Intelence (Page 5 of 9)

10 OVERDOSAGE

There is no specific antidote for overdose with INTELENCE. Human experience of overdose with INTELENCE is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with INTELENCE consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

11 DESCRIPTION

INTELENCE (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).

The chemical name for etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. Its molecular formula is C20 H15 BrN6 O and its molecular weight is 435.28. Etravirine has the following structural formula:

Chemical Structure

Etravirine is a white to slightly yellowish-brown powder. Etravirine is practically insoluble in water over a wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran).

INTELENCE 25 mg tablets are available as white to off-white, oval scored tablets for oral administration. Each 25 mg tablet contains 25 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

INTELENCE 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

INTELENCE 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and silicified microcrystalline cellulose.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Etravirine is an antiretroviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 41 healthy subjects, INTELENCE 200 mg twice daily or 400 mg once daily did not affect the QT/QTc interval.

12.3 Pharmacokinetics

The pharmacokinetic properties of INTELENCE were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects (Table 5) than in healthy subjects.

Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg Twice Daily in HIV-1-Infected Adult Subjects (Integrated Data from Phase 3 Trials at Week 48)*
Parameter EtravirineN=575
*
All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg twice daily as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 5 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE with darunavir/ritonavir.
AUC12h (ng∙h/mL)
Geometric mean ± standard deviation 4522 ± 4710
Median (range) 4380 (458–59084)
C0h (ng/mL)
Geometric mean ± standard deviation 297 ± 391
Median (range) 298 (2–4852)

Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals 4 ng/mL.

Absorption and Bioavailability

Following oral administration, etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of INTELENCE is unknown.

In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.

Effects of Food on Oral Absorption

The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to when INTELENCE was administered following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat).

Distribution

Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism

In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.

Elimination

After single dose oral administration of 800 mg 14 C-etravirine, 93.7% and 1.2% of the administered dose of 14 C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.

Specific Populations

Geriatric Patients

Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [see Use in Specific Populations (8.5)].

Pediatric Patients

The pharmacokinetics of etravirine in 115 treatment-experienced HIV-1-infected pediatric subjects, 2 years to less than 18 years of age showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving INTELENCE 200 mg twice daily [see Dosage and Administration (2.3)]. The pharmacokinetic parameters for etravirine (AUC12h and C0h ) are summarized in Table 6.

Table 6: Pharmacokinetic Parameters for Etravirine in Treatment-Experienced HIV-1-Infected Pediatric Subjects 2 Years to Less Than 18 Years of Age (TMC125-C213 [Population PK] and TMC125-C234/P1090)
Study TMC125-C213 TMC125-C234/IMPAACT P1090
Age Range (years) (6 years to less than 18 years) (2 years to less than 6 years)
Parameter N=101 N=14
AUC12h (ng∙h/mL)
Geometric mean ± standard deviation 3742 ± 4314 3504 ± 2923
Median (range) 4499 (62–28865) 3579 (1221–11815)
C0h (ng/mL)
Geometric mean ± standard deviation 205 ± 342 183 ± 240
Median (range) 287 (2–2276) 162 (54–908)

The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established [see Use in Specific Populations (8.4)].

Male and Female Patients

No significant pharmacokinetic differences have been observed between males and females.

Racial or Ethnic Groups

Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.

Patients with Renal Impairment

The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14 C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment

Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated [see Use in Specific Populations (8.6)].

Pregnancy and Postpartum

After intake of INTELENCE 200 mg twice daily in combination with other antiretroviral agents (13 subjects with 2 NRTIs, 1 subject with 2 NRTIs + lopinavir + ritonavir, 1 subject with 2 NRTIs + raltegravir), based on intra-individual comparison, the Cmax and AUC12h of total etravirine were 23 to 42% higher during pregnancy compared with postpartum (6–12 weeks). The Cmin of total etravirine was 78 to 125% higher during pregnancy compared with postpartum (6–12 weeks), while two subjects had Cmin <10 ng/mL in the postpartum period (6–12 weeks) [Cmin of total etravirine was 11 to 16% higher when these 2 subjects are excluded] (see Table 7) [see Use in Specific Populations (8.1)]. Increased etravirine exposures during pregnancy are not considered clinically significant. The protein binding of etravirine was similar (>99%) during the second trimester, third trimester, and postpartum period.

