Eviplera

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Eviplera 200 mg/25 mg/245 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride) and 
245 mg of tenofovir disoproxil (as fumarate). 
 
Excipients with known effect 
 
Each film-coated tablet contains 277 mg lactose monohydrate and 4 micrograms sunset yellow 
aluminium lake (E110). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Purplish-pink, capsule-shaped, film-coated tablet of dimensions 19 mm x 8.5 mm, debossed on one 
side with “GSI” and plain on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Eviplera is indicated for the treatment of adults infected with human immunodeficiency virus type 1 
(HIV-1) without known mutations associated with resistance to the non-nucleoside reverse 
transcriptase inhibitor (NNRTI) class, tenofovir or emtricitabine, and with a viral load ≤ 100,000 
HIV-1 RNA copies/mL (see sections 4.2, 4.4 and 5.1). 
 
Genotypic resistance testing and/or historical resistance data should guide the use of Eviplera (see 
sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Eviplera should be initiated by a physician experienced in the management of HIV infection. 
 
Posology 
 
Adults 
The recommended dose of Eviplera is one tablet, taken orally, once daily.  Eviplera must be taken 
with food (see section 5.2). 
 
Where discontinuation of therapy with one of the components of Eviplera is indicated or where dose 
modification is necessary, separate preparations of emtricitabine, rilpivirine hydrochloride and 
tenofovir disoproxil are available.  Please refer to the Summary of Product Characteristics for these 
medicinal products. 
 
If a patient misses a dose of Eviplera within 12 hours of the time it is usually taken, the patient should 
take Eviplera with food as soon as possible and resume the normal dosing schedule.  If a patient 
misses a dose of Eviplera by more than 12 hours, the patient should not take the missed dose and 
simply resume the usual dosing schedule. 



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If a patient vomits within 4 hours of taking Eviplera another Eviplera tablet should be taken with food.  
If a patient vomits more than 4 hours after taking Eviplera they do not need to take another dose of 
Eviplera until the next regularly scheduled dose. 
 
Dose adjustment 
If Eviplera is co-administered with rifabutin, an additional 25 mg tablet of rilpivirine per day is 
recommended to be taken concomitantly with Eviplera, for the duration of the rifabutin co-
administration (see section 4.5). 
 
Special populations 
 
Elderly 
Eviplera has not been studied in patients over the age of 65 years.  Eviplera should be administered 
with caution to elderly patients (see sections 4.4 and 5.2). 
 
Renal impairment 
Treatment with Eviplera resulted in an early small increase of mean serum creatinine levels which 
remained stable over time and is not considered clinically relevant (see section 4.8). 
 
Limited data from clinical studies support once daily dosing of Eviplera in patients with mild renal 
impairment (creatinine clearance (CrCl) 50-80 mL/min).  However, long-term safety data for the 
emtricitabine and tenofovir disoproxil components of Eviplera have not been evaluated in patients 
with mild renal impairment.  Therefore, in patients with mild renal impairment Eviplera should only 
be used if the potential benefits of treatment outweigh the potential risks (see sections 4.4 and 5.2). 
 
Eviplera is not recommended for patients with moderate or severe renal impairment (CrCl 
< 50 mL/min).  Patients with moderate or severe renal impairment require a dose interval adjustment 
of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet (see 
sections 4.4 and 5.2). 
 
Hepatic impairment 
There is limited information regarding the use of Eviplera in patients with mild or moderate hepatic 
impairment (Child-Pugh-Turcotte (CPT) Score A or B).  No dose adjustment of Eviplera is required in 
patients with mild or moderate hepatic impairment.  Eviplera should be used with caution in patients 
with moderate hepatic impairment.  Eviplera has not been studied in patients with severe hepatic 
impairment (CPT Score C).  Therefore, Eviplera is not recommended in patients with severe hepatic 
impairment (see sections 4.4 and 5.2). 
 
If Eviplera is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients 
should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4). 
 
Paediatric population 
The safety and efficacy of Eviplera in children under the age of 18 years have not been established.  
Currently available data are described in section 5.2, but no recommendation on a posology can be 
made. 
 
