INTELENCE 100 MG Oral Tablet
DRUG INTERACTIONS
7 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 ® (see Table 3 ).
[ See also Clinical Pharmacology (12.3) .] Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and 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 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE ® and/or co-administered drug may be recommended.
Drugs that are not recommended for co-administration with INTELENCE ® are also included in Table 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 Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment ↑ = increase, ↓ = decrease, ↔ = no change HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) efavirenz The interaction between INTELENCE ® and the drug was evaluated in a clinical study.
All other drug interactions shown are predicted.
nevirapine ↓ etravirine Combining two NNRTIs has not been shown to be beneficial.
Concomitant use of INTELENCE ® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE ® .
INTELENCE ® and other NNRTIs should not be co-administered.
delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial.
INTELENCE ® and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs) atazanavir (without ritonavir) ↓ atazanavir Concomitant use of INTELENCE ® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir.
INTELENCE ® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir ↓ atazanavir ↑ etravirine Concomitant use of INTELENCE ® with atazanavir/ritonavir may cause a significant decrease in atazanavir C min 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 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.
darunavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE ® was co-administered with darunavir/ritonavir.
Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE ® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir) ↑ amprenavir Concomitant use of INTELENCE ® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir.
INTELENCE ® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE ® and fosamprenavir/ritonavir have not been established.
INTELENCE ® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir) ↓ indinavir Concomitant use of INTELENCE ® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir.
INTELENCE ® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE ® with lopinavir/ritonavir (tablet).
Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE ® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir) ↑ nelfinavir Concomitant use of INTELENCE ® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir.
INTELENCE ® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir ↓ etravirine Concomitant use of INTELENCE ® with ritonavir 600 mg b.i.d.
may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE ® .
INTELENCE ® and ritonavir 600 mg b.i.d.
should not be co-administered.
saquinavir/ritonavir ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE ® was co-administered with saquinavir/ritonavir.
Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE ® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir ↓ etravirine Concomitant use of INTELENCE ® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE ® .
INTELENCE ® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists maraviroc ↔ etravirine ↓ maraviroc 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.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir ↔ etravirine ↑ maraviroc 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 Antiarrhythmics : digoxin ↔ etravirine ↑ digoxin 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.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine ↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE ® .
INTELENCE ® and antiarrhythmics should be co-administered with caution.
Drug concentration monitoring is recommended, if available.
Anticoagulants : warfarin ↑ anticoagulants Warfarin concentrations may be increased when co-administered with INTELENCE ® .
The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE ® .
Anticonvulsants : carbamazepine, phenobarbital, phenytoin ↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes.
INTELENCE ® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE ® .
Antifungals: fluconazole , voriconazole ↑ etravirine ↔ fluconazole ↑ voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures.
The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution.
No dose adjustment of INTELENCE ® or fluconazole is needed.
Co-administration of etravirine and voriconazole significantly increased etravirine exposures.
The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution.
No dose adjustment of INTELENCE ® or voriconazole is needed.
Antifungals : itraconazole, ketoconazole, posaconazole ↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine.
Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4.
Concomitant systemic use of itraconazole or ketoconazole and INTELENCE ® may increase plasma concentrations of etravirine.
Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE ® .
Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives : clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin Clarithromycin exposure was decreased by INTELENCE ® ; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased.
Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered.
Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials: rifampin, rifapentine ↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes.
INTELENCE ® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE ® .
Antimycobacterials: rifabutin ↓ etravirine ↓ rifabutin ↓ 25- O -desacetylrifabutin If INTELENCE ® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d.
is recommended.
If INTELENCE ® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam ↑ diazepam Concomitant use of INTELENCE ® with diazepam may increase plasma concentrations of diazepam.
A decrease in diazepam dose may be needed.
Corticosteroids : dexamethasone (systemic) ↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations.
This may result in loss of therapeutic effect of INTELENCE ® .
Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products : St.
John’s wort ( Hypericum perforatum ) ↓ etravirine Concomitant use of INTELENCE ® with products containing St.
John’s wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE ® .
INTELENCE ® and products containing St.
John’s wort should not be co-administered.
