Prezcobix (Darunavir Ethanolate And Cobicistat)

PREZCOBIX 800 mg darunavir/150 mg cobicistat is a pink, oval-shaped, film-coated tablet debossed with “800” on one side and “TG” on the other side.

PREZCOBIX 675 mg darunavir/150 mg cobicistat is a green to dark green, oval-shaped, scored film-coated tablet debossed with “675” on one side and “TG” on the other side.

• Pregnancy: PREZCOBIX is not recommended during pregnancy due to substantially lower exposures of darunavir and cobicistat during pregnancy. (
  
  
  8.1 Pregnancy

  Pregnancy Exposure Registry

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

  Risk Summary

  PREZCOBIX is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters

  [see Dosage and Administration (2.5)]

  . A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period

  (see Data)

  and

  [see Clinical Pharmacology (12.3)].

  Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir and cobicistat 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.

  In animal reproduction studies, no adverse developmental effects were observed when the components of PREZCOBIX were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in PREZCOBIX

  (see Data)

  . No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.2 times the human exposure at the recommended therapeutic dose.

  Clinical Considerations

  Not Recommended During Pregnancy

  PREZCOBIX is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy

  (see Data)

  and

  [see Clinical Pharmacology (12.3)]

  .

  PREZCOBIX should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with PREZCOBIX.

  Data

  Human Data

  PREZCOBIX in combination with a background regimen was evaluated in a clinical trial of 7 pregnant participants taking PREZCOBIX prior to enrollment and who were willing to remain on PREZCOBIX throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant participants completed the trial.

  Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum

  [see Clinical Pharmacology (12.3)]

  .

  One out of 6 pregnant participants who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant participants had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when PREZCOBIX is initiated during pregnancy.

  Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of PREZCOBIX are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

  There were no new clinically relevant safety findings compared with the known safety profile of PREZCOBIX in adults with HIV-1.

  Darunavir

  : 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.

  Cobicistat

  : Based on prospective reports to the APR of over 570 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 480 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% CI: 2.2% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens.

  Animal Data

  Darunavir

  : 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 co-administered with ritonavir.

  Cobicistat

  : Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6–17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.6 times higher than human exposures at the recommended daily dose of cobicistat.

  In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7–20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.8 times higher than human exposures at the recommended daily dose of cobicistat.

  In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose of cobicistat.
  ,
  
  
  12.3 Pharmacokinetics

  The pharmacokinetics of darunavir co-administered with cobicistat (150 mg) have been evaluated in healthy adults and in adults with HIV-1.

  Darunavir is primarily metabolized by CYP3A. Cobicistat inhibits CYP3A, thereby increasing the plasma concentrations of darunavir.

  Under fed (535 total kcal, 171 kcal from fat, 268 kcal from carbohydrates, 96 kcal from protein) and fasted conditions in healthy participants, the 90% confidence intervals when comparing darunavir exposure between PREZCOBIX (800 mg/150 mg) and darunavir 800 mg co-administered with cobicistat 150 mg as single entities were within 80–125%. No clinically significant difference was observed between PREZCOBIX (675 mg/150 mg) and darunavir 675 mg co-administered with cobicistat 150 mg as single entities under fed conditions.

  Darunavir exposure when comparing darunavir co-administered with cobicistat (as single entities) to darunavir co-administered with ritonavir was evaluated in a relative bioavailability trial

  [see cobicistat full prescribing information].

  Table 3 displays the pharmacokinetic estimates of darunavir after oral administration of darunavir 800 mg co-administered with ritonavir 100 mg once daily (based on sparse sampling in 335 participants in Trial TMC114-C211 and 280 participants in Trial TMC114-C229) and darunavir 800 mg co-administered with cobicistat 150 mg once daily administered as single entities (based on sparse sampling in 298 participants in Trial GS-US-216-0130) to HIV-1 participants.

  Table 3: Pharmacokinetic Estimates of Darunavir as Darunavir 800 mg Co-administered with Ritonavir 100 mg Once Daily (Trial TMC114-C211, 48 Week Analysis and Trial TMC114-C229, 48 Week Analysis) and Darunavir 800 mg Co-administered with Cobicistat 150 mg Once Daily (Trial GS-US-216-0130, 24 Week Analysis)

  	Trial TMC114-C211 (treatment-naïve) Darunavir 800 mg co-administered with ritonavir 100 mg once daily	Trial TMC114-C229 (treatment-experienced) Darunavir 800 mg co-administered with ritonavir 100 mg once daily	Trial GS-US-216-0130 (treatment-naïve and experienced) Darunavir 800 mg co-administered with cobicistat 150 mg once daily
  Parameter	N=335	N=280	N=298
  AUC0–24h=area under the concentration-time curve over a 24-hour dosing interval at steady state; C0h=plasma concentration at the end of a 24-hour dosing interval at steady state; N=number of participants; SD=standard deviation
  AUC0–24h(ng∙h/mL)
  Mean ± SD	93026 ± 27050	93334 ± 28626	100152 ± 32042
  Median (Range)	87854 (45000–219240)	87788 (45456–236920)	96900 (34500–224000)
  C0h(ng/mL)
  Mean ± SD	2282 ± 1168	2160 ± 1201	2043 ± 1257
  Median (Range)	2041 (368–7242)	1896 (184–7881)	1875 (70–6890)

  Absorption and Bioavailability

  In healthy participants, under fed conditions, when single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the maximum plasma concentration was achieved within approximately 4 to 4.5 hours for darunavir and approximately 4 to 5 hours for cobicistat.

