INTELENCE(tm) 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(tm) in combination with only N[t]RTIs. (1)
The safety and efficacy of INTELENCE(tm) have not been established in pediatric patients or treatment-naive adult patients. (1)
200 mg (two 100 mg tablets) taken twice daily following a meal.
(2)
100 mg tablets (3)
None
Severe and potentially life threatening skin reactions, including cases of Stevens-Johnson syndrome, hypersensitivity reaction, and erythema multiforme, have been reported. Discontinue treatment if severe rash develops. (5.1)
The most common adverse events (incidence > 10%) of any
intensity that occurred at a higher rate than placebo are rash and nausea. (6)
INTELENCE(tm) 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(tm) with drugs that inhibit or induce CYP3A4, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE(tm). (7)
Co-administration of INTELENCE(tm) with drugs that are substrates of CYP3A4, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse reaction profile of the co-administered drugs. (7)
Refer to the Full Prescribing Information for other drugs that should not be co-administered with INTELENCE(tm) and for other drugs that may require a change in dose or regimen. (7)
Pregnancy: Pregnancy Category B--Use during pregnancy only if the potential benefit justifies the potential risk. Antiviral Pregnancy Registry available. Register patients by calling 1- 800-258-4263. (8.1)
Nursing Mothers: Mothers should not breastfeed due to the potential for HIV transmission. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Severe Skin Reactions
Fat Redistribution
Immune Reconstitution Syndrome
ADVERSE REACTIONS
Clinical Trials Experience
DRUG INTERACTIONS USE IN SPECIFIC POPULATIONS
Pregnancy
Nursing MothersPediatric UseGeriatric UseHepatic ImpairmentRenal Impairment
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
Mechanism of Action
Pharmacodynamics
Pharmacokinetics
Microbiology
NON-CLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis,
Impairment of Fertility
Animal Toxicology and/or Pharmacology
CLINICAL STUDIES
Treatment-Experienced Subjects
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING
INFORMATION
[ *Sections or subsections omitted from the full prescribing information are not listed]
INTELENCE(tm) *, 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 24 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE(tm). 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(tm):
Treatment history and, when available, resistance testing, should guide the use of INTELENCE(tm).
The use of other active antiretroviral agents with INTELENCE(tm) 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(tm) in combination with only N[t]RTIs [see Clinical Studies (14)].
The risks and benefits of INTELENCE(tm) have not been established in pediatric patients or in treatment- naive adult patients.
The recommended oral dose of INTELENCE(tm) 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(tm) 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.
100 mg white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.
None
Severe and potentially life-threatening skin reactions have occurred in patients taking INTELENCE(tm), including Stevens-Johnson syndrome, hypersensitivity reaction, and erythema multiforme. These reactions have been reported in < 0.1% of subjects taking INTELENCE(tm). Treatment with INTELENCE(tm) should be discontinued and appropriate therapy initiated if severe rash develops. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy [see Adverse Reactions (6)]. A total of 2% of HIV-1-infected subjects receiving INTELENCE(tm) discontinued from Phase 3 trials due to rash.
*
Trademark of Tibotec Pharmaceuticals Ltd.
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.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE(tm). 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.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety assessment is based on all data from 1203 subjects in the ongoing Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE(tm) (200 mg b.i.d. ). In these pooled trials, the median exposure for subjects in the INTELENCE(tm) arm and placebo arm was 30.0 and 29.1 weeks, respectively. The most commonly (> 10%) reported adverse events of all intensities and regardless of causality that occurred at a higher rate in INTELENCE(tm)-treated subjects as compared to placebo-treated subjects are presented in Table 1.
| Table 1: Adverse Events of All Intensities and Regardless of Causality at a Higher Rate Compared to Placebo in > 10% of Adult Subjects in the INTELENCE(tm) Treatment Groups | ||
| Pooled TMC125-C206 and TMC125-C216 Trials | ||
| System Organ Class, Preferred Term, % | INTELENCE(tm) + BR N=599 | Placebo + BR N=604 |
| Gastrointestinal Disorders | ||
| Nausea | 13.9% | 11.1% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash (any type) | 16.9% | 9.3% |
| N=total number of subjects per treatment group, BR=background regimen | ||
The most frequently reported adverse drug reaction (ADR) at least Grade 2 in severity was rash (9.0%). Stevens-Johnson syndrome, hypersensitivity reaction, and erythema multiforme were reported in < 0.1% of subjects during clinical development with INTELENCE(tm). A total of 2% of HIV-1-infected subjects in Phase 3 trials receiving INTELENCE(tm) discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy [see Warnings and Precautions (5.1)]. The incidence of rash was higher in women compared to men in the INTELENCE(tm) arm. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE(tm)-related rash compared to patients without a history of NNRTI-related rash.
