Symtuza

SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg:

• who have no prior antiretroviral treatment history or
• who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (

Each SYMTUZA tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, film-coated tablet is debossed with "8121" on one side and "JG" on the other side.

• Pregnancy
  : SYMTUZA is not recommended during pregnancy due to substantially lower exposures of darunavir and cobicistat during pregnancy. (
  
  
  2.5 Not Recommended During Pregnancy

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

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

  .

  SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA.
  ,
  
  
  8.1 Pregnancy

  Pregnancy Exposure Registry

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

  Risk Summary

  SYMTUZA 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, cobicistat, emtricitabine, or tenofovir alafenamide (TAF) 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 SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively), at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA

  (see Data)

  . No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose.

  Clinical Considerations

  Not Recommended During Pregnancy

  SYMTUZA 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)]

  .

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

  Data

  Human Data

  Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals 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 individuals 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 individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy.

  Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of SYMTUZA 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.

  Darunavir

  : Based on prospective reports to the APR of over 960 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 640 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% CI: 2.4% to 5.5%) with first trimester exposure to darunavir containing-regimens and 2.5% (95% CI: 1.1% to 4.9%) with second/third trimester exposure to darunavir-containing regimens.

  Cobicistat

  : Based on prospective reports to the APR of over 560 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 470 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.1% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens.

  Emtricitabine

  : Based on prospective reports to the APR of over 5400 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 3900 exposed in the first trimester and over 1500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) with first trimester exposure to emtricitabine-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) with the second/third trimester exposure to emtricitabine-containing regimens.

  Tenofovir alafenamide (TAF)

  : Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) with first and second/third trimester exposure, respectively, to TAF-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 (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in SYMTUZA.

  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 1.7 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA.

  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 4.1 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA.

  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 1.1 times the human exposures at the recommended daily dose of cobicistat in SYMTUZA.

  Emtricitabine

  : Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA.

  In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (

  in utero

  ) through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA.

  Tenofovir Alafenamide (TAF)

  : TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in SYMTUZA.

  Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF.
  ,
  
  
  12.3 Pharmacokinetics

  Absorption, Distribution, Metabolism, and Excretion

  The bioavailability of the components of SYMTUZA was not affected when administered orally as a split tablet compared to administration as a tablet swallowed whole.

  Pharmacokinetic (PK) properties and PK parameters of the components of SYMTUZA are provided in Table 5 and Table 6, respectively.

  Table 5: Pharmacokinetic Properties of the Components of SYMTUZA

  	Darunavir	Cobicistat	Emtricitabine	TAF
  PBMCs = peripheral blood mononuclear cells; CES-1 = carboxylesterase-1
  Absorption
  Tmax(h)	3.0	3.0	1.5	0.5
  Effect of high-fat mealApproximately 928 kcal; 504 kcal from fat (56 g), 260 kcal from carbohydrates, and 164 kcal from protein.(compared to fasting)
  AUClastLS mean ratio, 90% CI	1.52 (1.32–1.76)	1.41 (1.02–1.96)	1.00 (0.96–1.04)	1.12 (1.01–1.23)
  CmaxLS mean ratio, 90% CI	1.82 (1.55–2.14)	1.30 (0.94–1.80)	0.79 (0.71–0.89)	0.55 (0.42–0.71)
  Distribution
  % bound to human plasma proteins	95Primarily alpha-1-acid glycoprotein	97–98	<4	~80
  Source of protein binding data	In vitro	In vitro	In vitro	Ex vivo
  Blood-to-plasma ratio	0.64	0.5	0.6	1.0
  Metabolism
  Metabolism	CYP3A	CYP3A (major) CYP2D6 (minor)	Not significantly metabolized	Cathepsin AIn vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon co-administration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.(PBMCs) CES1 (hepatocytes) CYP3A (minimal)
  Elimination
  t1/2(h)	9.4	3.2	7.5	0.5Note that the pharmacologically active metabolite tenofovir diphosphate has a half-life of 150–180 hours within PBMCs. Tenofovir in plasma has a median elimination half-life of approximately 44 hours.
  Major route of elimination	Metabolism	Metabolism	Glomerular filtration and active tubular secretion	Metabolism (>80% of oral dose)
  % of dose excreted in fecesDosing in mass balance studies: darunavir (single dose administration of [ 14C] darunavir co-administered with multiple dose ritonavir 100 mg); cobicistat (single dose administration of [ 14C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [ 14C] TAF).	79.5Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively.	86.2	13.7	31.7
  % of dose excreted in urine	13.9	8.2	70	<1

  Table 6: Steady State Pharmacokinetic Parameters of Darunavir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of SYMTUZA with Food in HIV-Infected Adults