Pregnancy 
Lower exposures of rilpivirine (one of the components of Eviplera) were observed during pregnancy; 
therefore viral load should be monitored closely.  Alternatively, switching to another antiretroviral 
regimen could be considered (see sections 4.4, 4.6, 5.1 and 5.2). 
 
Method of administration 
 
Eviplera must be taken orally, once daily with food (see section 5.2).  It is recommended that Eviplera 
be swallowed whole with water.  The film-coated tablet should not be chewed, crushed or split as it 
may impact the absorption of Eviplera. 



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4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Eviplera should not be co-administered with the following medicinal products as significant decreases 
in rilpivirine plasma concentrations may occur (due to cytochrome P450 [CYP]3A enzyme induction 
or gastric pH increase), which may result in loss of therapeutic effect of Eviplera: 
• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin 
• the antimycobacterials rifampicin, rifapentine 
• proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, 

rabeprazole 
• the systemic glucocorticoid dexamethasone, except as a single dose treatment 
• St. John’s wort (Hypericum perforatum) 
 
4.4 Special warnings and precautions for use 
 
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. 
 
Virologic failure and development of resistance 
 
Eviplera has not been evaluated in patients with previous virologic failure to any other antiretroviral 
therapy.  There is not sufficient data to justify the use in patients with prior NNRTI failure.  Resistance 
testing and/or historical resistance data should guide the use of Eviplera (see section 5.1). 
 
In the pooled efficacy analysis from the two Phase III clinical studies (C209 [ECHO] and C215 
[THRIVE]) through 96 weeks, patients treated with emtricitabine/tenofovir disoproxil + rilpivirine 
with a baseline viral load > 100,000 HIV-1 RNA copies/mL had a greater risk of virologic failure 
(17.6% with rilpivirine versus 7.6% with efavirenz) compared to patients with a baseline viral load 
≤ 100,000 HIV-1 RNA copies/mL (5.9% with rilpivirine versus 2.4% with efavirenz).  The virologic 
failure rate in patients treated with emtricitabine/tenofovir disoproxil + rilpivirine at week 48 and 
week 96 was 9.5% and 11.5% respectively, and 4.2% and 5.1% in the emtricitabine/tenofovir 
disoproxil + efavirenz arm.  The difference in the rate of new virologic failures from the week 48 to 
week 96 analysis between rilpivirine and efavirenz arms was not statistically significant.  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 NNRTI class.  More patients who failed 
virologically on rilpivirine than who failed virologically on efavirenz developed 
lamivudine/emtricitabine associated resistance (see section 5.1). 
 
Cardiovascular 
 
At supratherapeutic doses (75 mg and 300 mg once daily), rilpivirine has been associated with 
prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 5.1).  
Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant 
effect on QTc.  Eviplera should be used with caution when co-administered with medicinal products 
with a known risk of Torsade de Pointes. 
 
Co-administration of other medicinal products 
 
Eviplera should not be administered concomitantly with other medicinal products containing 
emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or other cytidine analogues, such as 
lamivudine (see section 4.5).  Eviplera should not be administered concomitantly with rilpivirine 
hydrochloride unless needed for dose adjustment with rifabutin (see sections 4.2 and 4.5).  Eviplera 
should not be administered concomitantly with adefovir dipivoxil (see section 4.5). 
 



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Co-administration of Eviplera and didanosine is not recommended since exposure to didanosine is 
significantly increased following co-administration with tenofovir disoproxil, which may increase the 
risk of didanosine-related adverse reactions (see section 4.5).  Rarely, pancreatitis and lactic acidosis, 
sometimes fatal, have been reported. 
 
Renal impairment 
 
Eviplera is not recommended for patients with moderate or severe renal impairment (CrCl 
< 50 mL/min).  Patients with moderate or severe renal impairment require a dose interval adjustment 
of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet (see 
sections 4.2 and 5.2).  Use of Eviplera should be avoided with concurrent or recent use of a 
nephrotoxic medicinal product (see section 4.5).  If concomitant use of Eviplera and nephrotoxic 
agents is unavoidable, renal function must be monitored weekly (see sections 4.5 and 4.8). 
 
Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory 
drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors 
for renal dysfunction.  If Eviplera is co-administered with an NSAID, renal function should be 
monitored adequately. 
 