Common Adverse Reactions
ADRs of moderate intensity or greater (>= Grade 2) and reported in >= 2% of subjects treated with INTELENCE(tm) are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3.
| Table 2: Treatment-Emergent Adverse Reactions * of at least Moderate Intensity + (Grades 2-4) in >= 2% of Adult Subjects in the INTELENCE(tm) Treatment Groups | ||
| System Organ Class, Preferred Term, % | Pooled TMC125-C206 and TMC125-C216 Trials | |
| INTELENCE(tm) + BR N=599 | Placebo + BR N=604 | |
| Gastrointestinal Disorders | ||
| Diarrhea | 5.2% | 9.6% |
| Nausea | 4.7% | 3.5% |
| Abdominal pain | 3.0% | 2.5% |
| Vomiting | 2.3% | 2.0% |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 3.3% | 4.0% |
| Nervous System Disorders | ||
| Peripheral neuropathy | 2.8% | 1.8% |
| Headache | 2.7% | 4.1% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 9.0% | 3.1% |
| Vascular Disorders | ||
| Hypertension | 2.8% | 2.2% |
| N=total number of subjects per treatment group , BR=background regimen * Includes adverse reactions at least possibly, probably, or very likely related to the drug. + Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). | ||
Less Common Adverse Reactions
Treatment-emergent ADRs occurring in less than 2% of subjects (n=599) receiving INTELENCE(tm) and of at least moderate intensity (>= Grade 2) are listed below by body system:
Cardiac Disorders
: myocardial infarction, angina pectoris, atrial fibrillation
Ear and Labyrinth Disorders
: vertigo
Eye Disorders
: blurred vision
Gastrointestinal Disorders
: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis
General Disorders and Administration Site Conditions
: sluggishness
Hematologic Disorders
: anemia, hemolytic anemia
Hepatobiliary Disorders: cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome Metabolism and Nutrition Disorders: diabetes mellitus, dyslipidemia, anorexia
Nervous System Disorders
: paraesthesia, somnolence, convulsion, hypoesthesia, syncope, amnesia, hypersomnia, tremor
Psychiatric Disorders
: insomnia, anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares
Renal and Urinary Disorders
: renal failure
Reproductive System and Breast Disorders
: gynecomastia
Respiratory,Thoracic and Mediastinal Disorders
: exertional dyspnea, bronchospasm
Skin and Subcutaneous Tissue Disorders
: night sweats, hyperhidrosis, prurigo, dry skin, lipohypertrophy, swelling face
Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects.
Laboratory Abnormalities in Treatment-Experienced Patients
Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with INTELENCE(tm) are presented in Table 3.
| Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects | |||
| Pooled TMC125-C206 and TMC125-C216 Trials | |||
| Laboratory Parameter Preferred Term, % | DAIDS Toxicity Range | INTELENCE(tm) + BR N=599 | Placebo + BR N=604 |
| GENERAL BIOCHEMISTRY | |||
| Pancreatic amylase | |||
| Grade 2 | > 1.5-2 x ULN | 5.9% | 7.3% |
| Grade 3 | > 2-5 x ULN | 6.3% | 7.0% |
| Grade 4 | > 5 x ULN | 1.2% | 1.0% |
| Lipase | |||
| Grade 2 | > 1.5-3 x ULN | 3.4% | 4.8% |
| Grade 3 | > 3-5 x ULN | 1.7% | 1.2% |
| Grade 4 | > 5xULN | 1.0% | 0.5% |
| Creatinine | |||
| Grade 2 | > 1.4-1.8 x ULN | 4.7% | 4.0% |
| Grade 3 | > 1.9-3.4 x ULN | 1.9% | 1.2% |
| Grade 4 | > 3.4 x ULN | 0% | 0.2% |
| HEMATOLOGY | |||
| Decreased hemoglobin | |||
| Grade 2 | 90-99 g/L | 1.9% | 3.5% |
| Grade 3 | 70-89 g/L | 1.0% | 0.7% |
| Grade 4 | < 70 g/L | 0.7% | 0.7% |
| Neutrophils | |||
| Grade 2 | 750-999/mm 3 | 4.4% | 5.3% |
| Grade 3 | 500-749/mm 3 | 2.7% | 3.5% |
| Grade 4 | < 500/mm 3 | 1.0% | 2.8% |
| Platelet count | |||
| Grade 2 | 50,000-99,999/mm 3 | 2.9% | 4.5% |
| Grade 3 | 25,000-49,999/mm 3 | 1.2% | 0.8% |
| Grade 4 | < 25,000/mm 3 | 0.2% | 0.2% |
| LIPIDS AND GLUCOSE | |||
| Total cholesterol | |||
| Grade 2 | > 6.20-7.77 mmol/L 240-300 mg/dL | 18.0% | 12.6% |
| Grade 3 | > 7.77 mmol/L > 300 mg/dL | 5.8% | 4.1% |
| Low density lipoprotein | |||
| Grade 2 | 4.13-4.9 mmol/L 160-190 mg/dL | 11.5% | 9.1% |
| Grade 3 | > 4.9 mmol/L | 5.2% | 5.4% |
| > 190 mg/dL | |||
| Triglycerides | |||
| Grade 2 | 5.65-8.48 mmol/L 500 -750 mg/dL | 7.1% | 6.5% |
| Grade 3 | 8.49-13.56 mmol/L 751 - 1200 mg/dL | 4.1% | 3.0% |
| Grade 4 | > 13.56 mmol/L > 1200 mg/dL | 2.9% | 1.3% |
| Elevated glucose levels | |||
| Grade 2 | 6.95-13.88 mmol/L 161-250 mg/dL | 13.1% | 10.8% |
| Grade 3 | 13.89-27.75 mmol/L 251 - 500 mg/dL | 2.5% | 1.8% |
| Grade 4 | > 27.75 mmol/L > 500 mg/dL | 0% | 0.2% |
| HEPATIC PARAMETERS | |||
| Alanine amino transferase | |||
| Grade 2 | 2.6-5 x ULN | 5.4% | 4.0% |
| Grade 3 | 5.1-10 x ULN | 1.9% | 1.3% |
| Grade 4 | > 10 x ULN | 0.7% | 0.3% |
| Aspartate amino transferase | |||
| Grade 2 | 2.6-5 x ULN | 5.1% | 6.5% |
| Grade 3 | 5.1-10 x ULN | 2.0% | 1.3% |
| Grade 4 | > 10 x ULN | 0.5% | 0.3% |
| ULN=Upper Limit of Normal, BR=background regimen | |||