Table 7: Pharmacokinetic Results of Total Etravirine After Administration of Etravirine 200 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum.
ParameterMean ± SD (median) PostpartumN=10 2nd TrimesterN=13 3rd TrimesterN=10*
*
n=9 for AUC12h
Two subjects had Cmin <10 ng/mL, Cmin was 334 ± 135 (315) in the postpartum period when these subjects were excluded from the descriptive analysis (N=8).
Cmin , ng/mL 269 ± 182 (284) 383 ± 210 (346) 349 ± 103 (371)
Cmax , ng/mL 569 ± 261 (528) 774 ± 300 (828) 785 ± 238 (694)
AUC12h , ng∙h/mL 5004 ± 2521 (5246) 6617 ± 2766 (6836) 6846 ± 1482 (6028)

Patients with Hepatitis B and/or Hepatitis C Virus Co-Infection

Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of INTELENCE [see Adverse Reactions (6)] , no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

Drug Interactions

Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE.

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-gp. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with INTELENCE may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).

Drug interaction studies were performed with INTELENCE and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax , and Cmin values of etravirine are summarized in Table 8 (effect of other drugs on INTELENCE). The effect of co-administration of INTELENCE on the AUC, Cmax , and Cmin values of other drugs are summarized in Table 9 (effect of INTELENCE on other drugs). For information regarding clinical recommendations, [see Drug Interactions (7)].