HMG-CoA Reductase Inhibitors : atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin ↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin The combination of INTELENCE ® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.
No interaction between pravastatin, rosuvastatin and INTELENCE ® is expected.
Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE ® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor.
Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE ® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor.
Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants : cyclosporine, sirolimus, tacrolimus ↓ immunosuppressant INTELENCE ® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics : methadone ↔ etravirine ↔ methadone INTELENCE ® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors : sildenafil , vardenafil, tadalafil ↓ sildenafil ↓ N-desmethyl-sildenafil INTELENCE ® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE ® .
Alternatives to clopidogrel should be considered.
In addition to the drugs included in Table 3, the interaction between INTELENCE ® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [ see Clinical Pharmacology (12.3) ]: didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.
INTELENCE ® should not be co-administered with the following antiretrovirals: Tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir Protease inhibitors administered without ritonavir NNRTIs Co-administration of INTELENCE ® with drugs that inhibit or induce CYP3A, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine.
( 7 ) 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 ) Refer to the Full Prescribing Information for other drugs that should not be co-administered with INTELENCE ® and for other drugs that may require a change in dose or regimen.
( 7 )
OVERDOSAGE
10 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.
If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage.
Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance.
Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.
DESCRIPTION
11 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 C 20 H 15 BrN 6 O and its molecular weight is 435.28.
Etravirine has the following structural formula: 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 ® is available as a white to off-white, oval tablet for oral administration containing 100 mg of etravirine.
Each tablet contains the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate.
Chemical Structure
CLINICAL STUDIES
14 14.1 Treatment-Experienced Subjects The clinical efficacy of INTELENCE ® is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2).
These trials are identical in design and the results below are pooled data from the two trials.
TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of INTELENCE ® in combination with a background regimen (BR) as compared to placebo in combination with a BR.
Eligible subjects were treatment-experienced HIV-1-infected patients with plasma HIV-1 RNA > 5000 copies/mL while on a stable antiretroviral regimen for at least 8 weeks.
In addition, subjects had 1 or more NNRTI resistance-associated mutations at screening or from prior genotypic analysis, and 3 or more of the following primary PI mutations at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M.
Randomization was stratified by the intended use of enfuvirtide (ENF) in the BR, previous use of darunavir/ritonavir (DRV/rtv), and screening viral load.
Virologic response was defined as undetectable viral load (< 50 HIV-1 RNA copies/mL) at 48 weeks.
All study subjects received DRV/rtv as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF).
Of INTELENCE ® -treated subjects, 25.5% used ENF for the first time ( de novo ) and 20.0% re-used ENF.
Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF.
In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the INTELENCE ® arm and the placebo arm.
Table 10 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE ® and placebo arms.
Table 10: Demographic and Baseline Disease Characteristics of Subjects in the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis) Pooled TMC125-C206 and TMC125-C216 Trials INTELENCE ® + BR N=599 Placebo + BR N=604 RAMs = Resistance-Associated Mutations, BR=background regimen FC = fold change in EC 50 Demographic Characteristics Median Age, years (range) 46 (18-77) 45 (18-72) Sex Male 90.0% 88.6% Female 10.0% 11.4% Race White 70.1% 69.8% Black 13.2% 13.0% Hispanic 11.3% 12.2% Asian 1.3% 0.6% Other 4.1% 4.5% Baseline Disease Characteristics Median Baseline Plasma HIV-1 RNA (range), log 10 copies/mL 4.8 (2.7-6.8) 4.8 (2.2-6.5) Percentage of Subjects with Baseline Viral Load: < 30,000 copies/mL 27.5% 28.8% ≥ 30,000 copies/mL and < 100,000 copies/mL 34.4% 35.3% ≥ 100,000 copies/mL 38.1% 35.9% Median Baseline CD4+ Cell Count (range), cells/mm 3 99 (1-789) 109 (0-912) Percentage of Subjects with Baseline CD4+ Cell Count: < 50 cells/mm 3 35.6% 34.7% ≥ 50 cells/mm 3 and 1 44.9% 45.4% Percentage of Subjects with Previous Use of the following NNRTIs: Efavirenz 70.3% 72.5% Nevirapine 57.1% 58.6% Delavirdine 13.7% 12.6% Median (range) Number of NNRTI RAMs Tibotec NNRTI RAMs [June 2008]: A98G, V90I, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/M/I, V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P255H, F227C/L, M230I/L, P236L, K238N/T, Y318F 2 (0-8) 2 (0-7) Median Fold Change of the Virus for the Following NNRTIs: Delavirdine 27.3 26.1 Efavirenz 63.9 45.4 Etravirine 1.6 1.5 Nevirapine 74.3 74.0 Percentage of Subjects with Previous Use of a Fusion Inhibitor 39.6% 42.2% Percentage of Subjects with a Phenotypic Sensitivity Score (PSS) for the background therapy The PSS was calculated for the background therapy (as determined on Day 7).