Patients co-infected with hepatitis B and/or hepatitis C virus
In Phase 3 trials TMC125-C206 and TMC125-C216, 140 subjects (12.4%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1130 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 22.8%, 21.4% and 5.7% respectively, of INTELENCE(tm)-treated co-infected subjects as compared to 5.5%, 6.1% and 1.2% of non-co-infected INTELENCE(tm)-treated subjects. In general, adverse events reported by INTELENCE(tm)-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to INTELENCE(tm)-treated subjects without hepatitis B and/or hepatitis C virus co-infection.
Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE(tm) with drugs that induce or inhibit CYP3A4, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE(tm) (see Table 4). [See also Clinical Pharmacology (12.3).] Etravirine is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Therefore, co-administration of drugs that are substrates of CYP3A4, CYP2C9 and CYP2C19 with INTELENCE(tm) may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4). [See also Drug Interactions (7) and Clinical
Pharmacology (12.3).] Table 4 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE(tm) and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE(tm) are also included in Table 4.
| Table 4: 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 |
| HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| efavirenz * nevirapine * | | etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE(tm) with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE(tm). INTELENCE(tm) and other NNRTIs should not be co-administered. |
| delavirdine | | etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE(tm) and delavirdine should not be co-administered. |
| HIV-Antiviral Agents: Protease Inhibitors (PIs)--Unboosted (i.e., without co-administration of low-dose ritonavir) | ||
| atazanavir * | | atazanavir | Concomitant use of INTELENCE(tm) with PIs without co- |
| fosamprenavir | | amprenavir | administration of low-dose ritonavir may cause a significant |
| nelfinavir | | nelfinavir | alteration in the plasma concentrations of the PI. INTELENCE(tm) |
| indinavir * | | indinavir | should not be co-administered with PIs without low-dose ritonavir. |
| (without ritonavir) | ||
| ritonavir * | | etravirine | Concomitant use of INTELENCE(tm) 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(tm). INTELENCE(tm) and ritonavir 600 mg b.i.d. should not be co- administered. |
| HIV-Antiviral Agents: Protease Inhibitors (PIs)--Boosted (with co-administration of low-dose ritonavir) | ||
| tipranavir/ritonavir * | | etravirine | Concomitant use of INTELENCE(tm) with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE(tm). INTELENCE(tm) and tipranavir/ritonavir should not be co- administered. |
| fosamprenavir/ritonavir * | | amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE(tm) and fosamprenavir/ritonavir have not been established. INTELENCE(tm) and fosamprenavir/ritonavir should not be co-administered. |
| atazanavir/ritonavir * | | atazanavir | etravirine | Concomitant use of INTELENCE(tm) with atazanavir/ritonavir may cause a significant decrease in atazanavir C m in by about 38% and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE(tm) with atazanavir/ritonavir is anticipated to be about 100% higher than the mean systemic exposure of etravirine observed in the Phase 3 trials. INTELENCE(tm) and |
| atazanavir/ritonavir should not be co-administered. | ||
| darunavir/ritonavir | | etravirine | The mean systemic exposure (AUC) of etravirine was reduced by about 37% when INTELENCE(tm) 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(tm) and darunavir/ritonavir can be co- administered without any dose adjustments. |
| lopinavir/ritonavir | | etravirine | The mean systemic exposure (AUC) of etravirine after co- administration of INTELENCE(tm) with lopinavir/ritonavir is anticipated to be about 85% higher than the mean systemic exposure of etravirine observed in the Phase 3 trials. The amount of safety data at these increased etravirine exposures is limited, therefore, INTELENCE(tm) and lopinavir/ritonavir should be co- administered with caution. |
| saquinavir/ritonavir | | etravirine | The mean systemic exposure (AUC) of etravirine was reduced by about 33% when INTELENCE(tm) 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(tm) and saquinavir/ritonavir can be co-administered without any dose adjustments. |
| Other Agents | ||
| Antiarrhythmics : amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine | | antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co- administered with INTELENCE(tm). INTELENCE(tm) 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(tm). The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE(tm). |