  Effects of Food on Oral Absorption

  When compared to fasted conditions, administration of PREZCOBIX to healthy adult participants with a high-fat meal (965 total kcal: 129 kcal from protein, 236 kcal from carbohydrates and 600 kcal from fat) resulted in a 70% increase in AUC_(0–inf)and a 127% increase in C_maxfor darunavir. Cobicistat exposures were not affected by food. PREZCOBIX should be taken with food.

  Distribution

  Darunavir

  : Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

  Cobicistat

  : Cobicistat is 97–98% bound to human plasma proteins and the mean blood–to-plasma ratio was approximately 0.5.

  Metabolism

  Darunavir

  :

  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 trial in healthy participants showed that after 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.

  Cobicistat

  : Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

  Elimination

  Darunavir

  : A mass balance trial in healthy participants 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.

  When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of darunavir was approximately 7 hours under fed conditions.

  Cobicistat

  : When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of cobicistat was approximately 4 hours under fed conditions. With single dose administration of¹⁴C-cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

  Specific Populations

  Hepatic Impairment

  Darunavir

  : Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir 600 mg co-administered with ritonavir 100 mg twice daily to participants 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 Use in Specific Populations (8.6)].

  Cobicistat

  : Cobicistat is primarily metabolized by the liver. A trial evaluating the pharmacokinetics of cobicistat was performed in participants with moderate hepatic impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with moderate hepatic impairment (Child-Pugh Class B) and healthy participants. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated

  [see Use in Specific Populations (8.6)].

  Hepatitis B or Hepatitis C Virus Co-Infection

  Darunavir

  : In participants with HIV-1 taking darunavir co-administered with ritonavir, the 48 week analysis of the data from clinical studies in participants with HIV-1 indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

  The effect of hepatitis B and/or C virus infection on the pharmacokinetics of PREZCOBIX have not been evaluated.

  Renal Impairment

  Darunavir

  : Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in participants with HIV-1 with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, n=20). There are no pharmacokinetic data available in participants with HIV-1 with severe renal impairment or end stage renal disease taking darunavir co-adminstered with either ritonavir or cobicistat

  [see Use in Specific Populations (8.7)].

  Cobicistat

  : A trial of the pharmacokinetics of cobicistat was performed in non-HIV participants with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with severe renal impairment and healthy participants

  [see Use in Special Populations (8.7)].

  Gender

  Darunavir

  : In participants with HIV-1 taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed higher mean darunavir exposure in females compared to males. This difference is not clinically relevant.

  Cobicistat

  : No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.

  Race

  Darunavir

  : Population pharmacokinetic analysis of darunavir in participants with HIV-1 taking darunavir co-administered with ritonavir indicated that race had no apparent effect on the exposure to darunavir.

  Cobicistat

  : Population pharmacokinetic analysis of cobicistat in participants with HIV-1 indicated that race had no clinically relevant effect on the exposure of cobicistat.

  Geriatric Patients

  Darunavir

  : In participants with HIV-1 taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed no considerable differences in darunavir pharmacokinetics for ages 18 to 75 years compared to ages greater than or equal to 65 years (n=12)

  [see Use in Specific Populations (8.5)]

  .

  Cobicistat

  : Insufficient data are available to determine whether potential differences exist in the pharmacokinetics of cobicistat in geriatric (65 years of age and older) participants compared to younger participants.

  Pediatrics Weighing at Least 25 kg

  Available pharmacokinetic data for the different components of PREZCOBIX indicate that there were no clinically relevant differences in darunavir exposure between adults and adolescents or children weighing at least 25 kg (see Table 4). Cobicistat exposures were similar between adults and adolescents but higher in children aged 6 to less than 12 years, weighing at least 25 kg. The difference observed in children for cobicistat is not considered clinically relevant.