  Parameter Mean (SD)	Darunavir		CobicistatFrom Phase 2 PK substudy (N=21)	Emtricitabine	TAF	Tenofovir
  Cmax, ng/mL	8826 (33.3)		1129 (35.3)	2056 (25.3)	163 (51.9)	18.8 (37.6)
  AUC24h, ng.h/mL	87909 (20232)From population PK analysis in SYMTUZA Phase 3 study TMC114FD2HTX3001 in ARV naïve subjects (N=355)	85972 (22413)From population PK analysis in SYMTUZA Phase 3 study TMC114IFD3013 in ARV experienced subjects (N=750)	8745 (43.9)	11918.0 (35.9)	132 (41)	339 (37.1)
  C0h, ng/mL	1899 (759)	1813 (859)	31 (135)	93.1 (58.3)	NA	11.7 (39.3)

  Specific Populations

  Geriatric Patients

  Darunavir

  : Pharmacokinetic analysis in HIV-infected subjects taking darunavir co-administered with cobicistat, emtricitabine, and tenofovir alafenamide showed no considerable differences in darunavir pharmacokinetics for ages below or equal to 65 years compared to ages greater than 65 years (N=25).

  Cobicistat and Emtricitabine

  : The pharmacokinetics of cobicistat and emtricitabine have not been fully evaluated in the elderly (65 years of age and older).

  Tenofovir alafenamide

  Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of TAF combined with emtricitabine, elvitegravir, and cobicistat showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.

  Pediatric Patients Weighing at Least 40 kg

  Available pharmacokinetic data for the different components of SYMTUZA indicate that there were no clinically relevant differences in exposure between adults and pediatric subjects weighing at least 40 kg.

  Darunavir and cobicistat

  : In pediatric subjects aged 12 to less than 18 years, weighing at least 40 kg who received darunavir 800 mg co-administered with cobicistat 150 mg (N=7), geometric mean darunavir C_maxvalues were similar between adults and pediatric subjects. Geometric mean darunavir AUC_24hand C_24hvalues were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in pediatric subjects relative to adults, respectively. These differences were not considered clinically significant. Geometric mean cobicistat AUC_24h, C_max, and C_24hvalues were comparable in pediatric subjects and adults (Table 7).

  Table 7: Multiple-Dose PK Parameters of Darunavir and Cobicistat Following Administration of Darunavir with Cobicistat in HIV 1 Infected Adults and Pediatric Subjects Weighing at least 40 kgFrom intensive PK analysis of trial GS-US-216-0128, where HIV-infected subjects were administered darunavir 800 mg and cobicistat 150 mg once daily with 2 NRTIs

  Parameter Geometric mean (CV%)	Darunavir	Cobicistat
  CV = Coefficient of Variation; mcg = microgram
  Pediatric Subjects	N=7	N=7
  AUC24h(mcg.hr/mL)	77.22 (29.5)	8.33 (34.9)
  Cmax(mcg/mL)	7.32 (21.7)	1.10 (20.0)
  C24h(mcg/mL)	0.68 (91.6)	0.02 (123.9)N=5; Data from two subjects who had undetectable cobicistat C 24h concentrations were excluded from summary statistics
  AdultsFrom intensive PK analysis of trial GS-US-299-0102 where HIV-infected subjects were administered SYMTUZA once daily	N=21	N=21
  AUC24h(mcg.hr/mL)	90.56 (45.3)	7.69 (43.9)
  Cmax(mcg/mL)	8.34 (33.3)	1.04 (35.3)
  C24h(mcg/mL)	1.00 (108.0)	0.02 (135.1)N=18

  Emtricitabine and tenofovir alafenamide

  : In 24 pediatric subjects aged 12 to less than 18 years, who received emtricitabine + TAF with elvitegravir + cobicistat, geometric mean emtricitabine C_max, and C_24hvalues were comparable to adults, with geometric mean ratios of 1.10 (90% CI: 0.98, 1.23) and 1.07 (90% CI: 0.88, 1.29), respectively (Table 8). Geometric mean emtricitabine AUC_24hwas 21% higher, with a geometric mean ratio of 1.21 (90% CI: 1.09, 1.34) in pediatric subjects relative to adults. Geometric mean tenofovir alafenamide C_maxand AUC_lastvalues were 29% and 23% lower in pediatric subjects versus adults with geometric mean ratios of 0.71 (90% CI: 0.50, 1.00) and 0.77 (90% CI: 0.59, 1.02), respectively (Table 8). The observed differences were not considered clinically significant.

