Intelence®1, 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.
- 1
- Registered trademark of Tibotec Pharmaceuticals
Intelence Dosage and Administration
The recommended oral dose of Intelence® tablets is 200 mg (one 200 mg tablet or 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® tablet(s) whole may disperse the tablet(s) 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.
Dosage Forms and Strengths
Intelence® 100 mg Tablets
Intelence® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.
Intelence® 200 mg Tablets
Intelence® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side.
Contraindications
None
Warnings and Precautions
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.
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.
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.
Adverse Reactions
The following adverse reactions are described in greater detail in other sections:
- Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)].
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 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® (200 mg b.i.d.). In these pooled trials, the median exposure for subjects in the Intelence® arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the Intelence® arm and 2.6% in the placebo arm.
The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in < 0.1% of subjects during clinical development with Intelence® [see Warnings and Precautions (5.1)]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving Intelence® 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. The incidence of rash was higher in women compared to men in the Intelence® arm in the Phase 3 trials. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of Intelence®-related rash compared to patients without a history of NNRTI-related rash.
Common Adverse Reactions
Clinical ADRs of moderate intensity or greater (≥ Grade 2) and reported in ≥ 2% of subjects treated with Intelence® and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2.
| System Organ Class, Preferred Term, % | Pooled TMC125-C206 and TMC125-C216 Trials | |
|---|---|---|
| Intelence® + BR N=599 | Placebo + BR N=604 | |
| N=total number of subjects per treatment group, BR=background regimen | ||
| ||
| Nervous System Disorders | ||
| Peripheral neuropathy | 4% | 2% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 10% | 3% |
Less Common Adverse Reactions
Treatment-emergent ADRs occurring in less than 2% of subjects (n=599) receiving Intelence® 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: hemolytic anemia
Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis
Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome
Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia
Nervous System Disorders: paraesthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor
Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares
Renal and Urinary Disorders: acute renal failure
Reproductive System and Breast Disorders: gynecomastia
Respiratory,Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm
Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, 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® are presented in Table 2.
| Pooled TMC125-C206 and TMC125-C216 Trials | |||
|---|---|---|---|
| Laboratory Parameter Preferred Term, % | DAIDS Toxicity Range | Intelence® + BR N=599 | Placebo + BR N=604 |
| ULN=Upper Limit of Normal, BR=background regimen | |||
| GENERAL BIOCHEMISTRY | |||
| Pancreatic amylase | |||
| Grade 2 | > 1.5–2 × ULN | 7% | 8% |
| Grade 3 | > 2–5 × ULN | 7% | 8% |
| Grade 4 | > 5 × ULN | 2% | 1% |
| Lipase | |||
| Grade 2 | > 1.5–3 × ULN | 4% | 6% |
| Grade 3 | > 3–5 × ULN | 2% | 2% |
| Grade 4 | > 5×ULN | 1% | < 1% |
| Creatinine | |||
| Grade 2 | > 1.4–1.8 × ULN | 6% | 5% |
| Grade 3 | > 1.9–3.4 × ULN | 2% | 1% |
| Grade 4 | > 3.4 × ULN | 0% | < 1% |
| HEMATOLOGY | |||
| Decreased hemoglobin | |||
| Grade 2 | 90–99 g/L | 2% | 4% |
| Grade 3 | 70–89 g/L | < 1% | < 1% |
| Grade 4 | < 70 g/L | < 1% | < 1% |
| White blood cell count | |||
| Grade 2 | 1,500–1,999/mm3 | 2% | 3% |
| Grade 3 | 1,000–1,499/mm3 | 1% | 4% |
| Grade 4 | < 1,000/mm3 | 1% | < 1% |
| Neutrophils | |||
| Grade 2 | 750–999/mm3 | 5% | 6% |
| Grade 3 | 500–749/mm3 | 4% | 4% |
| Grade 4 | < 500/mm3 | 2% | 3% |
| Platelet count | |||
| Grade 2 | 50,000–99,999/mm3 | 3% | 5% |
| Grade 3 | 25,000–49,999/mm3 | 1% | 1% |
| Grade 4 | < 25,000/mm3 | < 1% | < 1% |
| LIPIDS AND GLUCOSE | |||
| Total cholesterol | |||
| Grade 2 | > 6.20–7.77 mmol/L 240–300 mg/dL | 20% | 17% |
| Grade 3 | > 7.77 mmol/L > 300 mg/dL | 8% | 5% |
| Low density lipoprotein | |||
| Grade 2 | 4.13–4.9 mmol/L 160–190 mg/dL | 13% | 12% |
| Grade 3 | > 4.9 mmol/L > 190 mg/dL | 7% | 7% |
| Triglycerides | |||
| Grade 2 | 5.65–8.48 mmol/L 500 –750 mg/dL | 9% | 7% |
| Grade 3 | 8.49–13.56 mmol/L 751 – 1200 mg/dL | 6% | 4% |
| Grade 4 | > 13.56 mmol/L > 1200 mg/dL | 4% | 2% |
| Elevated glucose levels | |||
| Grade 2 | 6.95–13.88 mmol/L 161–250 mg/dL | 15% | 13% |
| Grade 3 | 13.89–27.75 mmol/L 251 – 500 mg/dL | 4% | 2% |
| Grade 4 | > 27.75 mmol/L > 500 mg/dL | 0% | < 1% |
| HEPATIC PARAMETERS | |||
| Alanine amino transferase | |||
| Grade 2 | 2.6–5 × ULN | 6% | 5% |
| Grade 3 | 5.1–10 × ULN | 3% | 2% |
| Grade 4 | > 10 × ULN | 1% | < 1% |
| Aspartate amino transferase | |||
| Grade 2 | 2.6–5 × ULN | 6% | 8% |
| Grade 3 | 5.1–10 × ULN | 3% | 2% |
| Grade 4 | > 10 × ULN | < 1% | < 1% |
Patients co-infected with hepatitis B and/or hepatitis C virus
In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 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 27.8%, 25.0% and 7.1% respectively, of Intelence®-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected Intelence®-treated subjects. In general, adverse events reported by Intelence®-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to Intelence®-treated subjects without hepatitis B and/or hepatitis C virus co-infection.
Postmarketing Experience
The following events have been identified during postmarketing use of Intelence®. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: Severe hypersensitivity reactions including cases of hepatic failure have been reported [see Warnings and Precautions (5.1)].
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis have been reported [see Warnings and Precautions (5.1)].
Drug Interactions
Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of Intelence® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of Intelence® (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.
| 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* 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 Cmin 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*† | ↔ 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/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone*, methadone* | ↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone | Intelence® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. 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*, tadalafil, vardenafil | ↓ 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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
No adequate and well-controlled studies of Intelence® 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® 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®, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
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®.
Pediatric use
Safety and effectiveness in pediatric patients have not been established.
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.
Hepatic Impairment
No dose adjustment of Intelence® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of Intelence® have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C).
Renal Impairment
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.
Overdosage
There is no specific antidote for overdose with Intelence®. Human experience of overdose with Intelence® is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with Intelence® consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. 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 Description
Intelence® (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).
The chemical name for etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O 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® 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloida
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