  Table 4: Pharmacokinetic Estimates Comparison of Darunavir AUC_0–24hand C_0hin Pediatric and Adult Studies

  Parameter	GS-US-216-0128 in Participants Aged ≥ 6 to < 12 Years and Weighing ≥ 25 to < 40 kg DRV 675 mg/COBI 150 mg N=8	GS-US-216-0128 in Participants Aged ≥ 12 to < 18 Years and Weighing ≥ 40 kg DRV 800 mg/COBI 150 mg N=8	TMC114FD2HTX3001 in Adult Participants DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg N=356
  AUC0–24h=area under the concentration-time curve over a 24-hour dosing interval at steady state; C0h=plasma concentration at the end of a 24-hour dosing interval at steady state; COBI=cobicistat; DRV=darunavir; FTC=emtricitabine; N=number of participants; TAF=tenofovir alafenamide
  AUC0–24h(ng ∙ h/mL) Mean ± standard deviation	92,052 ± 17,254	69,474 ± 10,359	87,909 ± 20,232
  C0h(ng/mL)	1,345 ± 569	938 ± 445	1,899 ± 759

  Pregnancy and Postpartum

  The exposure to total and unbound darunavir boosted with cobicistat after intake of PREZCOBIX as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 5and Figure 1).

  Table 5: Pharmacokinetic Results of Total Darunavir after Administration of PREZCOBIX Once Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy, and Postpartum

  Parameter	2ndTrimester of pregnancy N=7	3rdTrimester of pregnancy N=6	Postpartum (6–12 weeks) N=6
  Cmax=maximum plasma concentration at steady state; AUC0–24h=area under the concentration-time curve over a 24-hour dosing interval at steady state; Cmin=minimum plasma concentration at steady state
  Cmax(ng/mL)Mean ± standard deviation	4340 ± 1616	4910 ± 970	7918 ± 2199
  AUC0–24h(ng∙h/mL)	47293 ± 19058	47991 ± 9879	99613 ± 34862
  Cmin(ng/mL)	168 ± 149	184 ± 99	1538 ± 1344

  Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat after Administration of PREZCOBIX at 800/150 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 (i.e. second or third trimester / postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

  

  

  Drug Interactions

  Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-gp, BCRP, MATE1, OATP1B1, and OATP1B3. Based on

  in vitro

  data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on

  in vivo

  data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A

  in vitro

  induction data

  [see Drug Interactions (7)]

  .

  A drug-drug interaction study between darunavir/cobicistat and dabigatran etexilate was conducted in healthy participants. The effects of darunavir on co-administration with dabigatran etexilate are summarized in Table 6.

  Table 6: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of darunavir/cobicistat

  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/ cobicistat			Cmax	AUC	Cmin
  N = number of participants with data q.d. = once daily
  Dabigatran etexilate	150 mg	800/150 mg single dose	14	↑	2.64 (2.29–3.05)	2.64 (2.32–3.00)	-
  		800/150 mg q.d.800/150 mg q.d. for 14 days before co-administered with dabigatran etexilate.	14	↑	1.99 (1.72–2.30)	1.88 (1.65–2.13)	-
  )
  
• Lactation: Breastfeeding is not recommended. (
  
  
  8.2 Lactation

  Risk Summary

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

  (see Data)

  . Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) serious adverse reactions in breastfed infant similar to those seen in adults.

  Data

  Animal Data

  Darunavir

  : Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in 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 of darunavir with ritonavir.

  Cobicistat

  : During the pre/postnatal developmental toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.
  )
  
• Pediatrics: Not recommended for pediatric patients weighing less than 25 kg. (
  
  
  8.4 Pediatric Use

  The safety and effectiveness of PREZCOBIX for the treatment of HIV-1 in pediatric patients weighing at least 25 kg was established through a trial with components of PREZCOBIX. Use of PREZCOBIX in this group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and virologic data from a study of components of PREZCOBIX (Trial GS-US-216-0128) in pediatric participants with HIV-1 aged 6 to less than 18 years

  [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]

  .

  The safety and effectiveness of PREZCOBIX have not been established in pediatric patients weighing less than 25 kg. Darunavir, a component of PREZCOBIX is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

  Juvenile Animal Toxicity Data

  Darunavir:

  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.
  )
  

The following adverse reactions are discussed in other sections of the labeling:

• Hepatotoxicity
  
  
  [see
  
  

  5.1 Hepatotoxicity

  During the darunavir clinical development program (N=3063), where darunavir was co-administered with ritonavir 100 mg once or twice daily, drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) was reported in 0.5% of participants. 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 reactions.

  Post-marketing cases of liver injury, including some fatalities, have also been reported with darunavir co-administered with ritonavir. 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 co-administered with ritonavir has not been established.

  Appropriate laboratory testing should be conducted prior to initiating therapy with PREZCOBIX 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 PREZCOBIX 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 PREZCOBIX should prompt consideration of interruption or discontinuation of treatment.

  ]
  
  
• Severe skin reactions
  
  
  [see
  
  

  5.2 Severe Skin Reactions

  During the darunavir clinical development program (n=3063), where darunavir was co-administered with ritonavir 100 mg once or twice daily, severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, was reported in 0.4% of participants. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue PREZCOBIX 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.

  Mild-to-moderate rash was also reported and often occurred within the first four weeks of treatment and resolved with continued dosing.

  ]
  
  
• Effects on serum creatinine
  
  
  [see
  
  

  5.3 Effects on Serum Creatinine

  Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating PREZCOBIX, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.

