Intelence

Intelence

etravirine

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Etravirine.
Description
Each tablet also contains the following excipients: Lactose monohydrate (160 mg), hypromellose, microcrystalline cellulose, anhydrous colloidal silica, croscarmellose sodium, magnesium stearate.
Action
Pharmacotherapeutic Group: Non-nucleoside reverse transcriptase inhibitor (NNRTI). ATC Code: J05AG04.
Pharmacology: Pharmacodynamics: 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- 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 effective concentration (EC50) values ranging from 0.9-5.5 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 0.3-1.7 nM and from 11.5-21.7 nM, respectively. Although etravirine demonstrates in vitro activity against wild type HIV-2 with EC50 values ranging from 5.7-7.2 micromol, 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 NNRTIs and/or protease inhibitors (PIs). In addition, etravirine demonstrates a fold change (FC) in EC50 ≤3 against 60% of 6171 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) 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 Intelence-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 trials conducted with Intelence in HIV-1-infected patients, the most common emerged mutations are 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 Experience: Treatment-Experienced Patients: Pivotal Studies: The evidence of efficacy of Intelence is based on the analyses of 48-week data from 2 ongoing phase III trials DUET-1 and DUET-2. These trials were identical in design and similar efficacy for Intelence was seen in each trial. The results as follows are pooled data from the 2 trials.
Trial Characteristics: Design: Randomised (1:1), double-blinded, placebo-controlled.
Treatment: Intelence versus 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 >5000 HIV-1 RNA copies/mL at screening; ≥1 NNRTI RAMs at screening or from prior genotypic analysis (ie, archived resistance); ≥3 primary PI mutations at screening; on a stable antiretrovital regimen for at least 8 weeks.
Stratification: Randomisation was stratified by the intended use of ENF in the background regimen (BR), previous use of darunavir and screening viral load.
Virologic response was defined as achieving a confirmed undetecteable viral load (<50 HIV-1 RNA copies/mL).

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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 Intelence 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 1. (See Table 1.)
Significantly fewer patients in the Intelence arm reached a clinical endpoint (AIDS-defining illness 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 2. (See Table 2.)

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Baseline Genotype or Phenotype and Virologic Outcome Analysis: In DUET-1 and DUET-2, the presence at baseline of ≥3 of the following mutations: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S (Intelence RAMs) was associated with a decreased virologic response to Intelence (see Table 3). 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.

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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 Intelence. Furthermore, the presence of this mutation did not affect the response in the Intelence 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 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 selected patient populations in DUET-1 and DUET-2 and are not meant to represent definitive clinical susceptibility breakpoints for Intelence.
Exploratory Head to Head Comparison with Protease Inhibitor in Protease-Inhibitor Naive Patients (Trial TMC125-C227): TMC125-C227 was an exploratory, randomised, active-controlled open-label trial, which investigated the efficacy and safety of Intelence in a treatment regimen, which is not approved under the current indication. In the TMC125-C227 study, Intelence (N=59) was administered with 2 investigator-selected NRTIs (ie, 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-naive, 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 Intelence arm (-1.4 log10 copies/mL from baseline; n=40). This difference between treatment arms was statistically significant.
Based on these trial results, Intelence 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.
Intelence has been authorised under a so-called "conditional approval" scheme. This means that further evidence on Intelence is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.
Pharmacokinetics:
The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult treatment-experienced HIV-1 infected patients. Exposure to etravirine was slightly lower in HIV-1 infected patients than in healthy subjects.
Absorption: An IV formulation of etravirine is unavailable; thus, the absolute bioavailability of Intelence is unknown. After oral administration with food, the maximum plasma concentration of etravirine is generally achieved within 4 hrs. In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that are known to increase gastric pH.
Effect of Food on Absorption: The exposure to etravirine is similar when taken following a standard normal caloric meal (561 kcal) or high-fat high-caloric meal (1160 kcal). When compared to administration following a standard normal caloric meal, exposures decreased when etravirine was taken before a standard normal caloric meal (17%), following a croissant (20%) or fasted (51%). Therefore, to achieve optimal exposure, Intelence 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 (eg, 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 oxidative metabolism by the hepatic cytochrome P-450 (CYP) 3A 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 81.2-86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The terminal elimination half-life of etravirine was approximately 30-40 hrs.
Special Populations: Children and Adolescents: The pharmacokinetics of etravirine in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose (see Dosage & Administration).
Elderly: Population pharmacokinetic analysis in HIV-infected patients showed that etravirine pharmacokinetics are not considerably different in the age range (18-77 years) evaluated (see Dosage & Administration and Precautions).
Gender: No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in the studies.
Race: Population pharmacokinetic analysis of etravirine in HIV-infected patients indicated that race had no apparent effect on the exposure to etravirine.
Hepatic Impairment: Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild (Child-Pugh score A) hepatic impairment to 8 matched controls and 8 patients with moderate (Child-Pugh score 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. No dosing adjustment is required in patients with mild or moderate hepatic impairment. Intelence has not been studied in patients with severe hepatic impairment (Child-Pugh score C) (see Dosage & Administration and Precautions).
Hepatitis B and/or Hepatitis C Virus Co-infection: Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance for Intelence in HIV-1-infected patients with hepatitis B and/or C virus co-infection. Based upon the safety profile (see Adverse Reactions), 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 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 (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: 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. This is considered not relevant to humans. In rats, the key target organs identified were the liver, 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 dogs, changes in the liver and gallbladder were seen at exposures approximately 8-fold higher than human exposure observed at the recommended dose (200 mg bd).
In a study conducted in rats, there were no effects on mating or fertility with Intelence treatment up to 500 mg/kg/day and exposure levels equivalent to those in humans at the clinically recommended dose. There was no teratogenicity with etravirine in rats (1000 mg/kg) and rabbits (375 mg/kg) at exposures equivalent to those observed in humans at the recommended clinical dose. In a pre- and postnatal development assessment in rats, etravirine had no effect on offspring development during lactation or post-weaning when the mother was dosed up to 500 mg/kg and at exposures equivalent to those observed at the recommended clinical dose.
Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 50 mg/kg, 200 mg/kg and 400 mg/kg were administered to mice and doses of 70 mg/kg, 200 mg/kg and 600 mg/kg were administered to rats. 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. Administration of etravirine did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. 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 bd).
Etravirine has 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 micronucleous test in mice.
Indications/Uses
Intelence, in combination with a boosted protease inhibitor (PI) and other antiretroviral drugs, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients (see Pharmacology: Pharmacodynamics under Actions, Precautions and Interactions).
This indication is based on week 48 analyses from 2 randomised, double-blind, placebo-controlled phase III trials in highly pre-treated patients with viral strains harboring mutations of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and PIs, where Intelence was investigated in combination with an optimised background regimen (OBR) which included darunavir/ritonavir (see Pharmacology under Actions).
Dosage/Direction for Use
Therapy should be initiated by a physician experienced in the management of HIV infection. Intelence must always be given in combination with other antiretroviral drugs.
Adults: Recommended Dose: 200 mg (two 100-mg tablets) taken orally twice daily (see Pharmacology: Pharmacokinetics under Actions).
Elderly: There is limited information regarding the use of Intelence in patients >65 years (see Pharmacology: Pharmacokinetics under Actions); therefore, caution should be used in this population.
Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Intelence 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, Intelence is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Renal Impairment: No dose adjustment is required in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
If the patient misses a dose of Intelence within 6 hrs of the time it is usually taken, the patient should be told to 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 >6 hrs of the time it is usually taken, the patient should be told not to take the missed dose and simply resume the usual dosing schedule.
Administration: Dose should be taken following a meal.
Patients who are unable to swallow the Intelence tablets whole may disperse the tablets in a glass of water. Once dispersed, patients should stir the dispersion well and drink it immediately. The glass should be rinsed with water several times and each rinse completely swallowed to ensure the entire dose is consumed.
Overdosage
There is no specific antidote for overdose with Intelence. Human experience of overdose with Intelence is limited. 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 etravirine is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed etravirine. Since etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.
Contraindications
Hypersensitivity to etravirine or to any of the excipients of Intelence.
Special Precautions
Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.
Clinical studies are ongoing in HIV-1-infected children and adolescents 6-17 years.
Severe Skin and Hypersensitivity Reactions: Severe, potentially life-treatening, and fatal skin reactions have been reported with Intelence; Stevens-Johnson Syndrome and toxic epidermal necrolysis have been rarely (<0.1%) reported. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings and infrequently, organ dysfunction, including hepatic failure. Most frequently, rash was mild to moderate, occurred in the 2nd week of therapy and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1-2 weeks on continued therapy (see Adverse Reactions).
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, hepatitis, eosinophilia). 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.
Patients with Coexisting Conditions: Liver Disease: No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). The pharmacokinetics of Intelence have not been studied in patients with severe hepatic impairment (Child-Pugh score C). (See Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Renal Disease: 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 special precautions or 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 haemodialysis or peritoneal dialysis (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Fat Redistribution: Combination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors eg, older age and with drug-related factors eg, longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution (see Adverse Reactions).
Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution 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 (see Adverse Reactions).
Osteonecrosis: Although the etiology 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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects of Intelence on the ability to drive or operate machines have been performed. There is no evidence that Intelence may alter the patient's ability to drive and operate machines; however, the adverse drug reaction profile of Intelence should be taken into account (see Adverse Reactions).
Fertility: No human data on the effect of etravirine on fertility are available. In rats, there was no effect on mating or fertility with Intelence treatment (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in pregnancy & lactation: There are no adequate and well-controlled studies with etravirine in pregnant women. Studies in animals have not shown evidence of developmental toxicity or effect on reproductive function and fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Intelence should be used during pregnancy only if the potential benefit justifies the potential risk.
It is not known whether etravirine is excreted in human milk. Because of both the potential for HIV transmission and the potential for adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving Intelence.
Use in children: Intelence is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see Pharmacology: Pharmacokinetics under Actions).
Use in the elderly: Experience in geriatric patients is limited. In the phase III trials, 6 patients aged ≥65 years and 53 patients aged 56-64 years received Intelence. The type and incidence of adverse events in patients >55 years were similar to the ones in younger patients (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration ).
Use In Pregnancy & Lactation
There are no adequate and well-controlled studies with etravirine in pregnant women. Studies in animals have not shown evidence of developmental toxicity or effect on reproductive function and fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Intelence should be used during pregnancy only if the potential benefit justifies the potential risk.
It is not known whether etravirine is excreted in human milk. Because of both the potential for HIV transmission and the potential for adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving Intelence.
Adverse Reactions
Clinical Trials: The safety assessment is based on all data from 1203 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 Intelence (200 mg bd) (see Pharmacology under Actions). In these pooled trials, the median exposure for patients in the Intelence arm was 52.3 weeks.
The most frequently reported adverse drug reactions (ADRs) (incidence ≥10% in the Intelence arm) of all intensities occurring in the phase III studies were rash (19.2% in the Intelence arm vs 10.9% in the placebo arm), diarrhoea (18% in the Intelence arm vs 23.5% in the placebo arm), nausea (14.9% in the Intelence arm vs 12.7% in the placebo arm) and headache (10.9% in the Intetelence arm vs 12.7% in the placebo arm). The rates of discontinuation due to any adverse reaction were 7.2% in patients receiving Intelence and 5.6% in patients receiving placebo. The most common ADR leading to discontinuation was rash (2.2% in the Intelence arm vs 0% in the placebo arm).
Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the 2nd week of therapy and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1-2 weeks on continued therapy (see Precautions). The incidence of rash was higher in women compared to men in the Intelence arm in the DUET trials.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 (see Precautions).
Adverse drug reactions (ADRs) of moderate intensity or greater (≥grade 2) reported in patients treated with Intelence are summarised in Table 4 (background regimen is indicated as "BR"). (See Table 4.)
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 (≥1/1000 to <1/100). Rare and very rare ADRs cannot be detected based on the number of patients included in the DUET trials.

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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 patients. Stevens-Johnson syndrome (rare: <0.1%) and toxic epidermal necrolysis (very rare: <0.01%) have been reported during clinical development with Intelence.
Laboratory Abnormalities: Treatment-emergent clinical laboratory abnormalities (grade 3 or 4), considered ADRs, reported in ≥2% of patients in the Intelence arm versus the placebo arm, respectively, were increases in amylase (8.9% vs 9.4%), creatinine (2% 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%), aspartate amino transferase (AST) (3.2% vs 2%) and decreases in neutrophils (5% vs 7.4%) and white blood cell count (2% vs 4.3%).
Lipodystrophy: Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). (See Precautions.)
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 infections may arise (immune reconstitution syndrome). (See Precautions.)
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 (see Precautions).
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 Intelence compared to co-infected subjects in the placebo group. Intelence should be used with caution in these patients (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Post-Marketing Experience: Hypersensitivity reactions have been reported, and were characterized by rash, constitutional findings and infrequently, organ dysfunction including hepatic failure (see Precautions).
Drug Interactions
Drugs that Affect Etravirine Exposure: Etravirine is metabolised by CYP3A, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Drugs that induce CYP3A, CYP2C9 or CYP2C19 may increase the clearance of etravirine resulting in lowered plasma concentrations of etravirine. Co-administration of Intelence and drugs that inhibit CYP3A, CYP2C9, or CYP2C19 may decrease the clearance of etravirine and may result in increased plasma concentrations of etravirine.
Drugs that are Affected by the Use of Etravirine: Etravirine is a weak inducer of CYP3A. Co-administration of Intelence with drugs primarily metabolised by CYP3A may result in decreased plasma concentrations of such drugs, which could decrease or shorten their therapeutic effects. Etravirine is a weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein but not a substrate. Co-administration with drugs primarily metabolised by CYP2C9 or CYP2C19 or transported by P-glycoprotein may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect or adverse events profile.
Known and theoretical interactions with selected antiretrovirals and nonantiretroviral drugs are listed in Tables 5a, 5b, 5c and 5d.
Interaction Table: Interactions between etravirine and co-administered drugs are listed in Tables 5a, 5b, 5c and 5d (increase is indicated as "↑", decrease as "↓", no change as "↔", not done as "ND", once daily as "qds", once daily in the morning as "q.a.m." and twice daily as "bd", confidence interval as "CI"). (See Tables 5a, 5b, 5c and 5d).

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Incompatibilities: None known.
Caution For Usage
Instructions for Use and Handling: The plastic bottle comes with a child-resistant cap and should be opened as follows: Push the plastic screw cap down while turning it counter clockwise; remove the unscrewed cap.
Storage
Do not store above 30°C.
MIMS Class
ATC Classification
J05AG04 - etravirine ; Belongs to the class of non-nucleoside reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
Tab 100 mg (white to off-white, oval, debossed with “T125” on one side and “100” on the other side) x 120's.
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