Edurant

Edurant

rilpivirine

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Rilpivirine HCl.
Description
Each film-coated tablet also contains the following excipients: Tablet Core: Lactose monohydrate, croscarmellose sodium, povidone K30, polysorbate 20, silicified microcrystalline cellulose and magnesium stearate. Tablet Coating: Lactose monohydrate, hypromellose 2910 6 mPa.s, titanium dioxide E171, macrogol 3000 and triacetin.
Action
Pharmacotherapeutic Group: Antiviral for systemic use, non-nucleoside reverse transcriptase inhibitor (NNRTI). ATC Code: J05AG05.
Pharmacology: Pharmacodynamics: Mechanism of Action: Rilpivirine is a diarylpyrimidine NNRTI of human immunodeficiency virus type 1 (HIV-1). Rilpivirine activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular deoxyribonucleic acid (DNA) polymerases α, β and γ.
Antiviral Activity in vitro: Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Although rilpivirine demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2510-10,830 nM (920-3970 ng/mL), treatment of HIV-2 infection with Edurant is not recommended in the absence of clinical data.
Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07-1.01 nM (0.03-0.37 ng/mL) and group O primary isolates with EC50 values ranging from 2.88-8.45 nM (1.06-3.1 ng/mL).
Resistance: In cell culture, rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The most commonly observed resistance-associated mutations that emerged included L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.
A biological cut-off (BCO) for rilpivirine was determined at the fold change in EC50 value (FC) of 3.7, on the basis of the analysis of the susceptibility of a large panel of HIV-1 wild-type recombinant clinical isolates.
In treatment-naive subjects For the resistance analysis, a broader definition of virologic failure was used than in the primary efficacy analysis. In the week 48 pooled resistance analysis from the Phase III trials, 62 (of a total of 72) virologic failures in the Edurant arm had resistance data at baseline and time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. In the trials, the presence of the mutations V90I and V189I, at baseline, did not affect response. The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of 62 of rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combination of E138K and M184I. The most common mutations were the same in the week 48 and week 96 analyses.
In the week 96 pooled resistance analysis, lower rates of virologic failure were observed in the second 48 weeks than in the first 48 weeks of treatment. From the week 48 to the week 96 analysis, 24 (3.5%) and 14 (2.1%) additional virologic failures occurred in the Edurant and efavirenz arm, respectively. Of these virologic failures, 9 out of 24 and 4 out of 14 were in subjects with a baseline viral load <100,000 copies/mL, respectively.
Considering all of the available in vitro and in vivo data in treatment-naive subjects, the following resistance-associated mutations, when present at baseline, may affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, and M230L. These rilpivirine resistance-associated mutations should only guide the use of Edurant in the treatment-naive population. These resistance-associated mutations were derived from in vivo data involving treatment-naive subjects only and therefore cannot be used to predict the activity of rilpivirine in subjects who have virologically failed an antiretroviral-containing regimen.
As with other antiretroviral medicinal products, resistance testing should guide the use of Edurant.
Cross-Resistance: Site-Directed NNRTI Mutant Virus: In a panel of 67 HIV-1 recombinant laboratory strains with 1 resistance-associated mutation at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity against 64 (96%) of these strains. The single resistance-associated mutations associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.
Recombinant Clinical Isolates: Rilpivirine retained sensitivity (FC BCO) against 62% of 4786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.
Treatment-Naive HIV-1 Infected Patients: In the week 96 pooled resistance analysis of the Phase III trials (ECHO and THRIVE), 42 out of 86 subjects with virologic failure on Edurant showed treatment-emergent resistance to rilpivirine (genotypic analysis). In these patients, phenotypic cross-resistance to other NNRTIs was noted as follows: Etravirine 32/42, efavirenz 30/42 and nevirapine 16/42. In patients with a baseline viral load ≤100,000 copies/mL, 9 out of 27 patients with virologic failure on Edurant showed treatment-emergent resistance to rilpivirine (genotypic analysis), with the following frequency of phenotypic cross-resistance: Etravirine 4/9, efavirenz 3/9, and nevirapine 1/9.
Effects on Electrocardiogram (ECG): The effect of Edurant at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hrs at steady state. Edurant at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. When supratherapeutic doses of Edurant 75 mg once daily and 300 mg once daily were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) millisec, respectively. Steady-state administration of Edurant 75 mg once daily and 300 mg once daily resulted in a mean maximum plasma concentration (Cmax) approximately 2.6- and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 25 mg once daily dose of Edurant.