  Prior to initiating therapy with PREZCOBIX, assess estimated creatinine clearance

  [see Dosage and Administration (2.2)]

  . Dosage recommendations are not available for drugs that require dosage adjustments in PREZCOBIX-treated patients with renal impairment [see Drug Interactions (7.3)and Clinical Pharmacology (12.2)] . Consider alternative medications that do not require dosage adjustments in patients with renal impairment.

  Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.

  ]
  
  
• New onset or worsening renal impairment when used with tenofovir DF
  
  
  [see
  
  

  5.4 New Onset or Worsening Renal Impairment When Used With Tenofovir Disoproxil Fumarate

  Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat, a component of PREZCOBIX, was used in an antiretroviral regimen that contained tenofovir DF. Co-administration of PREZCOBIX and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min

  [see Dosage and Administration (2.3)]

  .

  • Document urine glucose and urine protein at baseline
    [see Dosage and Administration (2.2)]
    and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when PREZCOBIX is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF.
  • Co-administration of PREZCOBIX and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.

  See cobicistat full prescribing information for additional information regarding cobicistat.

  ]
  
  
• Immune Reconstitution Syndrome
  
  
  [see
  
  

  5.10 Immune Reconstitution Syndrome

  Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZCOBIX. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as

  Mycobacterium avium

  infection, cytomegalovirus,

  Pneumocystis jirovecii

  pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

  Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

  ]
  
  

• Co-administration of PREZCOBIX with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir or cobicistat. Consult the full prescribing information prior to and during treatment for potential drug interactions. (
  
  
  4 CONTRAINDICATIONS

  Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co-administration of PREZCOBIX with CYP3A inducers may lead to lower exposures of darunavir and cobicistat and potential loss of efficacy of darunavir and possible resistance. Examples of drugs that are contraindicated for co-administration with PREZCOBIX

  [see Drug Interactions (7.3)and Clinical Pharmacology (12.3)]

  are listed below.

  • Alpha 1-adrenoreceptor antagonist: alfuzosin
  • Anticonvulsants: carbamazepine, phenobarbital, phenytoin
  • Anti-gout: colchicine, in patients with renal and/or hepatic impairment
  • Antimycobacterial: rifampin
  • Antipsychotics: lurasidone, pimozide
  • Cardiac Disorders: dronedarone, ivabradine, ranolazine
  • Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine
  • Herbal product: St. John's wort (
    Hypericum perforatum
    )
  • Hepatitis C direct acting antiviral: elbasvir/grazoprevir
  • Lipid modifying agents: lomitapide, lovastatin, simvastatin
  • Opioid Antagonist: naloxegol
  • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
  • Sedatives/hypnotics: orally administered midazolam, triazolam

  PREZCOBIX is contraindicated in patients receiving certain co-administered drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect.

  ,
  
  
  5.6 Antiretrovirals Not Recommended

  PREZCOBIX is not recommended in combination with other antiretroviral drugs that require pharmacokinetic boosting (i.e., another protease inhibitor or elvitegravir) because dosing recommendations for such combinations have not been established and co-administration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance.

  PREZCOBIX is not recommended in combination with products containing the individual components of PREZCOBIX (darunavir and cobicistat) or with ritonavir. For additional recommendations on use of PREZCOBIX with other antiretroviral agents,

  [see Drug Interactions (7)]

  .
  ,
  
  
  7 DRUG INTERACTIONS

  • Co-administration of PREZCOBIX with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir or cobicistat. Consult the full prescribing information prior to and during treatment for potential drug interactions.

  7.1 Potential for PREZCOBIX to Affect Other Drugs

  Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of PREZCOBIX with drugs that are primarily metabolized by CYP3A and/or CYP2D6 or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events. Co-administration of PREZCOBIX with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 2).

  7.2 Potential for Other Drugs to Affect PREZCOBIX

  Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Co-administration of PREZCOBIX and drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat which may lead to loss of therapeutic effect and development of resistance. Co-administration of PREZCOBIX and other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 2).

  7.3 Established and Other Potentially Significant Drug Interactions

  Table 2 provides dosing recommendations for expected clinically relevant interactions with PREZCOBIX (this table is not all inclusive). These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect. The table includes examples of potentially significant interactions but is not all inclusive

  ,

  and therefore the label of each drug that is co-administered with PREZCOBIX should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co-administration. For the list of examples of contraindicated drugs,

  [see Contraindications (4)]

  .