| Anticonvulsants : carbamazepine, phenobarbital, phenytoin | | etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE(tm) 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(tm). |
| Antifungals : | | etravirine | Posaconazole is a potent inhibitor of CYP3A4 and fluconazole is a |
| fluconazole, | - fluconazole | potent inhibitor of CYP2C9; both may increase plasma |
| itraconazole, | | itraconazole | concentrations of etravirine. Itraconazole and ketoconazole are |
| ketoconazole, posaconazole, voriconazole | | ketoconazole - posaconazole | voriconazole | potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE(tm) may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be |
| decreased by INTELENCE(tm). Voriconazole is a CYP2C19 | ||
| substrate and CYP3A4, CYP2C9 and CYP2C19 inhibitor. | ||
| Concomitant use of voriconazole and INTELENCE(tm) may increase plasma concentrations of both drugs. Dose adjustments for itraconazole, ketoconazole or voriconazole may be necessary depending on other co-administered drugs. | ||
| Antiinfectives : clarithromycin * | | etravirine | clarithromycin | 14-OH- clarithromycin | Clarithromycin exposure was decreased by INTELENCE(tm); 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(tm) 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(tm). |
| Antimycobacterials: rifabutin * | | etravirine | rifabutin | 25- O - desacetylrifabutin | If INTELENCE(tm) is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE(tm) is co-administered with darunavir/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(tm) with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
| Corticosteroids : dexamethasone (systemic) | | etravirine | Systemic dexamethasone induces CYP3A4 and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE(tm). 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(tm) with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE(tm). INTELENCE(tm) 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(tm) and atorvastatin can be given without any dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE(tm) is expected. Lovastatin and simvastatin are CYP3A4 substrates and co- administration with INTELENCE(tm) may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE(tm) may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG- CoA reductase inhibitors may be necessary. |
| Immunosuppressants : | | | INTELENCE(tm) and systemic immunosuppressants should be co- |
| cyclosporine, sirolimus, tacrolimus | immunosuppressant | administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
| Narcotic Analgesics : methadone * | - etravirine - methadone | INTELENCE(tm) 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(tm) and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
| | = increase, | = decrease, - = no change * The interaction between INTELENCE(tm) and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
In addition to the drugs included in Table 4, the interaction between INTELENCE(tm) 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, ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.
Pregnancy Category B
No adequate and well-controlled studies of INTELENCE(tm) use in pregnant women have been conducted. In addition, no pharmacokinetic studies have been conducted in pregnant patients. Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the recommended human dose of 400 mg/day revealed no evidence of fetal harm. INTELENCE(tm) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to INTELENCE(tm), an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
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,
.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of INTELENCE(tm) 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.
No dose adjustment of INTELENCE(tm) is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of INTELENCE(tm) have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C).
Since the renal clearance of etravirine is negligible (< 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
There is no specific antidote for overdose with INTELENCE(tm). Human experience of overdose with INTELENCE(tm) is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with INTELENCE(tm) 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.
INTELENCE(tm) (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 C20H15BrN6O and its molecular weight is 435.28. Etravirine has the following structural formula:
N
N NH
N
Br
NH 2 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(tm) 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.
Etravirine is an antiviral drug [see Clinical Pharmacology (12.4)].
Effects on Electrocardiogram
In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered INTELENCE(tm) 200 mg b.i.d., INTELENCE(tm) 400 mg q.d., placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg b.i.d. and -1.0 ms (2.5 ms) for 400 mg q.d. dosing regimens.