Clinical Efficacy and Safety: Treatment-Naive HIV-1 Infected Patients: The evidence of efficacy of Edurant is based on the analyses of 96 week data from 2 randomised, double-blinded, active-controlled, Phase III trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE). The trials were identical in design, with the exception of the background regimen (BR). In the week 96 efficacy analysis, the virologic response rate [confirmed undetectable viral load (<50 HIV-1 RNA copies/mL)] was evaluated in patients receiving Edurant 25 mg once daily in addition to a BR versus patients receiving efavirenz 600 mg once daily in addition to a BR. Similar efficacy for Edurant was seen in each trial demonstrating noninferiority to efavirenz.
Antiretroviral treatment-naive HIV-1 infected patients were enrolled who had a plasma HIV-1 RNA ≥5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI resistance-associated mutations. In ECHO, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In THRIVE, the BR consisted of 2 investigator-selected N(t)RTIs: Tenofovir disoproxil fumarate plus emtricitabine, or zidovudine plus lamivudine or abacavir plus lamivudine. In ECHO, randomisation was stratified by screening viral load. In THRIVE, randomisation was stratified by screening viral load and by N(t)RTI BR.
This analysis included 690 patients in ECHO and 678 patients in THRIVE who had completed 96 weeks of treatment or discontinued earlier.
In the pooled analysis for ECHO and THRIVE, demographics and baseline characteristics were balanced between the Edurant arm and the efavirenz arm. Table 1 displays selected baseline disease characteristics of the patients in the Edurant and efavirenz arms. (See Table 1.)

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Table 2 shows the results of the week 48 and the week 96 efficacy analysis for patients treated with Edurant and patients treated with efavirenz from the pooled data from the ECHO and THRIVE trials. The response rate (confirmed undetectable viral load <50 HIV-1 RNA copies/mL) at week 96 was comparable between the Edurant arm and the efavirenz arm. The incidence of virologic failure was higher in the Edurant arm than the efavirenz arm at week 96; however, most of the virologic failures occurred within the first 48 weeks of treatment. Discontinuations due to adverse events were higher in the efavirenz arm at week 96 than the Edurant arm. Most of these discontinuations occurred in the first 48 weeks of treatment. (See Table 2.)

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At week 96, the mean change from baseline in CD4+ cell count was +228 x 106 cells/L in the Edurant arm and +219 x 106 cells/L in the efavirenz arm in the pooled analysis of the ECHO and THRIVE trials [estimated treatment difference (95% CI): 11.3 (-6.8; 29.4)].
From the week 96 pooled resistance analysis, the resistance outcome for patients with protocol defined virological failure, and paired genotypes (baseline and failure) is shown in Table 3.

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For those patients failing therapy with Edurant and who developed resistance, cross-resistance to other approved NNRTIs (etravirine, efavirenz, nevirapine) was generally seen.
Study TMC278-C204 was a randomised, active-controlled, Phase IIb trial in antiretroviral treatment-naive HIV-1 infected adult patients consisting of 2 parts: An initial partially blinded dose-finding part [(Edurant) doses blinded] up to 96 weeks, followed by a long-term, open label part. In the open label part of the trial, patients originally randomised to 1 of the 3 doses were all treated with Edurant 25 mg once daily in addition to a BR, once the dose for the Phase III studies was selected. Patients in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: Zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.
Study TMC278-C204 enrolled 368 HIV-1 infected treatment-naive adult patients who had a plasma HIV-1 RNA ≥5000 copies/mL, previously received 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI resistance-associated mutations.
At 96 weeks, the proportion of patients with <50 HIV-1 RNA copies/mL receiving Edurant 25 mg (N=93) compared to patients receiving efavirenz (N=89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 x 106 cells/L in patients receiving Edurant 25 mg and 160 x 106 cells/L in patients receiving efavirenz.
Of those patients who were responders at week 96, 74% of patients receiving Edurant remained with undetectable viral load (<50 HIV-1 RNA copies/mL) at week 240 compared to 81% of patients receiving efavirenz. There were no safety concerns identified in the week 240 analyses.
Paediatric Population: The European Medicines Agency has deferred the obligation to submit the results of studies with Edurant in ≥1 subsets of the paediatric population in the treatment of HIV-1 infection in ARV-naïve patients (see Dosage & Administration).
Pharmacokinetics: The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naive HIV-1 infected patients. Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.
Absorption: After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hrs. The absolute bioavailability of Edurant is unknown.
Effect of Food on Absorption: The exposure to rilpivirine was approximately 40% lower when Edurant was taken in a fasted condition as compared to a normal caloric meal (533 kCal) or high-fat high-caloric meal (928 kCal). When Edurant was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. Edurant must be taken with a meal to obtain optimal absorption. Taking Edurant in fasted condition or with only a nutritional drink may result in decreased plasma concentrations of rilpivirine, which could potentially reduce the therapeutic effect of Edurant (see Dosage & Administration).
