analgesic/treatment of opioid dependence (methadone, buprenorphine, buprenorphine/naloxone): No adjustment of methadone dosage is required when initiating co-administration of darunavir/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of darunavir/ritonavir. Clinical monitoring is recommended if darunavir/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.

Neuroleptics (risperidone, thioridazine): A dose decrease may be needed for these drugs when coadministered with darunavir/ritonavir.

Oral contraceptives/estrogen (ethinyl estradiol, norethindrone): Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.

PDE-5 inhibitors (sildenafil, vardenafil, tadalafil): Coadministration with darunavir/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):

• Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH).
• The following dose adjustments are recommended for use of tadalafil with darunavir/ritonavir: Coadministration of tadalafil in patients on darunavir/ritonavir: In patients receiving darunavir/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of darunavir/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of darunavir/ritonavir. Stop tadalafil at least 24 hours prior to starting darunavir/ritonavir. After at least one week following the initiation of darunavir/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

References

[1] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[2] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[3] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[4] FDA Prezista Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021976s022lbl.pdf. Accessed 03/04/2012.

[5] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[6] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[7] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[8] FDA Prezista Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021976s022lbl.pdf. Accessed 03/04/2012.

Contraindications

• Alfuzosin: Potential for serious and/or life-threatening reactions such as hypotension.
• Ergot Derivatives (Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine): Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
• Cisapride: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Pimozide: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Midazolam (orally administered), Triazolam: Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with darunavir/ritonavir may cause large increases in the concentrations of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
• St. John’s Wort (Hypericum perforatum): Patients taking darunavir/ritonavir should not use products containing St. John’s wort because coadministration may result in reduced plasma concentrations of darunavir. This may result in loss of therapeutic effect and development of resistance.
• HMG CoA Reductase Inhibitors (Lovastatin, Simvastatin): Potential for serious reactions such as myopathy including rhabdomyolysis. For dosing recommendation regarding atorvastatin and pravastatin, see Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.
• Rifampin: Rifampin is a potent inducer of CYP450 metabolism. Darunavir/ritonavir should not be used in combination with rifampin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to darunavir.
• Sildenafil (for treatment of pulmonary arterial hypertension): A safe and effective dose for the treatment of pulmonary arterial hypertension has not been established with darunavir/ritonavir. There is an increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). [1] [2]
   

References

[1] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[2] FDA Prezista Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021976s022lbl.pdf. Accessed 03/04/2012.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Darunavir.

Chemistry

CAS Name

(3R,3aS,6aR)-Hexahydrofuro(2,3-b)furan-3-yl N-((1S,2R)-1-benzyl-2-hydroxy-3- (N1-isobutylsulfanilamido)propyl)carbamate [1]

CAS Number

206361-99-1 [2]

Molecular Formula

C27-H37-N3-O7-S

Elemental Composition

C59.2%,H6.8%,N7.7%,O20.5%,S5.8%

Molecular Weight

593.73

Physical Description

Darunavir ethanolate: White to off-white powder. [3]

Solubility

Approximately 0.15 mg/mL in water at 20° C. [4]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 08/30/07.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 08/30/07.

[3] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

[4] FDA Prezista Prescribing Information, December 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s017lbl.pdf. Accessed 07/31/2011.

Further Reading

Prezista Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Busse KH, Penzak SR. Darunavir: a second-generation protease inhibitor. Am J Health Syst Pharm. 2007 Aug 1;64(15):1593-602.
Madruga JV, Berger D, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, Norris D, Lefebvre E, de Bethune MP, Tomaka F, De Pauw M, Vangeneugden T, Spinosa-Guzman S; TITAN study group. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007 Jul 7;370(9581):49-58.
Molina JM, Hill A. Darunavir (TMC114): a new HIV-1 protease inhibitor. Expert Opin Pharmacother. 2007 Aug;8(12):1951-64.
Rachlis A, Clotet B, Baxter J, Murphy R, Lefebvre E. Safety, Tolerability, and Efficacy of Darunavir (TMC114) with Low-Dose Ritonavir in Treatment-Experienced, Hepatitis B or C Co-infected Patients in POWER 1 and 3. HIV Clin Trials. 2007 Jul-Aug;8(4):213-20.
Rittweger M, Arasteh K. Clinical pharmacokinetics of darunavir. Clin Pharmacokinet. 2007;46(9):739-56.

Manufacturer Information

Darunavir

Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA 19067
Phone: 877-732-2488

Prezista

Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA 19067
Phone: 877-732-2488