  Table 2: Established and Other Potentially Significantthis table is not all inclusiveDrug Interactions: Alterations in Dose or Regimen May Be Recommended

  Concomitant Drug Class: Drug Name Examples	Effect on Concentration of Darunavir, Cobicistat, or Concomitant Drug	Clinical Comment
  HIV-1 antiviral agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
  didanosine	↔ darunavir ↔ cobicistat ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZCOBIX (administered with food).
  HIV-1 antiviral agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
  efavirenz	↓ cobicistat ↓ darunavir	Co-administration with efavirenz is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.
  etravirine	↓ cobicistat darunavir: effect unknown	Co-administration with etravirine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.
  nevirapine	↓ cobicistat darunavir: effect unknown	Co-administration with nevirapine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.
  HIV-1 antiviral agents: CCR5 co-receptor antagonists
  maraviroc	↑ maraviroc	Maraviroc is a substrate of CYP3A. When co-administered with PREZCOBIX, patients should receive maraviroc 150 mg twice daily.
  Other agents
  Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.
  Antibacterials: clarithromycin, erythromycin, telithromycin	↑ darunavir ↑ cobicistat ↑ antibacterial	Consider alternative antibiotics with concomitant use of PREZCOBIX.
  Anticancer agents: dasatinib, nilotinib	↑ anticancer agent	A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with PREZCOBIX. Consult the dasatinib and nilotinib prescribing information for dosing instructions.
  vinblastine, vincristine		For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when PREZCOBIX is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
  Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with PREZCOBIX depend on the apixaban dose. Refer to apixaban dosing instructions for co-administration with P-gp and strong CYP3A inhibitors in apixaban prescribing information.
  rivaroxaban	↑ rivaroxaban	Co-administration of rivaroxaban with PREZCOBIX is not recommended because it may lead to an increased bleeding risk.
  dabigatran etexilate edoxaban	↑ dabigatran ↑ edoxaban	Refer to the dabigatran etexilate or edoxaban prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the co-administered P-gp inhibitors on the concentration of dabigatran or edoxaban. Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with PREZCOBIX.
  Other Anticoagulants:
  warfarin	warfarin: effect unknown	Monitor the international normalized ratio (INR) when co-administering with warfarin.
  Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ darunavir ↓ cobicistat	Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance.
  Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g. eslicarbazepine, oxcarbazepine	↓ cobicistat darunavir: effect unknown	Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response.
  Anticonvulsants that are metabolized by CYP3A: e.g. clonazepam	↑ clonazepam	Clinical monitoring of anticonvulsants is recommended.
  Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g. paroxetine, sertraline	SSRIs: effects unknown	When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.
  Tricyclic Antidepressants (TCAs): e.g. amitriptyline, desipramine, imipramine, nortriptyline	↑ TCAs
  Other antidepressants: trazodone	↑ trazodone
  Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole	↑ darunavir ↑ cobicistat	Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions.
  	↑ itraconazole ↑ ketoconazole ↑ isavuconazole ↔ posaconazole	Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions.
  voriconazole	voriconazole: effects unknown	Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.
  Anti-gout: colchicine	↑ colchicine	Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. For patients without renal or hepatic impairment: Treatment of gout flares – co-administration of colchicine : 0.6 mg (1 tablet) × 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 – co-administration of colchicine : 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 – co-administration of colchicine : Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
  Antimalarial: artemether/lumefantrine	artemether: effect unknown lumefantrine: effect unknown	Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.
  Antimycobacterials:
  rifampin	↓ darunavir ↓ cobicistat	Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.
  rifabutin	↑ rifabutin cobicistat: effects unknown darunavir: effects unknown	When used in combination with PREZCOBIX, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis.
  rifapentine	↓ darunavir	Co-administration with rifapentine is not recommended.
  Antipsychotics: lurasidone	↑ lurasidone	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.
  pimozide	↑ pimozide	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  e.g. perphenazine, risperidone, thioridazine	↑ antipsychotic	A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with PREZCOBIX.
  quetiapine	↑ quetiapine	Initiation of PREZCOBIX in patients taking quetiapine : Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine- associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking PREZCOBIX : Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
  β-Blockers: e.g. carvedilol, metoprolol, timolol	↑ beta-blockers	Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6.
  Calcium channel blockers: e.g. amlodipine, diltiazem, felodipine, nifedipine, verapamil	↑ calcium channel blockers	Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A.
  Cardiac Disorders:
  ranolazine, ivabradine	↑ ranolazine ↑ ivabradine	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.
  dronedarone	↑ dronedarone	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  Other antiarrhythmics
  e.g. amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↑ antiarrhythmics	Clinical monitoring is recommended upon co-administration with antiarrhythmics.
  digoxin	↑ digoxin	When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