Distribution: Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (eg, cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
Biotransformation: In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P-450 (CYP) 3A system.
Elimination: The terminal elimination half-life of rilpivirine is approximately 45 hrs. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine.
Additional Information on Special Populations: Paediatric Population: The pharmacokinetics of rilpivirine in pediatric patients are under investigation. Dosing recommendations for pediatric patients cannot be made due to insufficient data.
Elderly: Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokinetics are not different across the age range (18-78 years) evaluated, with only 3 subjects ≥65 years. No dose adjustment of Edurant is required in elderly patients. It should be used with caution in this population (see Dosage & Administration).
Gender: No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
Race: Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
Hepatic Impairment: Rilpivirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate hepatic impairment.
No dose adjustment is suggested but caution is advised in patients with moderate hepatic impairment. Edurant has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, Edurant is not recommended in patients with severe hepatic impairment (see Dosage & Administration).
Hepatitis B and/or Hepatitis C Virus Co-Infection: Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
Renal Impairment: The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, Edurant should be used with caution, as plasma concentrations may be increased due to alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients with severe renal impairment or end-stage renal disease, the combination of Edurant with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Repeated-Dose Toxicity: Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs, cholestasis-like effects were noted.
Reproductive Toxicology Studies: Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect on reproductive function. There was no teratogenicity with rilpivirine in rats and rabbits. The exposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
Carcinogenesis and Mutagenesis: Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to rilpivirine were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily). In rats, there were no drug-related neoplasms. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific.
Rilpivirine has tested negative in the absence and presence of a metabolic activation system in the in vitro Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay. Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice.
Indications/Uses
Edurant, in combination with other antiretroviral medicinal products is indicated for the treatment of human immunodeficiency virus (HIV) type 1 infection in antiretroviral treatment-naive adult patients with a viral load ≤100,000 HIV-1 ribonucleic acid (RNA) copies/mL.
Dosage/Direction for Use
Therapy should be initiated by a physician experienced in the management of HIV infection.
Edurant must always be given in combination with other antiretroviral medicinal products.
Adults: 1 tab taken once daily.
Special Population: Elderly: There is limited information regarding the use of Edurant in patients >65 years. No dose adjustment of Edurant is required in elderly patients (see Pharmacology: Pharmacokinetics under Actions). Edurant should be use with caution in this population.
Children: The safety and efficacy of Edurant in children <18 years have not yet been established. No data are available.
Hepatic Impairment: There is limited information regarding the use of Edurant in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). No dose adjustment of Edurant is required in patients with mild or moderate hepatic impairment.
Renal Impairment: Edurant has mainly been studied in patients with normal renal function. No dose adjustment of Edurant is required in patients with mild or moderate renal impairment.
Missed Dose: If the patient misses a dose of Edurant within 12 hrs of the time it is usually taken, the patient must take the tablet with a meal as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Edurant by >12 hrs, the patient should not take the missed dose, but resume the usual dosing schedule.
If a patient vomits within 4 hrs of taking Edurant, another tablet should be taken with a meal. If a patient vomits >4 hrs after taking Edurant, the patient does not need to take another dose until the next regularly scheduled dose.
Administration: Edurant must be taken orally, once daily with a meal (see Pharmacology: Pharmacokinetics under Actions). It is recommended that the film-coated tablets be swallowed whole with water, and not be chewed or crushed.
Overdosage
There is no specific antidote for overdosage with Edurant. Human experience of overdosage with Edurant is limited. Treatment of overdosage with Edurant consists of general supportive measures including monitoring of vital signs and electrocardiogram (ECG), QT interval, as well as observation of the clinical status of the patient. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.
Contraindications
Hypersensitivity to rilpivirine hydrochloride or to any of the excipients of Edurant.
Edurant should not be co-administered with the following medicinal products, as significant decreases in rilpivirine plasma concentrations may occur (due to CYP3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of Edurant: Anticonvulsants (eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antimycobacterials (eg, rifabutin, rifampicin, rifapentine), proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole), systemic glucocorticoid dexamethasone, except as a single dose treatment, St. John's wort (Hypericum perforatum).
Special Precautions
Patients should be advised that current antiretroviral therapy does not cure HIV, and there is still a risk of passing HIV to others through sexual contact or contamination with blood when taking Edurant. Appropriate precautions to prevent the transmission of HIV should continue to be employed.
Virologic Failure and Development of Resistance: Edurant has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. The list of rilpivirine resistance-associated mutations presented in Pharmacology: Pharmacodynamics under Actions should only guide the use of Edurant in the treatment-naive population.