Pharmacokinetics in Adults
The pharmacokinetic properties of INTELENCE(tm) were determined in healthy adult subjects and in treatment- experienced HIV-1-infected adult subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1- infected subjects than in healthy subjects.
| 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 24) * | |
| Parameter | Etravirine 200 mg b.i.d. N = 574 |
| AUC 12h (ng *h/mL) | |
| Geometric Mean +- Standard Deviation | 4531.53 +- 4543.69 |
| Median (Interquartile Range) | 4450.7 (3091.3 - 6315.0) |
| C 0h (ng/mL) | |
| Geometric Mean +- Standard Deviation | 296.74 +- 377.52 |
| Median (Interquartile Range) | 298.8 (188.5 - 462.3) |
* 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(tm) with darunavir/ritonavir. Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro = 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(tm) 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(tm) was administered under fasting conditions, as compared to when INTELENCE(tm) was administered following a meal. Therefore, INTELENCE(tm) should always be taken 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). [see Dosage and Administration (2)].
Distribution
Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66%-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 CYP3A4, 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 14C-etravirine, 93.7% and 1.2% of the administered dose of 14C- 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.
Special Populations
Hepatic Impairment
Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE(tm) to subjects with normal hepatic function (n = 16), mild hepatic impairment (Child-Pugh Class A, n = 8), and moderate hepatic impairment (Child-Pugh Class B, n = 8). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated.
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 [see Adverse Reactions (6)], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.
Renal Impairment
The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that <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.
Gender
No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in clinical studies.
Race
Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.
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 pediatric patients have not been evaluated. Dosing recommendations for pediatric patients cannot be made due to insufficient data.
Drug Interactions
[See also Drug Interactions (7).] Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE(tm) with drugs that induce or inhibit CYP3A4, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE(tm). Etravirine is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Therefore, co-administration of drugs that are substrates of CYP3A4, CYP2C9 and CYP2C19 with INTELENCE(tm) may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). Drug interaction studies were performed with INTELENCE(tm) 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 6 (effect of other drugs on INTELENCE(tm)). The effect of co-administration of INTELENCE(tm) on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 7 (effect of INTELENCE(tm) on other drugs). For information regarding clinical recommendations, see Drug Interactions (7).
| Co-administered Co-administered 90% CI; No Effect = 1.00 | ||||||
| Drug Drug N Exposure C m ax | AUC | C min | ||||
| Co-Administration With Protease Inhibitors (PIs) | ||||||
| Atazanavir | 400 mg q.d. | 14 | | | 1.47 | 1.50 | 1.58 |
| (1.36-1.59) | (1.41-1.59) | (1.46-1.70) | ||||
| Atazanavir/ | 300/100 mg q.d. | 14 | | | 1.30 | 1.30 | 1.26 |
| ritonavir | (1.17-1.44) | (1.18-1.44) | (1.12-1.42) | |||
| Darunavir/ | 600/100 mg b.i.d. | 14 | | | 0.68 | 0.63 | 0.51 |
| ritonavir | (0.57-0.82) | (0.54-0.73) | (0.44-0.61) | |||
| Lopinavir/ | 400/100 mg b.i.d. | 13 | | | 1.15 | 1.17 | 1.23 |
| ritonavir | (0.94-1.41) | (0.96-1.43) | (0.98-1.53) | |||
| (soft gel capsule) | ||||||
| Ritonavir | 600 mg b.i.d. | 11 | | | 0.68 | 0.54 | N.A. |
| (0.55-0.85) | (0.41-0.73) | |||||
| Saquinavir/ | 1000/100 mg b.i.d. | 14 | | | 0.63 | 0.67 | 0.71 |
| ritonavir | (0.53-0.75) | (0.56-0.80) | (0.58-0.87) | |||
| Tipranavir/ | 500/200 mg b.i.d. | 19 | | | 0.29 | 0.24 | 0.18 |
| ritonavir | (0.22-0.40) | (0.18-0.33) | (0.13-0.25) | |||