  Corticosteroids: dexamethasone (systemic) Corticosteroids primarily metabolized by CYP3A: e.g. betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone	↓ darunavir ↓ cobicistat ↑ corticosteroids	Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to PREZCOBIX. Consider alternative corticosteroids. Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long-term use.
  Endothelin receptor antagonists: bosentan	↓ darunavir ↓ cobicistat ↑ bosentan	Initiation of bosentan in patients taking PREZCOBIX : In patients who have been receiving PREZCOBIX for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of PREZCOBIX in patients on bosentan : Discontinue use of bosentan at least 36 hours prior to initiation of PREZCOBIX. After at least 10 days following the initiation of PREZCOBIX, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from darunavir co-administered with ritonavir to PREZCOBIX in patients on bosentan : Maintain bosentan dose.
  Ergot derivatives: e.g. dihydroergotamine, ergotamine, methylergonovine	↑ ergot derivatives	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
  Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir	↑ elbasvir/grazoprevir	Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations.
  glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Co-administration of PREZCOBIX with glecaprevir/pibrentasvir is not recommended.
  Herbal product: St. John's wort ( Hypericum perforatum )	↓ darunavir ↓ cobicistat	Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance.
  Hormonal contraceptives:		Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen-containing contraceptives are co-administered with PREZCOBIX [see Use in Specific Populations (8.3)] .
  drospirenone/ethinylestradiol	↑ drospirenone ↓ ethinylestradiol	For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.
  Other progestin/estrogen contraceptives	progestin: effects unknown estrogen: effects unknown	No data are available to make recommendations on co-administration with other hormonal contraceptives.
  Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↑ immunosuppressants	These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use
  Immunosuppressant /neoplastic: everolimus	↑ immunosuppressants	Co-administration of everolimus and PREZCOBIX is not recommended.
  irinotecan		Discontinue PREZCOBIX at least 1 week prior to starting irinotecan therapy. Do not administer PREZCOBIX with irinotecan unless there are no therapeutic alternatives.
  Inhaled beta agonist: salmeterol	↑ salmeterol	Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
  Lipid Modifying Agents
  HMG-CoA reductase inhibitors: lovastatin, simvastatin	↑ lovastatin ↑ simvastatin	Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.
  atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin	↑ atorvastatin ↑ fluvastatin ↑ pravastatin ↑ rosuvastatin pitavastatin: effect unknown	For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety (e.g. myopathy). Dosage recommendations with atorvastatin or rosuvastatin are as follows: atorvastatin dosage should not exceed 20 mg/day rosuvastatin dosage should not exceed 20 mg/day
  Other lipid modifying agents: lomitapide	↑ lomitapide	Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide.
  Narcotic analgesics metabolized by CYP3A: e.g. fentanyl, oxycodone	↑ fentanyl ↑ oxycodone	Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration.
  tramadol	↑ tramadol	A dose decrease may be needed for tramadol with concomitant use.
  Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone	buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown	Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking PREZCOBIX : Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of PREZCOBIX in patients taking buprenorphine, buprenorphine/naloxone or methadone : A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.
  Opioid Antagonist
  naloxegol	↑ naloxegol	Co-administration of PREZCOBIX and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms.
  Phosphodiesterase PDE-5 inhibitors: e.g. avanafil, sildenafil, tadalafil, vardenafil	↑ PDE-5 inhibitors	Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established. Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with PREZCOBIX: Initiation of tadalafil in patients taking PREZCOBIX : In patients receiving PREZCOBIX for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Initiation of PREZCOBIX in patients taking tadalafil : Avoid use of tadalafil during the initiation of PREZCOBIX. Stop tadalafil at least 24 hours prior to starting PREZCOBIX. After at least one week following the initiation of PREZCOBIX, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Patients switching from darunavir co-administered with ritonavir to PREZCOBIX : Maintain tadalafil dose. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse reactions.
  Platelet aggregation inhibitor:
  ticagrelor	↑ ticagrelor	Co-administration of PREZCOBIX and ticagrelor is not recommended.
  clopidogrel	↓ clopidogrel active metabolite	Co-administration of PREZCOBIX with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel.
  prasugrel	↔ prasugrel active metabolite	No dose adjustment is needed when prasugrel is co-administered with PREZCOBIX.
  Sedatives/hypnotics: orally administered midazolam, triazolam	↑ midazolam ↑ triazolam	Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZCOBIX may cause large increases in the concentrations of these benzodiazepines.
  metabolized by CYP3A: e.g. buspirone, diazepam, estazolam, zolpidem	↑ sedatives/hypnotics	With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions.
  parenterally administered midazolam		Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered.
  Urinary antispasmodics
  fesoterodine	↑ fesoterodine	When fesoterodine is co-administered with PREZCOBIX, do not exceed a fesoterodine dose of 4 mg once daily.
  solifenacin	↑ solifenacin	When solifenacin is co-administered with PREZCOBIX, do not exceed a solifenacin dose of 5 mg once daily.

