HIV/AIDS Update -Intelence (etravirine) label updated to reflect dosing data through 48 weeks

HIV/AIDS Update -Intelence (etravirine) label updated to reflect dosing data through 48 weeks


On November 24, 2009, FDA approved revisions to the INTELENCE (etravirine) labeling to include updated results through 48 weeks of dosing for the two Phase 3 trials TMC125-C206 and TMC125-C216 in treatment-experienced patients. This constitutes the required confirmatory data for Traditional approval.
The section below includes the major changes to the labeling.

HIGHLIGHTS:
The following text depicted in bold type was added to DRUG INTERACTIONS
Co-administration of INTELENCE™ with drugs that are substrates of CYP3A, CYP2C9, and/or CYP2C19 or are transported by P-glycoprotein may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). (7)
FULL PRESCRIBING INFORMATION
Section 1: INDICATIONS AND USAGE was updated to include the indication is based on Week 48 analyses.

Section 5: WARNINGS AND PRECAUTIONS subsection 5.1 Severe Skin and Hypersensitivity Reactions was further revised since the September 15, 2009 action. Angioedema was added to the description of hypersensitivity reaction.

Section 6: ADVERSE REACTION was revised. Clinical adverse drug reactions (ADRs) of moderate intensity or greater (≥ Grade 2) and reported in ≥ 2% of subjects treated with INTELENCE™ and occurring at a higher rate compared to placebo (excess of 1%) are peripheral neuropathy and rash. The “Less common Adverse Reactions” subsection was updated and now includes hepatic failure, and acute renal failure.

Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects was updated to reflect the changes through Week 48

Section 7: DRUG INTERACTIONS was updated to include information on digoxin, maraviroc and provide further clarification to the atazanavir/ritonavir and lopinavir/ritonavir interaction as follows.

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19and P-glycoprotein.Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE™ may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 3). [See also Clinical Pharmacology (12.3).

Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
[See Clinical Pharmacology (12.3)]
...........................
Concomitant Drug Class: Drug Name = atazanavir/ritonavir*†
Effect on Concentration of Etravirine or Concomitant Drug = ↓ atazanavir ↑ etravirine
Clinical Comment = Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin by about 38% and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be about 100% higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered.
...........................
Concomitant Drug Class = lopinavir/ritonavir*†
Effect on Concentration of Etravirine or Concomitant Drug = ↑ etravirine
Clinical Comment = The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with lopinavir/ritonavir is anticipated to be about 85% higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). The amount of safety data at these increased etravirine exposures is limited, therefore, INTELENCE® and lopinavir/ritonavir should be co-administered with caution.
...........................
CCR5 Antagonists
...........................
Concomitant Drug Class = maraviroc*
Effect on Concentration of Etravirine or Concomitant Drug = ↔ etravirine ↓ maraviroc Clinical Comment = When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE® is needed
...........................
Concomitant Drug Class = maraviroc/darunavir/ritonavir*‡
Effect on Concentration of Etravirine or Concomitant Drug = ↔ etravirine ↑ maraviroc
Clinical Comment = When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE® is needed.
............................
Other Agents
............................
Concomitant Drug Class = Antiarrhythmics: digoxin*
Effect on Concentration of Etravirine or Concomitant Drug = ↔ etravirine ↑ digoxin Clinical Comment = For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed.The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
............................
↑ = increase,
↓ = decrease,
↔ = no change

* The interaction between INTELENCE® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

† The expected increase in the systemic exposure of etravirine when co-administered with either atazanavir/ritonavir (~100%) or lopinavir/ritonavir (~85%) is theoretical and is based on comparing exposures of etravirine from drug-drug interaction studies with exposures in the pivotal Phase 3 trials (in which darunavir/ritonavir was co-administered as part of the background regimen).

‡ The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir

Section 12: CLINICAL PHARMACOLOGY was updated to include the results of the drug interaction trials with maraviroc. The same footnote in Table 4 was added to Table 6.
Pharmacokinetics in Adults

Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Subjects (Integrated Data from Phase 3 Trials at Week 48)*
Parameter: AUC12h (ng•h/mL)
------------------------
Etravirine 200 mg b.i.d.
N= 575
------------------------
Parameter: Geometric Mean ± Standard Deviation
------------------------
Etravirine 200 mg b.i.d.
N= 575: 4522 ± 4710
------------------------
Parameter: Median (Range)
------------------------
Etravirine 200 mg b.i.d.
N= 575: 4380 (458 - 59084)
------------------------
Parameter: C0h (ng/mL)
------------------------
Etravirine 200 mg b.i.d.
N= 575
------------------------
Parameter: Geometric Mean ± Standard Deviation
------------------------
Etravirine 200 mg b.i.d.
N= 575: 297 ± 391
------------------------
------------------------
Parameter: Median (Range)
------------------------
Etravirine 200 mg b.i.d.
N= 575: 298 (2 - 4852)
------------------------
* All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. 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.