Table 8: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs
Co-administered Drug Dose/Schedule of Co-administered Drug N Exposure Mean Ratio of EtravirinePharmacokinetic Parameters90% CI; No Effect = 1.00
Cmax AUC Cmin
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change
*
The systemic exposure of etravirine when co-administered with atazanavir/ritonavir in HIV infected subjects is similar to exposures of etravirine observed in the Phase 3 trials after co-administration of INTELENCE and darunavir/ritonavir (as part of the background regimen).
The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir.
Co-administration with HIV protease inhibitors (PIs)
Atazanavir 400 mg once daily 14 1.47(1.36–1.59) 1.50(1.41–1.59) 1.58(1.46–1.70)
Atazanavir/ritonavir * 300/100 mg once daily 14 1.30(1.17–1.44) 1.30(1.18–1.44) 1.26(1.12–1.42)
Darunavir/ritonavir 600/100 mg twice daily 14 0.68(0.57–0.82) 0.63(0.54–0.73) 0.51(0.44–0.61)
Lopinavir/ritonavir(tablet) 400/100 mg twice daily 16 0.70(0.64–0.78) 0.65(0.59–0.71) 0.55(0.49–0.62)
Ritonavir 600 mg twice daily 11 0.68(0.55–0.85) 0.54(0.41–0.73) N.A.
Saquinavir/ritonavir 1000/100 mg twice daily 14 0.63(0.53–0.75) 0.67(0.56–0.80) 0.71(0.58–0.87)
Tipranavir/ritonavir 500/200 mg twice daily 19 0.29(0.22–0.40) 0.24(0.18–0.33) 0.18(0.13–0.25)
Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)
Didanosine 400 mg once daily 15 1.16(1.02–1.32) 1.11(0.99–1.25) 1.05(0.93–1.18)
Tenofovir disoproxil fumarate 300 mg once daily 23 0.81(0.75–0.88) 0.81(0.75–0.88) 0.82(0.73–0.91)
Co-administration with CCR5 antagonists
Maraviroc 300 mg twice daily 14 1.05(0.95–1.17) 1.06(0.99–1.14) 1.08(0.98–1.19)
Maraviroc (when co-administered with darunavir/ritonavir) 150/600/100 mg twice daily 10 1.08(0.98–1.20) 1.00(0.86–1.15) 0.81(0.65–1.01)
Co-administration with integrase strand transfer inhibitors
Raltegravir 400 mg twice daily 19 1.04(0.97–1.12) 1.10(1.03–1.16) 1.17(1.10–1.26)
Co-administration with other drugs
Artemether/lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours 14 1.11(1.06–1.17) 1.10(1.06–1.15) 1.08(1.04–1.14)
Atorvastatin 40 mg once daily 16 0.97(0.93–1.02) 1.02(0.97–1.07) 1.10(1.02–1.19)
Clarithromycin 500 mg twice daily 15 1.46(1.38–1.56) 1.42(1.34–1.50) 1.46(1.36–1.58)
Fluconazole 200 mg once daily in the morning 16 1.75(1.60–1.91) 1.86(1.73–2.00) 2.09(1.90–2.31)
Omeprazole 40 mg once daily 18 1.17(0.96–1.43) 1.41(1.22–1.62) N.A.
Paroxetine 20 mg once daily 16 1.05(0.96–1.15) 1.01(0.93–1.10) 1.07(0.98–1.17)
Ranitidine 150 mg twice daily 18 0.94(0.75–1.17) 0.86(0.76–0.97) N.A.
Rifabutin 300 mg once daily 12 0.63(0.53–0.74) 0.63(0.54–0.74) 0.65(0.56–0.74)
Voriconazole 200 mg twice daily 16 1.26(1.16–1.38) 1.36(1.25–1.47) 1.52(1.41–1.64)
Table 9: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of INTELENCE
Co-administered Drug Dose/Schedule of Co-administered Drug N Exposure Mean Ratio of Co-administered DrugPharmacokinetic Parameters90% CI; No effect = 1.00
Cmax AUC Cmin
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change
*
HIV-infected subjects
compared to maraviroc 150 mg twice daily
Co-administration with HIV protease inhibitors (PIs)
Atazanavir 400 mg once daily 14 0.97(0.73–1.29) 0.83(0.63–1.09) 0.53(0.38–0.73)
Atazanavir/ritonavir 300/100 mg once daily 13 0.97(0.89–1.05) 0.86(0.79–0.93) 0.62(0.55–0.71)
Atazanavir/ritonavir * 300/100 mg once daily 20 0.96(0.80–1.16) 0.96(0.76–1.22) 0.82(0.55–1.22)