Percentages are based on the number of subjects with available phenotype data.
For fusion inhibitors (enfuvirtide), subjects were considered resistant if the drug was used in previous therapy up to baseline.
INTELENCE ® is not included in this calculation.
of: 0 17.0% 16.2% 1 36.5% 38.7% 2 26.9% 27.8% ≥ 3 19.7% 17.3% Efficacy at Week 48 for subjects in the INTELENCE ® and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 11.
Table 11: Outcomes of Treatment at Week 48 of the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis) Pooled TMC125-C206 and TMC125-C216 Trials INTELENCE ® + BR N=599 Placebo + BR N=604 BR=background regimen Virologic Responders at Week 48 Viral Load < 50 HIV-1 RNA copies/mL 359 (60%) 232 (38%) Virologic Failures (VF) at Week 48 Viral Load ≥ 50 HIV-1 RNA copies/mL 123 (21%) 201 (33%) Death 11 (2%) 19 (3%) Discontinuations before Week 48: due to VF 58 (10%) 110 (18%) due to Adverse Events 31 (5%) 14 (2%) due to other reasons 17 (3%) 28 (5%) 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 log 10 copies/mL for INTELENCE ® -treated subjects and –1.46 log 10 copies/mL for placebo-treated subjects.
The mean CD4+ cell count increase from baseline for INTELENCE ® -treated subjects was 96 cells/mm 3 and 68 cells/mm 3 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.
Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial.
Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected patients with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis.
The virologic response was evaluated in 116 subjects who were randomized to INTELENCE ® (n=59) or an investigator-selected PI (n=57), each given with 2 investigator-selected N(t)RTIs.
INTELENCE ® -treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE ® as compared to the control PI-treated subjects.
HOW SUPPLIED
16 /STORAGE AND HANDLING INTELENCE ® tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine.
Each tablet is debossed with “TMC125” on one side and “100” on the other side.
They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod.
Code 53808-0787-1 100 mg 30 Tablets in a Blister Pack white to off white 59676-570 Store INTELENCE ® tablets at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F) [see USP controlled room temperature].
Store in the original bottle.
Keep the bottle tightly closed in order to protect from moisture.
Do not remove the desiccant pouches.
RECENT MAJOR CHANGES
Warnings and Precautions Severe Skin and Hypersensitivity Reactions ( 5.1 ) 08/2009
GERIATRIC USE
8.5 Geriatric use Clinical studies of INTELENCE ® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger subjects.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
DOSAGE FORMS AND STRENGTHS
3 100 mg white to off-white oval tablets debossed with “TMC125” on one side and “100” on the other side.
100 mg tablets ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Etravirine is an antiviral drug [ see Clinical Pharmacology (12.4) ].
INDICATIONS AND USAGE
1 INTELENCE ® Registered trademark of Tibotec Pharmaceuticals , in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.
This indication is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE ® .
Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t]RTI, PI) treatment-experienced adults.
The following points should be considered when initiating therapy with INTELENCE ® : Treatment history and, when available, resistance testing, should guide the use of INTELENCE ® .
The use of other active antiretroviral agents with INTELENCE ® is associated with an increased likelihood of treatment response.
In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE ® in combination with only N[t]RTIs [ see Clinical Studies (14) ].
The risks and benefits of INTELENCE ® have not been established in pediatric patients or in treatment-naïve adult patients.
INTELENCE ® is a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated: In combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents.
