Emtricitabine

Emtricitabine capsules are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

• Testing: Prior to or when initiating emtricitabine capsules test for hepatitis B virus infection. (
  2.1 Testing Prior to Initiation of Treatment with Emtricitabine Capsules

  Prior to or when initiating emtricitabine capsules, test patients for hepatitis B virus infection

  [see Warnings and Precautions (5.1)].
  )
• Emtricitabine capsules may be taken without regard to food. (
  2.2 Recommended Dosage

  Emtricitabine capsules are taken by mouth once daily and may be taken without regard to food

  [see Clinical Pharmacology (12.3)].
  )
• Adult Patients (18 years of age and older) (
  2.3 Recommended Dosage in Adult Patients (18 years of age and older)

  One 200 mg capsule administered once daily orally.
  ):
  • One 200 mg capsule administered once daily orally.

• Pediatric Patients (3 months through 17 years of age) (
  2.5 Recommended Dosage in Pediatric Patients (3 months through 17 years of age)

  For pediatric patients weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.
  ):
  • For children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.

• Dose interval adjustment in adult patients with renal impairment (
  2.6 Dosage Adjustment in Patients with Renal Impairment

  Table 1 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). The safety and effectiveness of dose adjustment recommendations in patients with moderate to severe renal impairment (creatinine clearance below 50 mL/min) have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients

  [see Warnings and Precautions (5.4), Use in Specific Populations (8.6)].

  Table 1 Dose Interval Adjustment for Adult Patients with Altered Creatinine Clearance

  a. Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.
  Formulation	Creatinine Clearance (mL/min)
  	≥50 mL/min	30 to 49 mL/min	15 to 29 mL/min	<15 mL/min or on hemodialysisa
  Capsule (200 mg)	200 mg every 24 hours	200 mg every 48 hours	200 mg every 72 hours	200 mg every 96 hours

  There are insufficient data available to make dosage recommendations in pediatric patients with renal impairment.
  ):

a. Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.

• Lactation: Breastfeeding is not recommended. (
  8.2 Lactation

  Risk Summary

  
  
  

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

  
  
  

  Based on published data, FTC has been shown to be present in human breast milk. It is not known if FTC affects milk production or has effects on the breastfed child.

  
  
  

  Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking emtricitabine.
  )
• Pediatrics: Dose adjustment based on age and weight. (
  2.5 Recommended Dosage in Pediatric Patients (3 months through 17 years of age)

  For pediatric patients weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.
  ,
  12.3 Pharmacokinetics

  Adults

  The pharmacokinetic properties of FTC were evaluated in healthy subjects and HIV-1-infected subjects. Emtricitabine pharmacokinetics are similar between these populations.

  
  
  

  Figure 1 shows the mean steady-state plasma FTC concentration-time profile in 20 HIV‑1-infected subjects receiving emtricitabine capsules.

  
  
  

  Figure 1  Mean (

  ±

  95% CI) Steady-State Plasma FTC Concentrations in HIV‑1 Infected Adults (N=20)

  
  
  
  
  

  Absorption

  
  
  

  Emtricitabine is rapidly and extensively absorbed following oral administration, with peak plasma concentrations occurring at 1 to 2 hours postdose. Following multiple dose oral administration of emtricitabine capsules to 20 HIV-1 infected subjects, the (mean ± SD) steady-state plasma FTC peak concentration (C_max) was 1.8 ± 0.7 mcg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 mcg·hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 mcg/mL. The mean absolute bioavailability of emtricitabine capsules was 93%, while the mean absolute bioavailability of emtricitabine oral solution was 75%. The relative bioavailability of emtricitabine oral solution was approximately 80% of emtricitabine capsules.

  
  
  

  The multiple dose pharmacokinetics of FTC are dose proportional over a dose range of 25 to 200 mg.

  
  
  

  Distribution

  
  
  

  In vitro

  binding of FTC to human plasma proteins was less than 4% and independent of concentration over the range of 0.02 to 200 mcg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.

  
  
  

  Metabolism

  
  
  

  Following administration of radiolabelled FTC, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of FTC includes oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2’-O-glucuronide (~4% of dose). No other metabolites were identifiable.

  
  
  

  Elimination

  
  
  

  The plasma FTC half-life is approximately 10 hours. The renal clearance of FTC is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

  
  
  

  Effects of Food on Oral Absorption

  
  
  

  Emtricitabine capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while C_maxdecreased by 29% when emtricitabine capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and C_maxwere unaffected when 200 mg emtricitabine oral solution was administered with either a high-fat or low-fat meal.

  Specific Populations

  
  
  

  Geriatric Patients

  
  
  

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

  
  
  

  Pediatric Patients

  
  
  

  The pharmacokinetics of FTC at steady state were determined in 77 HIV-1 infected pediatric subjects, and the pharmacokinetic profile was characterized in four age groups (Table 6). The FTC exposure achieved in pediatric subjects receiving a daily dose of 6 mg/kg up to a maximum of 240 mg oral solution or a 200 mg capsule is similar to exposures achieved in adult subjects receiving a once-daily dose of 200 mg.

  
  
  

  The pharmacokinetics of FTC were studied in 20 neonates born to HIV-1 positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 6 weeks of AZT prophylactically after birth. The neonates were administered two short courses of FTC oral solution (each 3 mg/kg once daily × 4 days) during the first 3 months of life. The AUC observed in neonates who received a daily dose of 3 mg/kg of FTC was similar to the AUC observed in pediatric subjects aged 3 months to 17 years who received a daily dose of FTC as a 6 mg/kg oral solution up to 240 mg or as a 200 mg capsule (Table 6).