  7.4 Drugs without Clinically Significant Interactions with PREZCOBIX

  Clinically relevant drug-drug interactions have not been observed or are not anticipated with concomitant use of darunavir and cobicistat with rilpivirine, dolutegravir, raltegravir, abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, tenofovir DF, lamivudine, stavudine, zidovudine, or acid modifying medications (antacids, H₂-receptor antagonists, proton pump inhibitors).
  ,
  
  
  12.3 Pharmacokinetics

  The pharmacokinetics of darunavir co-administered with cobicistat (150 mg) have been evaluated in healthy adults and in adults with HIV-1.

  Darunavir is primarily metabolized by CYP3A. Cobicistat inhibits CYP3A, thereby increasing the plasma concentrations of darunavir.

  Under fed (535 total kcal, 171 kcal from fat, 268 kcal from carbohydrates, 96 kcal from protein) and fasted conditions in healthy participants, the 90% confidence intervals when comparing darunavir exposure between PREZCOBIX (800 mg/150 mg) and darunavir 800 mg co-administered with cobicistat 150 mg as single entities were within 80–125%. No clinically significant difference was observed between PREZCOBIX (675 mg/150 mg) and darunavir 675 mg co-administered with cobicistat 150 mg as single entities under fed conditions.

  Darunavir exposure when comparing darunavir co-administered with cobicistat (as single entities) to darunavir co-administered with ritonavir was evaluated in a relative bioavailability trial

  [see cobicistat full prescribing information].

  Table 3 displays the pharmacokinetic estimates of darunavir after oral administration of darunavir 800 mg co-administered with ritonavir 100 mg once daily (based on sparse sampling in 335 participants in Trial TMC114-C211 and 280 participants in Trial TMC114-C229) and darunavir 800 mg co-administered with cobicistat 150 mg once daily administered as single entities (based on sparse sampling in 298 participants in Trial GS-US-216-0130) to HIV-1 participants.

  Table 3: Pharmacokinetic Estimates of Darunavir as Darunavir 800 mg Co-administered with Ritonavir 100 mg Once Daily (Trial TMC114-C211, 48 Week Analysis and Trial TMC114-C229, 48 Week Analysis) and Darunavir 800 mg Co-administered with Cobicistat 150 mg Once Daily (Trial GS-US-216-0130, 24 Week Analysis)

  	Trial TMC114-C211 (treatment-naïve) Darunavir 800 mg co-administered with ritonavir 100 mg once daily	Trial TMC114-C229 (treatment-experienced) Darunavir 800 mg co-administered with ritonavir 100 mg once daily	Trial GS-US-216-0130 (treatment-naïve and experienced) Darunavir 800 mg co-administered with cobicistat 150 mg once daily
  Parameter	N=335	N=280	N=298
  AUC0–24h=area under the concentration-time curve over a 24-hour dosing interval at steady state; C0h=plasma concentration at the end of a 24-hour dosing interval at steady state; N=number of participants; SD=standard deviation
  AUC0–24h(ng∙h/mL)
  Mean ± SD	93026 ± 27050	93334 ± 28626	100152 ± 32042
  Median (Range)	87854 (45000–219240)	87788 (45456–236920)	96900 (34500–224000)
  C0h(ng/mL)
  Mean ± SD	2282 ± 1168	2160 ± 1201	2043 ± 1257
  Median (Range)	2041 (368–7242)	1896 (184–7881)	1875 (70–6890)

  Absorption and Bioavailability

  In healthy participants, under fed conditions, when single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the maximum plasma concentration was achieved within approximately 4 to 4.5 hours for darunavir and approximately 4 to 5 hours for cobicistat.

  Effects of Food on Oral Absorption

  When compared to fasted conditions, administration of PREZCOBIX to healthy adult participants with a high-fat meal (965 total kcal: 129 kcal from protein, 236 kcal from carbohydrates and 600 kcal from fat) resulted in a 70% increase in AUC_(0–inf)and a 127% increase in C_maxfor darunavir. Cobicistat exposures were not affected by food. PREZCOBIX should be taken with food.

  Distribution

  Darunavir

  : Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

  Cobicistat

  : Cobicistat is 97–98% bound to human plasma proteins and the mean blood–to-plasma ratio was approximately 0.5.

  Metabolism

  Darunavir

  :

  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 trial in healthy participants showed that after 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.

  Cobicistat

  : Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

  Elimination

  Darunavir

  : A mass balance trial in healthy participants 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.

  When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of darunavir was approximately 7 hours under fed conditions.

  Cobicistat

  : When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of cobicistat was approximately 4 hours under fed conditions. With single dose administration of¹⁴C-cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

  Specific Populations

  Hepatic Impairment

  Darunavir

  : Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir 600 mg co-administered with ritonavir 100 mg twice daily to participants 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 Use in Specific Populations (8.6)].

  Cobicistat

  : Cobicistat is primarily metabolized by the liver. A trial evaluating the pharmacokinetics of cobicistat was performed in participants with moderate hepatic impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with moderate hepatic impairment (Child-Pugh Class B) and healthy participants. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated

  [see Use in Specific Populations (8.6)].

  Hepatitis B or Hepatitis C Virus Co-Infection

  Darunavir

  : In participants with HIV-1 taking darunavir co-administered with ritonavir, the 48 week analysis of the data from clinical studies in participants with HIV-1 indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

  The effect of hepatitis B and/or C virus infection on the pharmacokinetics of PREZCOBIX have not been evaluated.