In the pooled efficacy analysis from the Phase III trials through 96 weeks, patients treated with Edurant with a baseline viral load >100,000 HIV-1 RNA copies/mL had a greater risk of virologic failure (18.2% with Edurant vs 7.9% with efavirenz) compared to patients with a baseline viral load ≤100,000 HIV-1 RNA copies/mL (5.7% with Edurant vs 3.6% with efavirenz). The greater risk of virologic failure for patients in the Edurant arm was observed in the first 48 weeks of these trials (see Pharmacology: Pharmacodynamics under Actions). Patients with a baseline viral load <100,000 HIV-1 RNA copies/mL who experienced virologic failure exhibited a higher rate of treatment-emergent resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. More patients who failed virologically on Edurant than who failed virologically on efavirenz developed lamivudine/emtricitabine associated resistance (see Pharmacology: Pharmacodynamics under Actions).
As with other antiretroviral medicinal products, resistance testing should guide the use of Edurant (see Pharmacology: Pharmacodynamics under Actions).
Cardiovascular: At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the ECG (see Pharmacology: Pharmacokinetics under Actions, Adverse Reactions and Interactions). Edurant at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Edurant should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.
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 protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (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 Reactivation 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 1st 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).
Edurant contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Hepatic Impairment: Edurant should be used with caution in patients with moderate hepatic impairment. Edurant has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, Edurant is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetic under Actions).
Renal Impairment: In patients with severe renal impairment or end-stage renal disease, Edurant should be used with caution. In patients with severe renal impairment or end-stage renal disease, the combination of Edurant with a strong CYP3A inhibitor (eg, ritonavir-boosted HIV protease inhibitor) should only be used if the benefit outweighs the risk (see Pharmacology: Pharmacokinetic under Actions).
Treatment with Edurant resulted in an early small increase of mean serum creatinine levels which remained stable over time and is not considered clinically relevant (see Adverse Reactions).
Effects on the Ability to Drive or Operate Machinery: Edurant has no or negligible influence on the ability to drive and use machines. No studies on the effects of Edurant on the ability to drive and use machines have been performed. Fatigue, dizziness and somnolence have been reported in some patients taking Edurant and should be considered when assessing a patient's ability to drive or operate machinery.
Fertility: No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects on fertility were seen in animal studies (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in pregnancy & lactation: There are no adequate and well controlled or pharmacokinetic studies with Edurant in pregnant women. Studies in animals have shown no reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data: under Actions) and limited placenta passage. It is not known whether placental transfer of Edurant occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits. Edurant should not be used during pregnancy unless clearly needed.
It is not known whether rilpivirine is excreted in human milk. Edurant is excreted in the milk of rats. Because of both the potential for HIV transmission and the potential for adverse reactions in breastfed infants, mothers should be instructed not to breastfeed if they are receiving Edurant.
Use In Pregnancy & Lactation
There are no adequate and well controlled or pharmacokinetic studies with Edurant in pregnant women. Studies in animals have shown no reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data: under Actions) and limited placenta passage. It is not known whether placental transfer of Edurant occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits. Edurant should not be used during pregnancy unless clearly needed.
It is not known whether rilpivirine is excreted in human milk. Edurant is excreted in the milk of rats. Because of both the potential for HIV transmission and the potential for adverse reactions in breastfed infants, mothers should be instructed not to breastfeed if they are receiving Edurant.
Adverse Reactions
Summary of the Safety Profile: The safety assessment is based on the week 96 pooled data from 1368 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received Edurant (25 mg once daily) (see Pharmacology: Pharmacodynamics under Actions). The median duration of exposure for patients in the Edurant arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment.
Tabulated Summary of Adverse Reactions: Adverse drug reactions (ADRs) reported in adult patients treated with Edurant are summarised as follows. Selected treatment emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, are included in a footnote as follows. The ADRs are listed by system organ class (SOC) and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1000 to <1/100). Within each frequency grouping, ADRs are presented in order of decreasing frequency.
Adverse drug reactions reported in antiretroviral treatment-naive HIV-1 infected adult patients treated with Edurant (pooled data from the week 96 analysis of the Phase III ECHO and THRIVE trials), N=686: Blood and Lymphatic System: Common: Decreased white blood cell count#, decreased haemoglobin#, decreased platelet count#.
Immune System Disorders: Uncommon: Immune reactivation syndrome.
Metabolism and Nutrition Disorders: Very Common: Increased total cholesterol (fasted)#, increased low density lipoprotein (LDL)-cholesterol (fasted)#. Common: decreased appetite, increased triglycerides (fasted)#,
Psychiatric Dsorders: Very Common: Insomnia*. Common: Abnormal dreams, depression*, sleep disorders, depressed mood.
Nervous System Disorders: Very Common: Headache*, dizziness. Common: Somnolence.
Gastrointestinal Disorders: Very Common: Nausea, increased pancreatic amylase#. Common: Abdominal pain*, vomiting, increased lipase#, abdominal discomfort, dry mouth.
Hepatobiliary Disorders: Very Common: Increased transaminases#. Common: Increased bilirubin.
Skin and Subcutaneous Tissue Disorders: Common: Rash*.
General Disorders and Administration Site Conditions: Common: Fatigue.
N=number of subjects.
*In the week 96 analysis of the Phase III controlled trials ECHO and THRIVE, the most frequently reported adverse drug reactions (ADRs) (≥2%) that were at least of moderate intensity were depression (4.1%), headache (3.5%), insomnia (3.5%), rash (2.3%), and abdominal pain (2%).
#Selected treatment emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, reported in Edurant-treated patients from the 96 week pooled data from the ECHO and THRIVE trials were increased pancreatic amylase (3.8%), increased AST (2.3%), increased ALT (1.6%), increased LDL cholesterol (fasted, 1.5%), decreased white blood cell count (1.2%), increased lipase (0.9%), increased bilirubin (0.7%), increased triglycerides (fasted, 0.6%), decreased haemoglobin (0.1%), decreased platelet count (0.1%) and increased total cholesterol (fasted, 0.1%).
No new ADR terms were identified in adult patients in the Phase III ECHO and THRIVE trials between 48 weeks and 96 weeks nor in the Phase IIb TMC278-C204 trial through 240 weeks.
Laboratory Abnormalities: In the Edurant arm in the week 96 analysis of the Phase III ECHO and THRIVE trials, mean change from baseline in total cholesterol (fasted) was 5 mg/dL, in high density lipoprotein (HDL)-cholesterol (fasted) 4 mg/dL, in LDL-cholesterol (fasted) 1 mg/dL, and in triglycerides (fasted) -7 mg/dL.
In the pooled Phase III ECHO and THRIVE trials, serum creatinine increased minimally over 96 weeks of treatment with Edurant. Most of this increase occurred within the first 4 weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed overall. In subjects who entered the trials with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.
In the pooled Phase III ECHO and THRIVE trials, at week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.87; -7.39) nmol/L in the Edurant arm and of +0.1 (-12.63; 12.8) nmol/L in the efavirenz arm. At week 96, the mean change from baseline in adrenocorticotropic hormone (ACTH)-stimulated cortisol levels was lower in the Edurant group (+18.4±8.36 nmol/L) than in the efavirenz group (+54.1±7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at week 96 were within the normal range. These changes in adrenal safety parameters were not clinically relevant. There were no clinical signs or symptoms suggestive of adrenal or gonadal dysfunction in adults.
Description of Selected Adverse Reactions: Lipodystrophy: CART 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 Reactivation 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 reactivation syndrome) (see Precautions).
Other Special Populations: Patients Co-Infected with Hepatitis B and/or Hepatitis C Virus: In patients co-infected with hepatitis B or C virus receiving Edurant, the incidence of hepatic enzyme elevation was higher than in patients receiving who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected patients was comparable to that in patients without co-infection.
Drug Interactions
Medicinal Products that Affect Rilpivirine Exposure: Rilpivirine is primarily metabolised by CYP450 3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see Pharmacology: Pharmacokinetics under Actions). Co-administration of Edurant and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of Edurant.
Co-administration of Edurant and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine.
Co-administration of Edurant with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of Edurant.
Medicinal Products that are Affected by the Use of Rilpivirine: Edurant at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 micromolar). In a clinical study rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other drugs transported by P-glycoprotein that are more sensitive to intestinal P-gp inhibition eg, dabigatran etexilate.
Rilpivirine inhibits the active renal tubular secretion of creatinine. Via the same mechanism exposure to metformin may be increased. Patients should be carefully monitored when initiating or stopping the concomitant administration of rilpivirine and metformin.
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Tables 4a, 4b and 4c.

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Click on icon to see table/diagram/image

QT Prolonging Medicinal Products: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see Pharmacology: Pharmacodynamics under Actions). Edurant should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes.
Incompatibilities: Not applicable.
Storage
Protect from light.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
J05AG05 - rilpivirine ; Belongs to the class of non-nucleoside reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
FC tab (white to off-white, round, biconvex, 6.4 mm diameter, debossed with "TMC" on one side and "25" on the other side) 25 mg x 30's.
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