| Co-Administration Wi Didanosine | th Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 4 00 mg q.d. 15 - 1.16 | 1.11 | 1.05 | |||
| (1.02-1.32) | (0.99-1.25) | (0.93-1.18) | ||||
| Tenofovir disoproxil | 300 mg q.d. | 23 | | | 0.81 | 0.81 | 0.82 |
| fumarate | (0.75-0.88) | (0.75-0.88) | (0.73-0.91) | |||
| Co-Administration Wi Raltegravir | th Integrase Strand Transfer Inhi 400 mg b.i.d. 19 | bitors - | 1.04 | 1.10 | 1.17 | |
| (0.97-1.12) | (1.03-1.16) | (1.10-1.26) | ||||
| Co-Administration Wi Atorvastatin | th Other Drugs 40 mg q.d. | 16 | - | 0.97 | 1.02 | 1.10 |
| (0.93-1.02) | (0.97-1.07) | (1.02-1.19) | ||||
| Clarithromycin | 500 mg b.i.d. | 15 | | | 1.46 | 1.42 | 1.46 |
| (1.38-1.56) | (1.34-1.50) | (1.36-1.58) | ||||
| Omeprazole | 40 mg q.d. | 18 | | | 1.17 | 1.41 | N.A. |
| (0.96-1.43) | (1.22-1.62) | |||||
| Paroxetine | 20 mg q.d. | 16 | - | 1.05 | 1.01 | 1.07 |
| (0.96-1.15) | (0.93-1.10) | (0.98-1.17) | ||||
| Ranitidine | 150 mg b.i.d. | 18 | | | 0.94 | 0.86 | N.A. |
| (0.75-1.17) | (0.76-0.97) | |||||
| Rifabutin | 300 mg q.d. | 12 | | | 0.63 | 0.63 | 0.65 |
| (0.53-0.74) | (0.54-0.74) | (0.56-0.74) | ||||
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
| Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of INTELENCE(tm) | |||||||
| Co-administered Drug | Dose/Schedule of Co-administered Drug | N | Exposure | Mean Ratio of Co-administered Drug Pharmacokinetic Parameters 90% CI; No effect = 1.00 | |||
| C max | AUC | C min | |||||
| Co-Administration With Protease Inhibitors (PIs) | |||||||
| Atazanavir | 400 mg q.d. | 14 | | | 0.97 (0.73-1.29) | 0.83 (0.63-1.09) | 0.53 (0.38-0.73) | |
| Atazanavir/ ritonavir | 300/100 mg q.d. | 13 | | | 0.97 (0.89-1.05) | 0.86 (0.79-0.93) | 0.62 (0.55-0.71) | |
| Darunavir/ ritonavir | 600/100 mg b.i.d. | 15 | - | 1.11 (1.01-1.22) | 1.15 (1.05-1.26) | 1.02 (0.90-1.17) | |
| Fosamprenavir/ ritonavir | 700/100 mg b.i.d. | 8 | | | 1.62 (1.47-1.79) | 1.69 (1.53-1.86) | 1.77 (1.39-2.25) | |
| Lopinavir/ ritonavir (soft gel capsule) | 400/100 mg b.i.d. | 14 | | | 0.85 (0.62-1.05) | 0.80 (0.49-1.07) | 0.92 (0.15-1.68) | |
| Saquinavir/ ritonavir | 1000/100 mg b.i.d. | 15 | - | 1.00 (0.70-1.42) | 0.95 (0.64-1.42) | 0.80 (0.46-1.38) | |
| Tipranavir/ ritonavir | 500/200 mg b.i.d. | 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 q.d. | 14 | - | 0.91 (0.58-1.42) | 0.99 (0.79-1.25) | N.A. | |
| Tenofovir disoproxil fumarate | 300 mg q.d. | 19 | - | 1.15 (1.04-1.27) | 1.15 (1.09-1.21) | 1.19 (1.13-1.26) | |
| Co-Administration With Integrase Strand Transfer Inhibitors | |||||||
| Raltegravir | 400 mg b.i.d. | 19 | | | 0.89 (0.68-1.15) | 0.90 (0.68-1.18) | 0.66 (0.34-1.26) | |
| Co-Administration With Other Drugs | ||||||
| Atorvastatin 2-hydroxy- | 40 mg q.d. | 16 16 | | | | 1.04 (0.84-1.30) 1.76 | 0.63 (0.58-0.68) 1.27 | N.A. N.A. |
| atorvastatin | (1.60-1.94) | (1.19-1.36) | ||||
| Clarithromycin 14-hydroxy- | 500 mg b.i.d. | 15 15 | | | | 0.66 (0.57-0.77) 1.33 | 0.61 (0.53-0.69) 1.21 | 0.47 (0.38-0.57) 1.05 |
| clarithromycin | (1.13-1.56) | (1.05-1.39) | (0.90-1.22) | |||
| Ethinylestradiol Norethindrone | 0.035 mg q.d. 1 mg q.d. | 16 16 | | - | 1.33 (1.21-1.46) 1.05 | 1.22 (1.13-1.31) 0.95 | 1.09 (1.01-1.18) 0.78 |
| (0.98-1.12) | (0.90-0.99) | (0.68-0.90) | ||||
| R(-) Methadone | Individual dose | 16 | - | 1.02 | 1.06 | 1.10 |
| regimen ranging | (0.96-1.09) | (0.99-1.13) | (1.02-1.19) | |||
| from 60 to | ||||||
| 130 mg/day | ||||||
| S(+) Methadone | 16 | - | 0.89 | 0.89 | 0.89 | |
| (0.83-0.97) | (0.82-0.96) | (0.81-0.98) | ||||
| Paroxetine | 20 mg q.d. | 16 | - | 1.06 | 1.03 | 0.87 |
| (0.95-1.20) | (0.90-1.18) | (0.75-1.02) | ||||
| Rifabutin | 300 mg q.d. | 12 | | | 0.90 | 0.83 | 0.76 |
| (0.78-1.03) | (0.75-0.94) | (0.66-0.87) | ||||
| 25- O - | 300 mg q.d. | 12 | | | 0.85 | 0.83 | 0.78 |
| desacetylrifabutin | (0.72-1.00) | (0.74-0.92) | (0.70-0.87) | |||
| Sildenafil | 50 mg single dose | 15 | | | 0.55 | 0.43 | N.A. |
| (0.40-0.75) | (0.36-0.51) | |||||
| N-desmethyl- | 15 | | | 0.75 | 0.59 | N.A. | |
| sildenafil | (0.59-0.96) | (0.52-0.68) | ||||
| 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 | ||||||
Mechanism of Action
Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases a, b, and g.