  Renal Impairment

  Darunavir

  : Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in participants with HIV-1 with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, n=20). There are no pharmacokinetic data available in participants with HIV-1 with severe renal impairment or end stage renal disease taking darunavir co-adminstered with either ritonavir or cobicistat

  [see Use in Specific Populations (8.7)].

  Cobicistat

  : A trial of the pharmacokinetics of cobicistat was performed in non-HIV participants with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with severe renal impairment and healthy participants

  [see Use in Special Populations (8.7)].

  Gender

  Darunavir

  : In participants with HIV-1 taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed higher mean darunavir exposure in females compared to males. This difference is not clinically relevant.

  Cobicistat

  : No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.

  Race

  Darunavir

  : Population pharmacokinetic analysis of darunavir in participants with HIV-1 taking darunavir co-administered with ritonavir indicated that race had no apparent effect on the exposure to darunavir.

  Cobicistat

  : Population pharmacokinetic analysis of cobicistat in participants with HIV-1 indicated that race had no clinically relevant effect on the exposure of cobicistat.

  Geriatric Patients

  Darunavir

  : In participants with HIV-1 taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed no considerable differences in darunavir pharmacokinetics for ages 18 to 75 years compared to ages greater than or equal to 65 years (n=12)

  [see Use in Specific Populations (8.5)]

  .

  Cobicistat

  : Insufficient data are available to determine whether potential differences exist in the pharmacokinetics of cobicistat in geriatric (65 years of age and older) participants compared to younger participants.

  Pediatrics Weighing at Least 25 kg

  Available pharmacokinetic data for the different components of PREZCOBIX indicate that there were no clinically relevant differences in darunavir exposure between adults and adolescents or children weighing at least 25 kg (see Table 4). Cobicistat exposures were similar between adults and adolescents but higher in children aged 6 to less than 12 years, weighing at least 25 kg. The difference observed in children for cobicistat is not considered clinically relevant.

  Table 4: Pharmacokinetic Estimates Comparison of Darunavir AUC_0–24hand C_0hin Pediatric and Adult Studies

  Parameter	GS-US-216-0128 in Participants Aged ≥ 6 to < 12 Years and Weighing ≥ 25 to < 40 kg DRV 675 mg/COBI 150 mg N=8	GS-US-216-0128 in Participants Aged ≥ 12 to < 18 Years and Weighing ≥ 40 kg DRV 800 mg/COBI 150 mg N=8	TMC114FD2HTX3001 in Adult Participants DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg N=356
  AUC0–24h=area under the concentration-time curve over a 24-hour dosing interval at steady state; C0h=plasma concentration at the end of a 24-hour dosing interval at steady state; COBI=cobicistat; DRV=darunavir; FTC=emtricitabine; N=number of participants; TAF=tenofovir alafenamide
  AUC0–24h(ng ∙ h/mL) Mean ± standard deviation	92,052 ± 17,254	69,474 ± 10,359	87,909 ± 20,232
  C0h(ng/mL)	1,345 ± 569	938 ± 445	1,899 ± 759

  Pregnancy and Postpartum

  The exposure to total and unbound darunavir boosted with cobicistat after intake of PREZCOBIX as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 5and Figure 1).

  Table 5: Pharmacokinetic Results of Total Darunavir after Administration of PREZCOBIX Once Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy, and Postpartum

  Parameter	2ndTrimester of pregnancy N=7	3rdTrimester of pregnancy N=6	Postpartum (6–12 weeks) N=6
  Cmax=maximum plasma concentration at steady state; AUC0–24h=area under the concentration-time curve over a 24-hour dosing interval at steady state; Cmin=minimum plasma concentration at steady state
  Cmax(ng/mL)Mean ± standard deviation	4340 ± 1616	4910 ± 970	7918 ± 2199
  AUC0–24h(ng∙h/mL)	47293 ± 19058	47991 ± 9879	99613 ± 34862
  Cmin(ng/mL)	168 ± 149	184 ± 99	1538 ± 1344

  Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat after Administration of PREZCOBIX at 800/150 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 (i.e. second or third trimester / postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

  

  

  Drug Interactions

  Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-gp, BCRP, MATE1, OATP1B1, and OATP1B3. Based on

  in vitro

  data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on

  in vivo

  data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A

  in vitro

  induction data

  [see Drug Interactions (7)]

  .

  A drug-drug interaction study between darunavir/cobicistat and dabigatran etexilate was conducted in healthy participants. The effects of darunavir on co-administration with dabigatran etexilate are summarized in Table 6.

  Table 6: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of darunavir/cobicistat

  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/ cobicistat			Cmax	AUC	Cmin
  N = number of participants with data q.d. = once daily
  Dabigatran etexilate	150 mg	800/150 mg single dose	14	↑	2.64 (2.29–3.05)	2.64 (2.32–3.00)	-
  		800/150 mg q.d.800/150 mg q.d. for 14 days before co-administered with dabigatran etexilate.	14	↑	1.99 (1.72–2.30)	1.88 (1.65–2.13)	-
  )