Drug Interactions
Table 5: 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 Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax
AUC
Cmin
------------------------
Co-Administration wtih CCR5 Antagonists
------------------------
Co-administered Drug = Atazanavir/ritonavir*
Dose/Schedule of Co-administered Drug = 300/100 mg q.d.
N = 14
Exposure = ↑
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 1.30 (1.17-1.44)
AUC = 1.30 (1.18-1.44)
Cmin = 1.26 (1.2-1.42)
------------------------
Co-administered Drug = Lopinavir/ritonavir (soft gel capsule)
Dose/Schedule of Co-administered Drug = 400/100 mg b.i.d.
N = 13
Exposure = ↑
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 1.15 (0.94-1.41)
AUC = 1.15 (0.94-1.41)
Cmin = 1.23 (0.98-1.53)
------------------------
Co-administered Drug = Maraviroc
Dose/Schedule of Co-administered Drug = 300 mg b.i.d
N = 14
Exposure = ↔
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 1.05 (0.95-1.17)
AUC = 1.06 (0.99-1.14)
Cmin = 1.08 (0.9-1.9)
------------------------
Co-administered Drug = Maraviroc (when co-administered with darunavir/ritonavir) † Dose/Schedule of Co-administered Drug = 150/600/100 mg b.i.d
N = 10
Exposure = ↔
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 1.08 (0.98-1.20)
AUC = 1.00 (0.86-1.15)
Cmin = 0.81 (0.65-1.01)
-------------------------
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily
-------------------------
*: The expected increase in the systemic exposure of etravirine when co-administered with either atazanavir/ritonavir (~100 %) or lopinavir/ritonavir (~85 %) is theoretical and is based on comparing exposures of etravirine from drug-drug interaction studies with exposures in the pivotal phase 3 trials (in which darunavir/ritonavir was co-administered as part of the background regimen).
-------------------------
†#160; The reference for etravirine exposures is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir


Table 6: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 Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax
AUC
Cmin
=========================
Co-Administration wtih CCR5 Antagonists
=========================
Co-administered = Maraviroc
Drug Dose/Schedule of Co-administered Drug = 300 mg b.i.d.
N = 14
Exposure = ↓
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 0.40 (0.28-0.57)
AUC = 0.47 (0.38-0.58)
Cmin = 0.61 (0.53-0.71)
=========================
Co-administered = Maraviroc (when co-administered with darunavir/ritonavir)*
Drug Dose/Schedule of Co-administered Drug = 150/600/100 mg b.i.d.
N = 10
Exposure = ↑
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 1.77 (1.20-2.60)
AUC = 3.10 (2.57-3.74)
Cmin = 5.27 (4.516.15)
=========================
Co-administered = Digoxin
Drug Dose/Schedule of Co-administered Drug = 0.5 mg single dose
N = 16
Exposure = ↑
Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Cmax = 1.19 (0.96-1.49)
AUC = 1.18 (0.90-1.56)
Cmin = NA
=========================
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily
=========================
* compared to maraviroc 150 mg b.i.d..
=========================


Section 12.4 Microbiology was updated to include the results of trials C206 and C216 through Week 48. Additionally virologic response by baseline number of IAS-USA Defined NNRTI substitutions, by baseline phenotype and Enfuvirtide use, and by PSS (phenotypic susceptibility score) were updated with the Week 48 results

Section 13: NONCLINICAL TOXICOLOGY was updated to include the results of the carcinogenicity findings in mice and rats as follows:
Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg/kg were administered to mice and doses of 70, 200 and 600 mg/kg were administered to rats in the initial period of approximately 41-52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50-66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-0.7-fold (rats).

Section 14: CLINICAL STUDIES was updated to include the 48 week results. Highlights include the following:

Table 12: Outcomes of Treatment at Week 48 of the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Pooled TMC125-C206 and TMC125-C216 Trials
INTELLENCE™ + BR [N=599]
Placebo + BR [N=604]
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Virologic Responders at Week 48
Viral Load < 50 HIV-1 RNA copies/mL
INTELLENCE™ + BR [N=599] = 359 (60%)
Placebo + BR [N=604] = 232 (38%)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Virologic Failures (VF) at Week 48
Viral Load ≥ 50 HIV-1 RNA copies/mL 201 (33%)
INTELLENCE™ + BR [N=599] = 123 (21%)
Placebo + BR [N=604] = 201 (33%)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Death
INTELLENCE™ + BR [N=599] = 11 (2%)
Placebo + BR [N=604] = 19 (3%)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Discontinuations before Week 48:
...............................
due to VF
INTELLENCE™ + BR [N=599] = 58 (10%)
Placebo + BR [N=604] = 110 (18%)
...............................
due to Adverse Events
INTELLENCE™ + BR [N=599] = 31 (5%)
Placebo + BR [N=604] = 14 (2%)
...............................
due to other reasons
INTELLENCE™ + BR [N=599] = 17 (3%)
Placebo + BR [N=604] = 28 (5%)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
BR=background regimen

At Week 48, 70.8% of INTELENCE™-treated subjects achieved HIV-1 RNA < 400 copies/mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was –2.23 log10 copies/mL for INTELENCE™-treated subjects and –1.46 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE™-treated subjects was 96 cells/mm3 and 68 cells/mm3 for placebo-treated subjects.

Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE™-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Of the study population using ENF de novo, 67.3% of INTELENCE™-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL.

Treatment-emergent CDC category C events occurred in 4% of INTELENCE-treated subjects and 8.4% of placebo-treated subjects.

Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration