There are no data with regard to symptomatic overdose with Интеленс, but it is possible that the most frequent ADRs of Интеленс, i.e. rash, diarrhoea, nausea, and headache would be the most common symptoms noted. There is no specific antidote for overdose with Интеленс. Treatment of overdose with Интеленс consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.
Co-administration with elbasvir/grazoprevir.
Not applicable.
Summary of the safety profile
The safety assessment is based on all data from 1,203 patients in the Phase III placebo-controlled trials DUET-1 and DUET-2 in antiretroviral treatment-experienced HIV-1 infected adult patients, 599 of whom received Интеленс (200 mg b.i.d.). In these pooled trials, the median exposure for patients in the Интеленс arm was 52.3 weeks.
The most frequently reported adverse drug reactions (ADRs) (incidence > 10% in the Интеленс arm) of all intensities occurring in the Phase III studies were rash (19.2% in the Интеленс arm versus 10.9% in the placebo arm), diarrhoea (18.0% in the Интеленс arm versus 23.5% in the placebo arm), nausea (14.9% in the Интеленс arm versus 12.7% in the placebo arm) and headache (10.9% in the Интеленс arm versus 12.7% in the placebo arm). The rates of discontinuation due to any adverse reaction were 7.2% in patients receiving Интеленс and 5.6% in patients receiving placebo. The most common ADR leading to discontinuation was rash (2.2% in the Интеленс arm versus 0% in the placebo arm).
Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the second week of therapy, and was infrequent after week 4. Rash was mostly self-limiting, and generally resolved within 1-2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the Интеленс arm in the DUET trials (rash > grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men). There was no gender difference in severity or treatment discontinuation due to rash. The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reaction cannot be excluded.
Tabulated list of adverse reactions
ADRs of moderate intensity or greater (> grade 2) reported in patients treated with Интеленс are summarised in table 2 (background regimen is indicated as “BRâ€). Laboratory abnormalities considered ADRs are included in a paragraph below table 2. The ADRs are listed by system organ class (SOC) and frequency. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10) and uncommon (> 1/1,000 to < 1/100). Rare and very rare ADRs cannot be detected based on the number of patients included in the DUET trials.
| Table 2: DUET-1 and DUET-2 trials | ||
| System Organ Class (SOC) | Frequency Category | ADRs (Интеленс + BR versus Placebo + BR) |
| Blood and lymphatic system disorders | common | thrombocytopaenia (1.3% vs 1.5%), anaemia (4.0% vs 3.8%) |
| Immune system disorders | uncommon | immune reconstitution syndrome (0.2% vs 0.3%), drug hypersensitivity (0.8% vs 1.2%) |
| Metabolism and nutrition disorders | common | diabetes mellitus (1.3% vs 0.2%), hyperglycaemia (1.5% vs 0.7%), hypercholesterolaemia (4.3% vs 3.6%), hypertriglyceridaemia (6.3% vs 4.3%), hyperlipidaemia (2.5% vs 1.3%) |
| uncommon | anorexia (0.8% vs 1.5%), dyslipidaemia (0.8% vs 0.3%) | |
| Psychiatric disorders | common | anxiety (1.7% vs 2.6%), insomnia (2.7% vs 2.8%) |
| uncommon | confusional state (0.2% vs 0.2%), disorientation (0.2% vs 0.3%), nightmares (0.2% vs 0.2%), sleep disorders (0.5% vs 0.5%), nervousness (0.2% vs 0.3%), abnormal dreams (0.2% vs 0.2%) | |
| Nervous system disorders | common | peripheral neuropathy (3.8% vs 2.0%), headache (3.0% vs 4.5%) |
| uncommon | convulsion (0.5% vs 0.7%), syncope (0.3% vs 0.3%), amnesia (0.3% vs 0.5%), tremor (0.2% vs 0.3%), somnolence (0.7% vs 0.5%), paraesthesia (0.7% vs 0.7%), hypoaesthesia (0.5% vs 0.2%), hypersomnia (0.2% vs 0%), disturbance in attention (0.2% vs 0.2%) | |
| Eye disorders | uncommon | blurred vision (0.7% vs 0%) |
| Ear and labyrinth disorders | uncommon | vertigo (0.2% vs 0.5%) |
| Cardiac disorders | common | myocardial infarction (1.3% vs 0.3%) |
| uncommon | atrial fibrillation (0.2% vs 0.2%), angina pectoris (0.5% vs 0.3%) | |
| Vascular disorders | common | hypertension (3.2% vs 2.5%) |
| Respiratory, thoracic and mediastinal disorders | uncommon | bronchospasm (0.2% vs 0%), exertional dyspnoea (0.5% vs 0.5%) |
| Gastrointestinal disorders | common | gastrooesophageal reflux disease (1.8% vs 1.0%), diarrhoea (7.0% vs 11.3%), vomiting (2.8% vs 2.8%), nausea (5.2% vs 4.8%), abdominal pain (3.5% vs 3.1%), flatulence (1.5% vs 1.0%), gastritis (1.5% vs 1.0%) |
| uncommon | pancreatitis (0.7% vs 0.3%), haematemesis (0.2% vs 0%), stomatitis (0.2% vs 0.2%), constipation (0.3% vs 0.5%), abdominal distension (0.7% vs 1.0%), dry mouth (0.3% vs 0%), retching (0.2% vs 0%) | |
| Hepatobiliary disorders | uncommon | hepatitis (0.2% vs 0.3%), hepatic steatosis (0.3% vs 0%), cytolytic hepatitis (0.3% vs 0%), hepatomegaly (0.5% vs 0.2%) |
| Skin and subcutaneous tissue disorders | very common | rash (10.0% vs 3.5%) |
| common | night sweats (1.0% vs 1.0%) | |
| uncommon | swelling face (0.3% vs 0%), hyperhidrosis (0.5% vs 0.2%), prurigo (0.7% vs 0.5%), dry skin (0.3% vs 0.2%) | |
| Renal and urinary disorders | common | renal failure (2.7% vs 2.0%) |
| Reproductive system and breast disorders | uncommon | gynaecomastia (0.2% vs 0%) |
| General disorders and administration site conditions | common | fatigue (3.5% vs 4.6%) |
| uncommon | sluggishness (0.2% vs 0%) | |
Additional ADRs of at least moderate intensity observed in other trials were angioneurotic oedema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of patients. Stevens-Johnson Syndrome (rare; < 0.1%) and toxic epidermal necrolysis (very rare; < 0.01%) have been reported during clinical development with Интеленс.
Laboratory abnormalities
Treatment emergent clinical laboratory abnormalities (grade 3 or 4), considered ADRs, reported in > 2% of patients in the Интеленс arm versus the placebo arm, respectively, were increases in amylase (8.9% vs 9.4%), creatinine (2.0% vs 1.7%), lipase (3.4% vs 2.6%), total cholesterol (8.1% vs 5.3%), low density lipoprotein (LDL) (7.2% vs 6.6%), triglycerides (9.2% vs 5.8%), glucose (3.5% vs 2.4%), alanine aminotransferase (ALT) (3.7% vs 2.0%), aspartate amino transferase (AST) (3.2% vs 2.0%) and decreases in neutrophils (5.0% vs 7.4%) and white blood cell count (2.0% vs 4.3%).
Description of selected adverse reactions
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy
Immune reconstitution syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy. The frequency of this is unknown.
Paediatric population (6 years to less than 18 years of age)
The safety assessment in children and adolescents is based on the week 48 analysis of the single-arm, Phase II PIANO trial in which 101 antiretroviral treatment-experienced HIV-1 infected paediatric patients, 6 years to less than 18 years of age and weighing at least 16 kg, received Интеленс in combination with other antiretroviral agents. The frequency, type and severity of adverse drug reactions in paediatric patients were comparable to those observed in adults. Rash was reported more frequently in female subjects than in male subjects (rash > grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Most often, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was mostly self-limiting and generally resolved within 1 week on continued therapy.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
In the pooled analysis for DUET-1 and DUET-2, the incidence of hepatic events tended to be higher in co-infected subjects treated with Интеленс compared to co-infected subjects in the placebo group.2).
Adverse drug reactions identified through post marketing experience with Интеленс
Hypersensitivity reactions, including DRESS, have been reported with Интеленс. These hypersensitivity reactions were characterised by rash, fever and sometimes organ involvement (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and eosinophilia).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via
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HPRA Pharmacovigilance
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Animal toxicology studies have been conducted with etravirine in mice, rats, rabbits and dogs. In mice, the key target organs identified were the liver and the coagulation system. Haemorrhagic cardiomyopathy was only observed in male mice and was considered to be secondary to severe coagulopathy mediated via the vitamin K pathway. In the rat, the key target organs identified were the liver, the thyroid and the coagulation system. Exposure in mice was equivalent to human exposure while in rats it was below the clinical exposure at the recommended dose. In the dog, changes were observed in the liver and gall bladder at exposures approximately 8-fold higher than human exposure observed at the recommended dose (200 mg b.i.d.).
In a study conducted in rats, there were no effects on mating or fertility at exposure levels equivalent to those in humans at the clinically recommended dose. There was no teratogenicity with etravirine in rats and rabbits at exposures equivalent to those observed in humans at the recommended clinical dose. Etravirine had no effect on offspring development during lactation or post weaning at maternal exposures equivalent to those observed at the recommended clinical dose.
Etravirine was not carcinogenic in rats and in male mice. An increase in the incidences of hepatocellular adenomas and carcinomas were observed in female mice. The observed hepatocellular findings in female mice are generally considered to be rodent specific, associated with liver enzyme induction, and of limited relevance to humans. At the highest tested doses, the systemic exposures (based on AUC) to etravirine were 0.6-fold (mice) and between 0.2- and 0.7-fold (rats), relative to those observed in humans at the recommended therapeutic dose (200 mg b.i.d.).
In vitro and in vivo studies with etravirine revealed no evidence of a mutagenic potential.
Интеленс, in combination with a boosted protease inhibitor and other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients and in antiretroviral treatment-experienced paediatric patients from 6 years of age.
The indication in adults is based on week 48 analyses from 2 Phase III trials in highly pre-treated patients where Интеленс was investigated in combination with an optimised background regimen (OBR) which included darunavir/ritonavir. The indication in paediatric patients is based on 48-week analyses of a single-arm, Phase II trial in antiretroviral treatment-experienced paediatric patients.
Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors, ATC code: J05AG04.
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.
Antiviral activity in vitro
Etravirine exhibits activity against wild type HIV-1 in T-cell lines and primary cells with median EC50 values ranging from 0.9 to 5.5 nM. Etravirine demonstrates activity against HIV-1 group M (subtypes A, B, C, D, E, F, and G) and HIV-1 group O primary isolates with EC50 values ranging from 0.3 to 1.7 nM and from 11.5 to 21.7 nM, respectively. Although etravirine demonstrates in vitro activity against wild type HIV-2 with median EC50 values ranging from 5.7 to 7.2 µM, treatment of HIV-2 infection with etravirine is not recommended in the absence of clinical data. Etravirine retains activity against HIV-1 viral strains resistant to nucleoside reverse transcriptase and/or protease inhibitors. In addition, etravirine demonstrates a fold change (FC) in EC50 ≤ 3 against 60% of 6,171 NNRTI-resistant clinical isolates.
Resistance
Etravirine efficacy in relation to NNRTI resistance at baseline has mainly been analysed with etravirine given in combination with darunavir/ritonavir (DUET-1 and DUET-2). Boosted protease inhibitors, like darunavir/ritonavir, show a higher barrier to resistance compared to other classes of antiretrovirals. The breakpoints for reduced efficacy with etravirine (> 2 etravirine-associated mutations at baseline, see clinical results section) applies when etravirine is given in combination with a boosted protease inhibitor. This breakpoint might be lower in antiretroviral combination therapy not including a boosted protease inhibitor.
In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in patients with virologic failure to the Интеленс containing regimen were V108I, V179F, V179I, Y181C and Y181I, which usually emerged in a background of multiple other NNRTI resistance-associated mutations (RAMs). In all the other trials conducted with Интеленс in HIV-1 infected patients, the following mutations emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y.
Cross-resistance
Following virologic failure of an etravirine-containing regimen it is not recommended to treat patients with efavirenz and/or nevirapine.
Clinical efficacy and safety
Treatment-experienced adult patients
Pivotal studies
The evidence of efficacy of Интеленс is based on 48-week data from 2 Phase III trials DUET-1 and DUET-2. These trials were identical in design and similar efficacy for Интеленс was seen in each trial. The results below are pooled data from the two trials.
Trial characteristics
- Design: randomised (1:1), double-blinded, placebo-controlled.
- Treatment: Интеленс vs. placebo, in addition to a background regimen including darunavir/ritonavir (DRV/rtv), investigator-selected N(t)RTIs and optional enfuvirtide (ENF).
- Main inclusion criteria:
- HIV-1 plasma viral load > 5,000 HIV-1 RNA copies/ml at screening
- 1 or more NNRTI resistance-associated mutations (RAMs) at screening or from prior genotypic analysis (i.e., archived resistance)
- 3 or more primary PI mutations at screening
- on a stable antiretroviral regimen for at least 8 weeks.
- Stratification: Randomisation was stratified by the intended use of ENF in the BR, previous use of darunavir and screening viral load.
- Virologic response was defined as achieving a confirmed undetectable viral load (< 50 HIV-1 RNA copies/ml).
Summary of efficacy results
| Table 3: DUET-1 and DUET-2 pooled 48-week data | |||
|
| Интеленс + BR N = 599 | Placebo + BR N = 604 | Treatment difference (95% CI) |
| Baseline characteristics | |||
| Median plasma HIV-1 RNA | 4.8 log10 copies/ml | 4.8 log10 copies/ml |
|
| Median CD4 cell count | 99 x 106 cells/l | 109 x 106 cells/l |
|
| Outcomes | |||
| Confirmed undetectable viral load (< 50 HIV-1 RNA copies/ml)a n (%) | |||
| Overall | 363 (60.6%) | 240 (39.7%) | 20.9% (15.3%; 26.4%)d |
| De novo ENF | 109 (71.2%) | 93 (58.5%) | 12.8% (2.3%; 23.2%)f |
| Not de novo ENF | 254 (57.0%) | 147 (33.0%) | 23.9% (17.6%; 30.3%)f |
| < 400 HIV-1 RNA copies/mla n (%) | 428 (71.5%) | 286 (47.4%) | 24.1% (18.7%; 29.5%)d |
| HIV-1 RNA log10 mean change from baseline (log10 copies/ml)b | -2.25 | -1.49 | -0.6 (-0.8; -0.5)c |
| CD4 cell count mean change from baseline (x 106/l)b | +98.2 | +72.9 | 24.4 (10.4; 38.5)c |
| Any AIDS defining illness and/or death n (%) | 35 (5.8%) | 59 (9.8%) | -3.9% (-6.9%; -0.9%)e |
| a Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response). b Non-completer is failure (NC = F) imputation. c Treatment differences are based on Least Square Means from an ANCOVA model including the stratification factors. P-value < 0.0001 for mean decrease in HIV-1 RNA; P-value = 0.0006 for mean change in CD4 cell count. d Confidence interval around observed difference of response rates; P-value < 0.0001 from logistic regression model, including stratification factors. e Confidence interval around observed difference of response rates; P-value = 0.0408. f Confidence interval around observed difference of response rates; P-value from CMH test controlling for stratification factors = 0.0199 for de novo, and < 0.0001 for not de novo. | |||
Since there was a significant interaction effect between treatment and ENF, the primary analysis was done for 2 ENF strata (patients reusing or not using ENF versus patients using ENF de novo). The week 48 results from the pooled analysis of DUET-1 and DUET-2 demonstrated that the Интеленс arm was superior to the placebo arm irrespective of whether ENF was used de novo (p = 0.0199) or not (p < 0.0001). Results of this analysis (week 48 data) by ENF stratum are shown in table 3.
Significantly fewer patients in the Интеленс arm reached a clinical endpoint (AIDS-defining illness and/or death) as compared to the placebo arm (p = 0.0408).
A subgroup analysis of the virologic response (defined as a viral load < 50 HIV-1 RNA copies/ml) at week 48 by baseline viral load and baseline CD4 count (pooled DUET data) is presented in table 4.
| Table 4: DUET-1 and DUET-2 pooled data | ||
| Subgroups | Proportion of subjects with HIV-1 RNA < 50 copies/ml at week 48 | |
| Интеленс + BR N = 599 | Placebo + BR N = 604 | |
| Baseline HIV-1 RNA < 30,000 copies/ml > 30,000 and < 100,000 copies/ml > 100,000 copies/ml |
75.8% 61.2% 49.1% |
55.7% 38.5% 28.1% |
| Baseline CD4 count (x 106/l) < 50 > 50 and < 200 > 200 and < 350 > 350 |
45.1% 65.4% 73.9% 72.4% |
21.5% 47.6% 52.0% 50.8% |
| Note: Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response) | ||
Baseline genotype or phenotype and virologic outcome analyses
In DUET-1 and DUET-2, the presence at baseline of 3 or more of the following mutations: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S, (Интеленс RAMs) was associated with a decreased virologic response to Интеленс (see table 5). These individual mutations occurred in the presence of other NNRTI RAMs. V179F was never present without Y181C.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
| Table 5: Proportion of subjects with < 50 HIV-1 RNA copies/ml at week 48 by baseline number of Интеленс RAMs in the non-viral failure excluded population of pooled DUET-1 and DUET-2 trials | ||
| Baseline number of Интеленс RAMs* | Etravirine arms N = 549 | |
|
| Reused/not used ENF | De novo ENF |
| All ranges | 63.3% (254/401) | 78.4% (109/139) |
| 0 | 74.1% (117/158) | 91.3% (42/46) |
| 1 | 61.3% (73/119) | 80.4% (41/51) |
| 2 | 64.1% (41/64) | 66.7% (18/27) |
| > 3 | 38.3% (23/60) | 53.3% (8/15) |
| Placebo arms N = 569 | ||
| All ranges | 37.1% (147/396) | 64.1% (93/145) |
| * Интеленс RAMs = V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S Note: all patients in the DUET trials received a background regimen consisting of darunavir/rtv, investigator-selected NRTIs and optional enfuvirtide. | ||
The presence of K103N alone, which was the most prevalent NNRTI mutation in DUET-1 and DUET-2 at baseline, was not identified as a mutation associated with resistance to Интеленс. Furthermore, the presence of this mutation alone did not affect the response in the Интеленс arm. Additional data is required to conclude on the influence of K103N when associated with other NNRTIs mutations.
Data from the DUET studies suggest that baseline fold change (FC) in EC50 to etravirine was a predictive factor of virologic outcome, with gradually decreasing responses observed above FC 3 and FC 13.
FC subgroups are based on the select patient populations in DUET-1 and DUET-2 and are not meant to represent definitive clinical susceptibility breakpoints for Интеленс.
Exploratory head to head comparison with protease inhibitor in protease inhibitor naïve patients (trial TMC125-C227)
TMC125-C227 was an exploratory, randomised, active-controlled open-label trial, which investigated the efficacy and safety of Интеленс in a treatment regimen, which is not approved under the current indication. In the TMC125-C227 study, Интеленс (N = 59) was administered with 2 investigator-selected NRTIs (i.e. without a ritonavir-boosted PI) and compared to an investigator-selected combination of a PI with 2 NRTIs (N = 57). The trial population included PI-naïve, NNRTI-experienced patients with evidence of NNRTI resistance.
At week 12, virologic response was greater in the control-PI arm (-2.2 log10 copies/ml from baseline; n = 53) compared to the Интеленс arm (-1.4 log10 copies/ml from baseline; n = 40). This difference between treatment arms was statistically significant.
Based on these trial results, Интеленс is not recommended for use in combination with N(t)RTIs only in patients who have experienced virological failure on an NNRTI- and N(t)RTI-containing regimen.
Paediatric population
Treatment-experienced paediatric patients (6 years to less than 18 years of age)
PIANO is a single-arm, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of Интеленс in 101 antiretroviral treatment-experienced HIV-1 infected paediatric patients 6 years to less than 18 years of age and weighing at least 16 kg. The study enrolled patients on a stable but virologically failing antiretroviral treatment regimen, with a confirmed HIV-1 RNA plasma viral load > 500 copies/ml. Sensitivity of the virus to Интеленс at screening was required.
The median baseline plasma HIV-1 RNA was 3.9 log10 copies/ml, and the median baseline CD4 cell count was 385 x 106 cells/l.
| Table 6: Virologic responses (ITT - TLOVR), change from baseline in log10 viral load (NC = F), and change from baseline in CD4 percentage and cell count (NC = F) at week 24 in the TMC125-C213 and pooled DUET studies | ||||
| Study Age at screening Treatment group |
TMC125-C213 6 to < 12 years ETR N = 41 |
TMC125-C213 12 to < 18 years ETR N = 60 |
TMC125-C213 6 to < 18 years ETR N = 101 | Pooled DUET Studies > 18 years ETR N = 599 |
| Virologic parameters | ||||
| Viral load < 50 copies/ml at week 24, n (%) | 24 (58.5) | 28 (46.7) | 52 (51.5) | 363 (60.6) |
| Viral load < 400 copies/ml at week 24, n (%) | 28 (68.3) | 38 (63.3) | 66 (65.3) | 445 (74.3) |
| > 1 log10 decrease from baseline at week 24, n (%) | 26 (63.4) | 38 (63.3) | 64 (63.4) | 475 (79.3) |
| Change from baseline in log10 viral load (copies/ml) at week 24, mean (SE) and median (range) | -1.62 (0.21) -1.68 (-4.3; 0.9) | -1.44 (0.17) -1.68 (-4.0; 0.7) | -1.51 (0.13) -1.68 (-4.3; 0.9) | -2.37 (0.05) -2.78 (-4.6; 1.4) |
| Immunologic parameters | ||||
| Change from baseline in CD4 cell count (x 106 cells/l), mean (SE) and median (range) | 125 (33.0) 124 (-410; 718) | 104 (17.5) 81 (-243; 472) | 112 (16.9) 108 (-410; 718) | 83.5 (3.64) 77.5 (-331; 517) |
| Change from baseline in CD4 percentage, median (range) | 4% (-9; 20) | 3% (-4; 14) | 4% (-9; 20) | 3% (-7; 23) |
| N = number of subjects with data; n = number of observations. | ||||
At week 48, 53.5% of all paediatric patients had a confirmed undetectable viral load < 50 HIV-1 RNA copies/ml according to the TLOVR algorithm. The proportion of paediatric patients with < 400 HIV-1 RNA copies/ml was 63.4%. The mean change in plasma HIV-1 RNA from baseline to week 48 was -1.53 log10 copies/ml, and the mean CD4 cell count increase from baseline was 156 x 106 cells/l.
Pregnancy and postpartum
Интеленс (200 mg b.i.d.), evaluated in combination with other antiretroviral medicinal products in a study of 15 pregnant women during the second and third trimesters of pregnancy and postpartum, demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum, and less so for unbound etravirine exposure. There were no new clinically relevant safety findings in the mothers or in the newborns in this trial.
The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult and paediatric treatment-experienced HIV-1 infected patients. Exposure to etravirine was lower (35-50%) in HIV-1 infected patients than in healthy subjects.
| Table 7: Population pharmacokinetic estimates of etravirine 200 mg b.i.d. in HIV-1 infected adult subjects (integrated data from Phase III trials at week 48)* | |
| Parameter | Etravirine 200 mg b.i.d. N = 575 |
| AUC12h (ng-h/ml) |
|
| Geometric Mean ± Standard Deviation | 4,522 ± 4,710 |
| Median (Range) | 4,380 (458 - 59,084) |
| C0h (ng/ml) |
|
| Geometric Mean ± Standard Deviation | 297 ± 391 |
| Median (Range) | 298 (2 - 4,852) |
| * All HIV-1 infected subjects enrolled in Phase III clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in the table account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of Интеленс with darunavir/ritonavir. Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro = 4 ng/ml. | |
Absorption
An intravenous formulation of etravirine is unavailable, thus, the absolute bioavailability of etravirine is unknown. After oral administration with food, the maximum plasma concentration of etravirine is generally achieved within 4 hours.
In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, medicinal products that are known to increase gastric pH.
Effect of food on absorption
The systemic exposure (AUC) to etravirine was decreased by about 50% when Интеленс was administered under fasting conditions, as compared to administration following a meal. Therefore, Интеленс should be taken following a meal.
Distribution
Etravirine is approximately 99.9% bound to plasma proteins, primarily to albumin (99.6%) and α1-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.
Biotransformation
In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes oxidative metabolism by the hepatic cytochrome CYP450 (CYP3A) system and, to a lesser extent, by the CYP2C family, followed by glucuronidation.
Elimination
After administration of a radiolabeled 14C-etravirine dose, 93.7% and 1.2% of the administered dose of 14C-etravirine could be retrieved in faeces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in faeces. Unchanged etravirine in faeces is likely to be unabsorbed drug. Unchanged etravirine was not detected in urine. The terminal elimination half-life of etravirine was approximately 30-40 hours.
Special populations
Paediatric population (6 years to less than 18 years of age)
The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1 infected paediatric patients, 6 years to less than 18 years of age and weighing at least 16 kg, showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving Интеленс 200 mg b.i.d. when administered at a dose corresponding to 5.2 mg/kg b.i.d. The population pharmacokinetic estimates for etravirine AUC12h and C0h are summarised in the table below.
| Table 8: Population pharmacokinetic estimates for etravirine (all doses combined) in treatment-experienced HIV-1 infected paediatric patients 6 years to less than 18 years of age (PIANO 48 week analysis) | |
| Parameter | Etravirine N = 101 |
| AUC12h (ng-h/ml) |
|
| Geometric Mean ± Standard Deviation | 3,729 ± 4,305 |
| Median (Range) | 4,560 (62 - 28,865) |
| C0h (ng/ml) |
|
| Geometric Mean ± Standard Deviation | 205 ± 342 |
| Median (Range) | 287 (2 - 2,276) |
Paediatric population (less than 6 years of age)
The pharmacokinetics of etravirine in paediatric patients less than 6 years of age are under investigation. There are insufficient data at this time to recommend a dose in paediatric patients less than 6 years of age or weighing less than 16 kg.
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that etravirine pharmacokinetics are not considerably different in the age range (18 to 77 years) evaluated, with 6 subjects aged 65 years or older.
Gender
No significant pharmacokinetic differences have been observed between males and females. A limited number of females were included in the studies.
Race
Population pharmacokinetic analysis of etravirine in HIV infected patients indicated no apparent difference in the exposure to etravirine between Caucasian, Hispanic and Black subjects. The pharmacokinetics in other races have not been sufficiently evaluated.