Antiviral Activity in Cell Culture
Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC50 values ranging from 0.29 to 1.65 nM and EC50 values ranging from 11.5 to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs--the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; and the fusion inhibitor enfuvirtide (ENF).
Resistance
In Cell Culture
Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.
In Treatment-Experienced Subjects
In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 24 to the INTELENCE(tm)-containing regimen were V179F, V179I, Y181C, and Y181I which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE(tm) in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance associated substitutions which emerged on etravirine treatment in < 10% of the virologic failure isolates included K101E, K103N, V106I/M, V108I, Y188L, V189I, G190S/C and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.
Cross-Resistance
Site-Directed NNRTI Mutant Virus
Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility > 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC50 value) and Y181V (17-fold change in EC50 value). Mutant strains containing a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change > 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).
Clinical Isolates Etravirine retained a fold-change <= 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125- C206 and TMC125-C216, 35% of the baseline isolates had decreased susceptibility to etravirine (fold-change > 3) and 61%, 71%, and 79% of these isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine- containing regimen for the virologic failure isolates.
Baseline Genotype/Phenotype and Virologic Outcome Analyses
In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions V179D, V179F, V179T, Y181V, or G190S was associated with a decreased virologic response to etravirine. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE(tm) arm. Response rates to etravirine decreased as the number of baseline NNRTI mutations increased. The presence at baseline of 3 or more IAS-USA-defined NNRTI substitutions (2007) resulted in a decreased virologic response to INTELENCE(tm) (shown as the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at Week 24) (Table 8).
| Table 8: Proportion of Subjects with < 50 HIV-1 RNA copies/mL at Week 24 by Baseline Number of IAS- USA-Defined NNRTI Mutations in the As-Treated Population of Pooled TMC125-C206 and TMC125-C216 Trials | ||
| # IAS-USA-Defined NNRTI * | Etravirine Arms N = 565 | |
| Re-Used/Not Used ENF | De Novo ENF | |
| All ranges | 60% (251/420) | 70% (102/145) |
| 0 - 2 | 66% (213/322) | 76% (80/105) |
| >= 3 | 39% (38/98) | 55% (22/40) |
| Placebo Arms N = 593 | ||
| All ranges | 34% (149/434) | 62% (99/159) |
| * 2007 IAS-USA defined mutations = V90I, A98G, L100I, K101E/P, K103N, V106A/I/M, V108I, V179D/F, Y181C/I/V, Y188C/H/L, G190A/S, P225H | ||
Response rates assessed by baseline etravirine phenotype are shown in Table 9. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for INTELENCE(tm). The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment- experienced patients.
| Table 9: Proportion of Subjects with < 50 HIV-1 RNA copies/mL at Week 24 by Baseline Phenotype and ENF Use in the Pooled TMC125-C206 and TMC125-C216 Trials * | ||||
| Etravirine Fold Change | Etravirine Arms N = 561 | |||
| Re-Used/Not Used ENF | De Novo ENF | Clinical Response Range | ||
| All ranges | 60% (249/416) | 70% (102/145) | Overall Response | |
| 0 - 3 | 70% (190/273) | 82% (75/92) | Higher than Overall Response | |
| > 3 - 13 | 47% (37/78) | 50% (19/38) | Lower than Overall Response | |
| > 13 | 34% (22/65) | 53% (8/15) | Lower than Overall Response | |
| Placebo Arms N = 593 | ||||
| All ranges | 34% (149/434) | 62% (99/159) | ||
| * As-treated analysis | ||||
Carcinogenesis and Mutagenesis
Carcinogenicity studies of etravirine in rodents are ongoing. Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice. [See Nonclinical Toxicology (13.2).]
Impairment of Fertility
No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure up to the recommended human dose (400 mg/day).
Reproductive Toxicology Studies
Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1000 mg/kg/day). In both species, no treatment-related embryo-fetal effects including malformations were observed. In addition, no treatment-related effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic drug exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day).