  Table 8: Multiple-Dose PK Parameters of Emtricitabine and Tenofovir Alafenamide Following Oral Administration with Food in HIV 1 Infected Adults and Pediatric Subjects

  Parameter Geometric mean (CV%)	Emtricitabine	Tenofovir alafenamide
  CV = Coefficient of Variation; mcg = microgram; NA = not applicable
  Pediatric SubjectsFrom intensive PK analysis in trial GS-US-292-0106 in treatment-naïve pediatric subjects with HIV-1 infection	N=24	N=24
  AUC24h(mcg.hr/mL)AUC last for tenofovir alafenamide	14.0 (23.9)	0.16 (55.8)
  Cmax(mcg/mL)	2.2 (22.5)	0.14 (64.4)
  C24h(mcg/mL)	0.10 (38.9)N=23	NA
  AdultsFrom intensive PK analysis in trial GS-US-292-0102 in HIV-infected adults treated with emtricitabine+tenofovir alafenamide and elvitegravir+cobicistat	N=19	N=19
  AUC24h(mcg.hr/mL)	11.6 (16.6)	0.21 (47.3)
  Cmax(mcg/mL)	2.0 (20.2)	0.19 (64.6)
  C24h(mcg/mL)	0.09 (46.7)	NA

  Gender and Race

  There were no clinically relevant differences in the pharmacokinetics of darunavir, cobicistat, emtricitabine, or tenofovir alafenamide based on gender or race.

  Patients with Renal Impairment

  Darunavir

  : The pharmacokinetics of darunavir were not altered in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, estimated by Cockcroft-Gault method, N=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end-stage renal disease taking darunavir co-administered with cobicistat

  [see Use in Specific Populations (8.6)]

  .

  Cobicistat

  : There were no clinically relevant differences in cobicistat pharmacokinetics observed between subjects with severe renal impairment (creatinine clearance below 30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects

  [see Use in Specific Populations (8.6)]

  .

  Emtricitabine

  : Mean systemic emtricitabine exposure was higher in patients with severe renal impairment (creatinine clearance less than 30 mL/min, estimated by Cockcroft-Gault method) than in subjects with normal renal function

  [see Use in Specific Populations (8.6)]

  .

  Tenofovir alafenamide

  : In studies of TAF, no clinically relevant differences in the pharmacokinetics of TAF or its metabolite tenofovir were observed between subjects with severe renal impairment (creatinine clearance of 15–30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects

  [see Use in Specific Populations (8.6)]

  .

  Patients with Hepatic Impairment

  Darunavir

  : There were no clinically relevant differences in the pharmacokinetics of darunavir (600 mg with ritonavir 100 mg twice daily) in subjects with mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8), compared to subjects with normal hepatic function (n=16). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated

  [see Use in Specific Populations (8.7)]

  .

  Cobicistat

  : There were no clinically relevant differences in the cobicistat pharmacokinetics between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated

  [see Use in Specific Populations (8.7)]

  .

  Emtricitabine

  : The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited

  [see Use in Specific Populations (8.7)]

  .

  Tenofovir Alafenamide

  : Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild, moderate (Child-Pugh Class A and B), or severe hepatic impairment (Child-Pugh Class C);

  [see Use in Specific Populations (8.7)]

  .

  Patients with Hepatitis B and/or Hepatitis C Virus Coinfection

  Darunavir

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

  Cobicistat

  : There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

  Emtricitabine and tenofovir alafenamide

  : The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

  Pregnancy and Postpartum

  The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat 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 9and Figure 1).

  Table 9: Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy, and Postpartum

  Pharmacokinetics of total darunavir (mean ± SD)	2ndTrimester of pregnancy N=7	3rdTrimester of pregnancy N=6	Postpartum (6–12 weeks) N=6
  Cmax, ng/mL	4340 ± 1616	4910 ± 970	7918 ± 2199
  AUC24h, 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 Darunavir/Cobicistat 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.

  Figure 1

  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.

  Emtricitabine is not an inhibitor of human CYP450 enzymes.

  In vitro

  and clinical drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A. It is not an inhibitor or inducer of CYP3A

  in vivo

  .

  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 10.

  Table 10: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of darunavir/cobicistat

  	Dose/Schedule				LS Mean ratio (90% CI) of co-administered drug pharmacokinetic parameters with/without darunavir no effect =1.00
  Co-administered drug	Co-administered drug	Darunavir/ cobicistat	N	PK	Cmax	AUC	Cmin
  N = number of subjects 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

  The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

  Based on published data, emtricitabine has been shown to be present in human breast milk. There are no data on the presence of darunavir, cobicistat, or TAF 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. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF

  (see Data)

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

  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 post-natal 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 66% 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.

  Tenofovir Alafenamide

  : Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.
  )
  
• Pediatrics
  : Not recommended for pediatric patients weighing less than 40 kg (
  
  
  8.4 Pediatric Use

  The safety and effectiveness of SYMTUZA for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg was established through studies with components of SYMTUZA. Use of SYMTUZA in this group is supported by evidence from adequate and well-controlled studies of SYMTUZA in adults with additional pharmacokinetic, safety, and virologic data from studies of components of SYMTUZA (Trials GS-US-216-0128 and GS-US-292-0106) in pediatric subjects with HIV-1 infection aged 12 to less than 18 years

  [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)]

  .

  The safety and effectiveness of SYMTUZA have not been established in pediatric patients weighing less than 40 kg.

  Darunavir, a component of SYMTUZA 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.
  )