Hepatic impairment
Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild (Child-Pugh Class A) hepatic impairment to 8 matched controls and 8 patients with moderate (Child-Pugh Class B) hepatic impairment to 8 matched controls, the multiple dose pharmacokinetic disposition of etravirine was not altered in patients with mild to moderate hepatic impairment. However, unbound concentrations have not been assessed. Increased unbound exposure could be expected. No dose adjustment is suggested but caution is adviced in patients with moderate hepatic impairment. Интеленс has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is therefore not recommended.
Hepatitis B and/or hepatitis C virus co-infection
Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance (potentially leading to increased exposure and alteration of the safety profile) for Интеленс in HIV-1 infected patients with hepatitis B and/or hepatitis C virus co-infection. In view of the limited data available in hepatitis B and/or C co-infected patients, particular caution should be paid when Интеленс is used in these patients.
Renal impairment
The pharmacokinetics of etravirine have not been studied in patients with renal insufficiency. Results from a mass balance study with radioactive 14C-etravirine showed that < 1.2% of the administered dose of etravirine is excreted in the urine. No unchanged drug was detected in urine so the impact of renal impairment on etravirine elimination is expected to be minimal. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.
Pregnancy and postpartum
Study TMC114HIV3015 evaluated etravirine 200 mg b.i.d. in combination with other antiretroviral medicinal products in 15 pregnant women during the second and third trimesters of pregnancy and postpartum. The total etravirine exposure after intake of etravirine 200 mg b.i.d. as part of an antiretroviral regimen was generally higher during pregnancy compared with postpartum (see Table 9). The differences were less pronounced for unbound etravirine exposure.
In women receiving etravirine 200 mg b.i.d., higher mean values for Cmax, AUC12h and Cmin were observed during pregnancy compared to postpartum. During the 2nd and 3rd trimester of pregnancy mean values of these parameters were comparable.
| Table 9: Pharmacokinetic results of total etravirine after administration of etravirine 200 mg b.i.d. as part of an antiretroviral regimen, during the 2nd trimester of pregnancy, the 3rd trimester of pregnancy, and postpartum. | |||
| Pharmacokinetics of etravirine Mean ± SD (median) | Etravirine 200 mg b.i.d. postpartum N = 10 | Etravirine 200 mg b.i.d. 2nd trimester N = 13 | Etravirine 200 mg b.i.d. 3rd trimester N = 10a |
| Cmin, ng/mL | 269 ± 182 (284) | 383 ± 210 (346) | 349 ± 103 (371) |
| Cmax, ng/mL AUC12h, h*ng /mL | 569 ± 261 (528) 5004 ± 2521 (5246) | 774 ± 300 (828) 6617 ± 2766 (6836) | 785 ± 238 (694) 6846 ± 1482 (6028) |
| a n = 9 for AUC12h | |||
Each subject served as her own control, and with an intra-individual comparison, the total etravirine Cmin, Cmax and AUC12h values were 1.2-, 1.4- and 1.4-fold higher, respectively, during the 2nd trimester of pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based during the 3rd trimester of pregnancy as compared to postpartum.
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Интеленс should optimally be combined with other antiretrovirals that exhibit activity against the patient's virus.
A decreased virologic response to etravirine was observed in patients with viral strains harbouring 3 or more among the following mutations V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
No data other than drug-drug interaction data are available when etravirine is combined with raltegravir or maraviroc.
Severe cutaneous and hypersensitivity reactions
Severe cutaneous adverse drug reactions have been reported with Интеленс; Stevens-Johnson Syndrome and erythema multiforme have been rarely (< 0.1%) reported. Treatment with Интеленс should be discontinued if a severe cutaneous reaction develops.
The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reactions cannot be excluded. Caution should be observed in such patients, especially in case of history of a severe cutaneous drug reaction.
Cases of severe hypersensitivity syndromes, including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and TEN (toxic epidermal necrolysis), sometimes fatal, have been reported with the use of Интеленс. The DRESS syndrome is characterised by rash, fever, eosinophilia and systemic involvement (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and eosinophilia). Time to onset is usually around 3-6 weeks and the outcome in most cases is favourable upon discontinuation and after initiation of corticosteroid therapy.
Patients should be informed to seek medical advice if severe rash or hypersensitivity reactions occur. Patients who are diagnosed with a hypersensitivity reaction whilst on therapy must discontinue Интеленс immediately.
Delay in stopping Интеленс treatment after the onset of severe rash may result in a life-threatening reaction.
Patients who have stopped treatment due to hypersensitivity reactions should not restart therapy with Интеленс.
Rash
Rash has been reported with Интеленс. Most frequently, rash was mild to moderate, occurred in the second week of therapy, and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1 to 2 weeks on continued therapy. When prescribing Интеленс to females, prescribers should be aware that the incidence of rash was higher in females.