The clinical efficacy of INTELENCE(tm) is derived from the analyses of 24-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(tm) 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 24 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(tm)-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(tm) arm and the placebo arm. Table 10 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE(tm) 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(tm) + BR N=599 | Placebo + BR N=604 | |
| Demographic Characteristics | ||
| Median Age, years (range) | 46 | 45 |
| (18-77) | (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 | 4.8 | 4.8 |
| (range), log 10 copies/mL | (2.7-6.8) | (2.2-6.5) |
| Percentage of Subjects with Baseline | 27.5% | 28.8% |
| Viral Load: | ||
| < 30,000 copies/mL | ||
| >= 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 | 99 | 109 |
| (range), cells/mm 3 | (1-789) | (0-912) |
| Percentage of Subjects with Baseline | 35.6% | 34.7% |
| CD4+ Cell Count: | ||
| < 50 cells/mm 3 | ||
| >= 50 cells/mm 3 and < 200 cells/mm 3 | 34.8% | 34.5% |
| >= 200 cells/mm 3 | 29.6% | 30.8% |
| Median (range) Number of Primary PI | 4 | 4 |
| Mutations * | (0-7) | (0-7) |
| Percentage of Subjects with Previous | 8.2% | 7.9% |
| Use of NNRTIs: | ||
| 0 | ||
| 1 | 46.9% | 46.7% |
| >1 | 44.9% | 45.4% |
| Percentage of Subjects with Previous | 70.3% | 72.5% |
| Use of the following NNRTIs: | ||
| Efavirenz | ||
| Nevirapine | 57.1% | 58.6% |
| Delavirdine | 13.7% | 12.7% |
| Median (range) Number of NNRTI | 2 | 2 |
| RAMs + | (0-5) | (0-4) |
| Median Fold Change of the Virus for | 27.4 | 26.4 |
| the Following NNRTIs: | ||
| Delavirdine | ||
| Efavirenz | 63.9 | 46.1 |
| Etravirine | 1.6 | 1.5 |
| Nevirapine | 74.3 | 74.3 |
| Percentage of Subjects with Previous | ||
| Use of Enfuvirtide | 39.6% | 41.9% |
| RAMs = Resistance-Associated Mutations, BR=background regimen FC = fold change in EC 50 * IAS-USA primary PI mutations [November 2005]: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, L90M + Tibotec NNRTI RAMs [March 2007]: A98G, L100I, K101E/P/Q, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V, Y188C/H/L, G190A/C/E/Q/S, H221Y, P225H, F227C/L, M230I/L, P236L, K238N/T, Y318F | ||
Efficacy at Week 24 for subjects in the INTELENCE(tm) 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 24 of the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis) | ||
| Pooled TMC125-C206 and TMC125-C216 Trials | ||
| INTELENCE(tm) + BR N=599 | Placebo + BR N=604 | |
| Virologic Responders at Week 24 | 358 (59.8%) | 243 (40.2%) |
| Viral Load < 50 HIV-1 RNA copies/mL | ||
| Virologic Failures (VF) at Week 24 | 190 (31.7%) | 320 (53.0%) |
| Viral Load >= 50 HIV-1 RNA copies/mL | ||
| Death * | 9 (1.5%) | 16 (2.6%) |
| Discontinuations before Week 24 + : | ||
| due to VF | 2 (0.3%) | 3 (0.5%) |
| due to Adverse Events | 28 (4.7%) | 11 (1.8%) |
| due to other reasons | 12 (2.0%) | 11 (1.8%) |
| * all deaths, including the follow-up period + all discontinuations up to and including day 154 of the treatment period BR=background regimen | ||
At Week 24, 74.0% of INTELENCE(tm)-treated subjects achieved HIV-1 RNA < 400 copies/mL as compared to 51.5% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 24 was - 2.37 log10 copies/mL for INTELENCE(tm)-treated subjects and -1.68 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE(tm)-treated subjects was 81 cells/mm3 and 64 cells/mm3 for placebo-treated subjects. Of the study population who either re-used or did not use ENF, 56.7% of INTELENCE(tm)-treated subjects and 32.7% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Of the study population using ENF de novo, 68.6% of INTELENCE(tm)-treated subjects and 61.3% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naive 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(tm) (n=59) or an investigator-selected PI (n=57), each given with 2 investigator- selected N(t)RTIs. INTELENCE(tm)-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE(tm) as compared to the control PI-treated subjects.
INTELENCE(tm) 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. INTELENCE(tm) tablets are packaged in bottles in the following configuration: 100 mg tablets--bottles of 120 (NDC 59676-570-01). Each bottle contains 3 desiccant pouches. Store INTELENCE(tm) tablets at 25degC (77degF); with excursions permitted to 15deg-30degC (59deg-86degF) [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.