( 1 ) In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE ® in combination with only N[t]RTIs.
( 1 ) The safety and efficacy of INTELENCE ® have not been established in pediatric patients or treatment-naïve adult patients.
( 1 )
PEDIATRIC USE
8.4 Pediatric use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy
NUSRING MOTHERS
8.3 Nursing mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
It is not known whether etravirine is secreted in human milk.
Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving INTELENCE ® .
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Severe, potentially life threatening and fatal skin reactions have been reported.
This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, toxic epidermal necrolysis and erythema multiforme.
Immediately discontinue treatment if severe hypersensitivity, severe rash or rash with systemic symptoms or liver transaminase elevations develops and monitor clinical status, including liver transaminases closely.
( 5.1 ) 5.1 Severe Skin and Hypersensitivity Reactions Severe, potentially life-threatening, and fatal skin reactions have been reported.
These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme.
Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure.
In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE ® compared to 0.2% of placebo subjects.
A total of 2.2% of HIV-1-infected subjects receiving INTELENCE ® discontinued from Phase 3 trials due to rash [ see Adverse Reactions (6) ].
Rash occurred most commonly during the first 6 weeks of therapy.
Discontinue INTELENCE ® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema).
Clinical status including liver transaminases should be monitored and appropriate therapy initiated.
Delay in stopping INTELENCE ® treatment after the onset of severe rash may result in a life-threatening reaction.
5.2 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE ® .
During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION [See FDA-approved patient labeling ].
A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with INTELENCE ® from your healthcare provider.
A Patient Package Insert for INTELENCE ® is available for patient information.
Patients should be informed that INTELENCE ® is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease.
Patients should be informed that INTELENCE ® does not reduce the risk of passing HIV to others through sexual contact, sharing needles, or being exposed to blood.
Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood.
Patients should also be advised to never re-use or share needles.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should remain under the care of a physician while using INTELENCE ® .
Patients should be advised to take INTELENCE ® following a meal twice a day as prescribed.
The type of food does not affect the exposure to etravirine.
Patients should be instructed to swallow the tablets as a whole with a liquid such as water.
Patients who are unable to swallow the INTELENCE ® tablets whole may disperse the tablets in a glass of water.
Once dispersed, patients should stir the dispersion well, and drink it immediately.
The glass should be rinsed with water several times, and each rinse completely swallowed to ensure the entire dose is consumed.
INTELENCE ® must always be used in combination with other antiretroviral drugs.
Patients should not alter the dose of INTELENCE ® or discontinue therapy with INTELENCE ® without consulting their physician.
If the patient misses a dose of INTELENCE ® within 6 hours of the time it is usually taken, the patient should be told to take INTELENCE ® following a meal as soon as possible, and then take the next dose of INTELENCE ® at the regularly scheduled time.
If a patient misses a dose of INTELENCE ® by more than 6 hours of the time it is usually taken, the patient should be told not to take the missed dose and simply resume the usual dosing schedule.
Inform the patient that he or she should not take more or less than the prescribed dose of INTELENCE ® at any one time.
INTELENCE ® may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St.
John’s wort.
Patients should be informed that severe and potentially life-threatening rash has been reported with INTELENCE ® .
Rash has been reported most commonly in the first 6 weeks of therapy.
Patients should be advised to immediately contact their healthcare provider if they develop rash.
Instruct patients to immediately stop taking INTELENCE ® and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of your skin or whites of your eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on your right side below your ribs).
Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including INTELENCE ® , and that the cause and long-term health effects of these conditions are not known at this time.
DOSAGE AND ADMINISTRATION
2 The recommended oral dose of INTELENCE ® tablets is 200 mg (two 100 mg tablets) taken twice daily following a meal [ see Clinical Pharmacology (12.3) ].
The type of food does not affect the exposure to etravirine.
Patients who are unable to swallow INTELENCE ® tablets whole may disperse the tablets in a glass of water.
Once dispersed, patients should stir the dispersion well and drink it immediately.
The glass should be rinsed with water several times and each rinse completely swallowed to ensure the entire dose is consumed.
200 mg (two 100 mg tablets) taken twice daily following a meal.
( 2 )