Elderly
Experience in geriatric patients is limited: in the Phase III trials, 6 patients aged 65 years or older and 53 patients aged 56-64 years received Интеленс. The type and incidence of adverse reactions in patients > 55 years of age were similar to the ones in younger patients.
Pregnancy
Given the increased etravirine exposure during pregnancy, caution should be applied for those pregnant patients that require concomitant medications or have comorbidities that may further increase etravirine exposure.
Patients with coexisting conditions
Hepatic impairment
Etravirine is primarily metabolised and eliminated by the liver and highly bound to plasma proteins. Effects on unbound exposure could be expected (has not been studied) and therefore caution is advised in patients with moderate hepatic impairment. Интеленс has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and its use is therefore not recommended in this group of patients.
Co-infection with HBV (hepatitis B virus) or HCV (hepatitis C virus)
Caution should be exercised in patients co-infected with hepatitis B or C virus due to the current limited data available. A potential increased risk of liver enzymes increase cannot be excluded.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Immune reconstitution syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Interactions with medicinal products
It is not recommended to combine etravirine with tipranavir/ritonavir, due to a marked pharmacokinetic interaction (76% decrease of etravirine AUC) that could significantly impair the virologic response to etravirine.
The combination of etravirine with simeprevir, daclatasvir, atazanavir/cobicistat or darunavir/cobicistat is not recommended.
Lactose intolerance and lactase deficiency
Интеленс 25 mg tablets
Each tablet contains 40 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Интеленс 100 mg tablets
Each tablet contains 160 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Интеленс has no or negligible influence on the ability to drive and use machines. Adverse drug reactions such as somnolence and vertigo have been reported in Интеленс treated subjects at incidences similar to placebo. There is no evidence that Интеленс may alter the patient's ability to drive and operate machines, however, the adverse drug reaction profile should be taken into account.
Therapy should be initiated by a physician experienced in the management of HIV infection.
Интеленс must always be given in combination with other antiretroviral medicinal products.
Posology
Adults
The recommended dose of Интеленс for adults is 200 mg (two 100 mg tablets) taken orally twice daily (b.i.d.), following a meal.
Paediatric population (6 years to less than 18 years of age)
The recommended dose of Интеленс for paediatric patients (6 years to less than 18 years of age and weighing at least 16 kg) is based on body weight (see table below). Интеленс tablet(s) should be taken orally, following a meal.
| Recommended dose of Интеленс for paediatric patients 6 years to less than 18 years of age | ||
| Body weight | Dose | Tablets |
| > 16 to < 20 kg | 100 mg b.i.d. | four 25 mg tablets twice daily or one 100 mg tablet twice daily |
| > 20 to < 25 kg | 125 mg b.i.d. | five 25 mg tablets twice daily or one 100 mg tablet and one 25 mg tablet twice daily |
| > 25 to < 30 kg | 150 mg b.i.d. | six 25 mg tablets twice daily or one 100 mg tablet and two 25 mg tablets twice daily |
| > 30 kg | 200 mg b.i.d. | eight 25 mg tablets twice daily or two 100 mg tablets twice daily or one 200 mg tablet twice daily |
Missed dose
If the patient misses a dose of Интеленс within 6 hours of the time it is usually taken, the patient should take it following a meal as soon as possible and then take the next dose at the regularly scheduled time. If a patient misses a dose by more than 6 hours of the time it is usually taken, the patient should not take the missed dose and simply resume the usual dosing schedule.
Elderly
There is limited information regarding the use of Интеленс in patients > 65 years of age , therefore caution should be used in this population.
Hepatic impairment
No dose adjustment is suggested in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B); Интеленс should be used with caution in patients with moderate hepatic impairment. The pharmacokinetics of etravirine have not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Интеленс is not recommended in patients with severe hepatic impairment.
Renal impairment
No dose adjustment is required in patients with renal impairment.
Paediatric population (less than 6 years of age)
The safety and efficacy of Интеленс in children less than 6 years of age or weighing less than 16 kg have not yet been established. No data are available.
Pregnancy and postpartum
Based on limited data available, no dose adjustment is required during pregnancy and postpartum.
Method of administration
Oral use.
Patients should be instructed to swallow the tablet(s) whole with a liquid such as water. Patients who are unable to swallow the tablet(s) whole may disperse the tablet(s) in a glass of water.
Patients who are unable to swallow the tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:
- place the tablet(s) in 5 ml (1 teaspoon) of water, or at least enough liquid to cover the medicine,
- stir well until the water looks milky;
- if desired, add more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water);
- drink it immediately;
- rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose.
The use of warm (> 40°C) or carbonated beverages should be avoided.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