  Table 6 Mean ± SD Pharmacokinetic Parameters by Age Groups for Pediatric Subjects and Neonates Receiving Emtricitabine Capsules or Oral Solution

  a. Two pharmacokinetic evaluations were conducted in 20 neonates over the first 3 months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5 to 81) days. b. Mean (range).
  	HIV-1- exposed Neonates	HIV-1 Infected Pediatric Subjects
  Age	0 to 3 mo (N=20) a	3 to 24 mo (N=14)	25 mo to 6 yr (N=19)	7 to 12 yr (N=17)	13 to 17 yr (N=27)
  Formulation	0	0	0	10	26
  Capsule (n)
  Oral Solution (n)	20	14	19	7	1
  Dose (mg/kg)b	3.1 (2.9 to 3.4)	6.1 (5.5 to 6.8)	6.1 (5.6 to 6.7)	5.6 (3.1 to 6.6)	4.4 (1.8 to 7.0)
  Cmax(mcg/mL)	1.6 ± 0.6	1.9 ± 0.6	1.9 ± 0.7	2.7 ± 0.8	2.7 ± 0.9
  AUC (mcg · hr/mL)	11.0 ± 4.2	8.7 ± 3.2	9.0 ± 3.0	12.6 ± 3.5	12.6 ± 5.4
  T1/2(hr)	12.1 ± 3.1	8.9 ± 3.2	11.3 ± 6.4	8.2 ± 3.2	8.9 ± 3.3

  Gender

  
  
  

  FTC pharmacokinetics are similar in adult male and female subjects.

  
  
  

  Race

  
  
  

  No pharmacokinetic differences due to race have been identified.

  
  
  

  Patients with Renal Impairment

  
  
  

  The pharmacokinetics of FTC are altered in subjects with renal impairment

  [see

  Warnings and   Precautions (5.4)]

  . In adult subjects with creatinine clearance below 50 mL/min or with end-stage renal

  disease (ESRD) requiring dialysis, C_maxand AUC of FTC were increased (Table 7). The effects of renal impairment on FTC pharmacokinetics in pediatric patients are not known.

  
  
  

  Table 7 Pharmacokinetic Parameters (Mean ± SD) of FTC in Adult Subjects with Varying Degrees of Renal Function

  Creatinine Clearance (mL/min)	>80 (N=6)	50 to 80 (N=6)	30 to 49 (N=6)	<30 (N=5)	ESRDa <30 (N=5)
  Baseline creatinine clearance (mL/min)	107 ± 21	59.8 ± 6.5	40.9 ± 5.1	22.9 ± 5.3	8.8 ± 1.4
  Cmax(mcg/mL)	2.2 ± 0.6	3.8 ± 0.9	3.2 ± 0.6	2.8 ± 0.7	2.8 ± 0.5
  AUC (mcg.hr/mL)	11.8 ± 2.9	19.9 ± 1.2	25.1 ± 5.7	33.7± 2.1	53.2 ± 9.9
  CL/F (mL/min)	302 ± 94	168 ± 10	138 ± 28	99 ± 6	64 ± 12
  CLr (mL/min)	213 ± 89	121 ± 39	69 ± 32	30 ± 11	NAb

  a. ESRD subjects requiring dialysis

  b. NA = Not Applicable

  
  
  

  Patients with Hepatic Impairment

  
  
  

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

  
  
  

  Assessment of Drug Interactions

  
  
  

  At concentrations up to 14-fold higher than those observed

  in vivo

  , FTC did not inhibit

  in vitro

  drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. FTC did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these

  in vitro

  experiments and the known elimination pathways of FTC, the potential for CYP-mediated interactions involving FTC with other medicinal products is low.

  
  
  

  Emtricitabine has been evaluated in healthy volunteers in combination with TDF, AZT, indinavir, famciclovir, and d4T. Tables 8 and 9 summarize the pharmacokinetic effects of coadministered drug on FTC pharmacokinetics and effects of FTC on the pharmacokinetics of coadministered drug.

  
  
  

  Table 8 Drug Interactions: Change in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drug^a

  a. All interaction trials conducted in healthy volunteers. b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable
  Coadministered Drug	Dose of Coadministered Drug (mg)	FTC Dose (mg)	N	% Change of FTC Pharmacokinetic Parametersb(90% CI)
  				Cmax	AUC	Cmin
  Famciclovir	500 × 1	200 × 1	12	⇔	⇔	NA
  Indinavir	800 × 1	200 × 1	12	⇔	⇔	NA
  Stavudine	40 × 1	200 × 1	6	⇔	⇔	NA
  Tenofovir DF	300 once daily × 7 days	200 once daily × 7 days	17	⇔	⇔	↑ 20 (↑ 12 to ↑ 29)
  Zidovudine	300 twice daily × 7 days	200 once daily × 7 days	27	⇔	⇔	⇔

  Table 9 Drug Interactions: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of FTC^a

  a. All interaction trials conducted in healthy volunteers. b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable
  Coadministered Drug	Dose of Coadministered Drug (mg)	FTC Dose (mg)	N	% Change of Coadministered Drug Pharmacokinetic Parametersb(90% CI)
  				Cmax	AUC	Cmin
  Famciclovir	500 × 1	200 × 1	12	⇔	⇔	NA
  Indinavir	800 × 1	200 × 1	12	⇔	⇔	NA
  Stavudine	40 × 1	200 × 1	6	⇔	⇔	NA
  Tenofovir DF	300 once daily × 7 days	200 once daily × 7 days	17	⇔	⇔	⇔
  Zidovudine	300 twice daily × 7 days	200 once daily × 7 days	27	↑ 17 (↑ 0 to ↑ 38)	↑ 13 (↑ 5 to ↑ 20)	⇔

  
  
  

  

  )