Darunavir/ritonavir 600/100 mg twice daily 15 1.11(1.01–1.22) 1.15(1.05–1.26) 1.02(0.90–1.17)
Fosamprenavir/ritonavir 700/100 mg twice daily 8 1.62(1.47–1.79) 1.69(1.53–1.86) 1.77(1.39–2.25)
Lopinavir/ritonavir(tablet) 400/100 mg twice daily 16 0.89(0.82–0.96) 0.87(0.83–0.92) 0.80(0.73–0.88)
Saquinavir/ritonavir 1000/100 mg twice daily 15 1.00(0.70–1.42) 0.95(0.64–1.42) 0.80(0.46–1.38)
Tipranavir/ritonavir 500/200 mg twice daily 19 1.14(1.02–1.27) 1.18(1.03–1.36) 1.24(0.96–1.59)
Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)
Didanosine 400 mg once daily 14 0.91(0.58–1.42) 0.99(0.79–1.25) N.A.
Tenofovir disoproxil fumarate 300 mg once daily 19 1.15(1.04–1.27) 1.15(1.09–1.21) 1.19(1.13–1.26)
Co-administration with CCR5 antagonists
Maraviroc 300 mg twice daily 14 0.40(0.28–0.57) 0.47(0.38–0.58) 0.61(0.53–0.71)
Maraviroc (when co-administered with darunavir/ritonavir) 150/600/100 mg twice daily 10 1.77(1.20–2.60) 3.10(2.57–3.74) 5.27(4.51–6.15)
Co-administration with integrase strand transfer inhibitors
Dolutegravir 50 mg once daily 16 0.48(0.43 to 0.54) 0.29(0.26 to 0.34) 0.12(0.09 to 0.16)
Dolutegravir (when co-administered with darunavir/ritonavir) 50 mg once daily + 600/100 mg twice daily 9 0.88(0.78 to 1.00) 0.75(0.69 to 0.81) 0.63(0.52 to 0.76)
Dolutegravir (when co-administered with lopinavir/ritonavir 50 mg once daily + 400/100 mg twice daily 8 1.07(1.02 to 1.13) 1.11(1.02 to 1.20) 1.28(1.13 to 1.45)
Raltegravir 400 mg twice daily 19 0.89(0.68–1.15) 0.90(0.68–1.18) 0.66(0.34–1.26)
Co-administration with other drugs
Artemether 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours 15 0.72(0.55–0.94) 0.62(0.48–0.80) 0.82(0.67–1.01)
Dihydroartemisinin 15 0.84(0.71–0.99) 0.85(0.75–0.97) 0.83(0.71–0.97)
Lumefantrine
15 1.07(0.94–1.23) 0.87(0.77–0.98) 0.97(0.83–1.15)
Atorvastatin 40 mg once daily 16 1.04(0.84–1.30) 0.63(0.58–0.68) N.A.
2-hydroxy-atorvastatin 16 1.76(1.60–1.94) 1.27(1.19–1.36) N.A.
Buprenorphine Individual dose regimen ranging from 4/1 mg to 16/4 mg once daily 16 0.89(0.76–1.05) 0.75(0.66–0.84) 0.60(0.52–0.68)
Norbuprenorphine 16 1.08(0.95–1.23) 0.88(0.81–0.96) 0.76(0.67–0.87)
Clarithromycin 500 mg twice daily 15 0.66(0.57–0.77) 0.61(0.53–0.69) 0.47(0.38–0.57)
14-hydroxy-clarithromycin 15 1.33(1.13–1.56) 1.21(1.05–1.39) 1.05(0.90–1.22)
Digoxin 0.5 mg single dose 16 1.19(0.96–1.49) 1.18(0.90–1.56) N.A.
Ethinylestradiol 0.035 mg once daily 16 1.33(1.21–1.46) 1.22(1.13–1.31) 1.09(1.01–1.18)
Norethindrone 1 mg once daily 16 1.05(0.98–1.12) 0.95(0.90–0.99) 0.78(0.68–0.90)
Fluconazole 200 mg once daily in the morning 15 0.92(0.85–1.00) 0.94(0.88–1.01) 0.91(0.84–0.98)
R(-) Methadone Individual dose regimen ranging from 60 to 130 mg/day 16 1.02(0.96–1.09) 1.06(0.99–1.13) 1.10(1.02–1.19)
S(+) Methadone 16 0.89(0.83–0.97) 0.89(0.82–0.96) 0.89(0.81–0.98)
Paroxetine 20 mg once daily 16 1.06(0.95–1.20) 1.03(0.90–1.18) 0.87(0.75–1.02)
Rifabutin 300 mg once daily 12 0.90(0.78–1.03) 0.83(0.75–0.94) 0.76(0.66–0.87)
25-O -desacetylrifabutin 300 mg once daily 12 0.85(0.72–1.00) 0.83(0.74–0.92) 0.78(0.70–0.87)
Sildenafil 50 mg single dose 15 0.55(0.40–0.75) 0.43(0.36–0.51) N.A.
N-desmethyl-sildenafil 15 0.75(0.59–0.96) 0.59(0.52–0.68) N.A.
Voriconazole 200 mg twice daily 14 0.95(0.75–1.21) 1.14(0.88–1.47) 1.23(0.87–1.75)

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