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy 
(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinical 
practice (see section 4.8). 
 
It is recommended that CrCl is calculated in all patients prior to initiating therapy with Eviplera and 
renal function (CrCl and serum phosphate) is also monitored after two to four weeks of treatment, 
after three months of treatment and every three to six months thereafter in patients without renal risk 
factors.  In patients at risk for renal impairment, a more frequent monitoring of renal function is 
required. 
 
If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or CrCl is decreased to < 50 mL/min in any patient 
receiving Eviplera, renal function should be re-evaluated within one week, including measurements of 
blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal 
tubulopathy).  Since Eviplera is a combination product and the dosing interval of the individual 
components cannot be altered, treatment with Eviplera must be interrupted in patients with confirmed 
CrCl decreased to < 50 mL/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/L).  
Interrupting treatment with Eviplera should also be considered in case of progressive decline of renal 
function when no other cause has been identified.  Where discontinuation of therapy with one of the 
components of Eviplera is indicated or where dose modification is necessary, separate preparations of 
emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil are available. 
 
Bone effects 
 
A dual energy X ray absorptiometry (DXA) substudy for both the Phase III studies (C209 and C215) 
investigated the effect of rilpivirine as compared with control, overall and by background regimen on 
changes in whole body bone mineral density (BMD) and bone mineral content (BMC) at week 48 and 
week 96.  DXA substudies showed that small but statistically significant decreases from baseline in 
whole body BMD and BMC were similar for rilpivirine and control at week 48 and week 96.  There 
was no difference in the change from baseline in whole body BMD or BMC for rilpivirine compared 
with control, in the overall population or in those patients treated with a backbone regimen including 
tenofovir disoproxil. 
 
In a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in 
combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in BMD of 
the hip and spine were observed in both treatment groups.  Decreases in BMD of spine and changes in 
bone biomarkers from baseline were significantly greater in the tenofovir disoproxil treatment group at 
144 weeks.  Decreases in BMD of hip were significantly greater in this group until 96 weeks.  



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However, there was no increased risk of fractures or evidence for clinically relevant bone 
abnormalities over 144 weeks. 
 
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen 
in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease 
inhibitor (PI).  Alternative treatment regimens should be considered for patients with osteoporosis that 
are at a high risk for fractures. 
 
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal 
tubulopathy (see section 4.8).  If bone abnormalities are suspected then appropriate consultation 
should be obtained. 
 
Patients with HIV and hepatitis B or C virus co-infection 
 
Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for 
severe and potentially fatal hepatic adverse reactions. 
 
Physicians should refer to current HIV treatment guidelines for the optimal management of 
HIV infection in patients co-infected with HBV. 
 
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary 
of Product Characteristics for these medicinal products. 
 
The safety and efficacy of Eviplera have not been established for the treatment of chronic 
HBV infection.  Emtricitabine and tenofovir individually and in combination have shown activity 
against HBV in pharmacodynamic studies (see section 5.1). 
 
Discontinuation of Eviplera therapy in patients co-infected with HIV and HBV may be associated with 
severe acute exacerbations of hepatitis.  Patients co-infected with HIV and HBV who discontinue 
Eviplera should be closely monitored with both clinical and laboratory follow-up for at least several 
months after stopping treatment.  If appropriate, resumption of hepatitis B therapy may be warranted.  
In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended 
since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. 
 
Liver disease 
 
The safety and efficacy of Eviplera have not been established in patients with significant underlying 
liver disorders.  The pharmacokinetics of emtricitabine has not been studied in patients with hepatic 
impairment.  Emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver 
impairment should be limited.  No dose adjustment is required for rilpivirine hydrochloride in patients 
with mild or moderate hepatic impairment (CPT Score A or B).  Rilpivirine hydrochloride has not 
been studied in patients with severe hepatic impairment (CPT Score C).  The pharmacokinetics of 
tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required in 
these patients. 
 
It is unlikely that a dose adjustment would be required for Eviplera in patients with mild or moderate 
hepatic impairment (see sections 4.2 and 5.2).  Eviplera should be used with caution in patients with 
moderate hepatic impairment (CPT Score B) and is not recommended in patients with severe hepatic 
impairment (CPT Score C). 
 
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy (CART) and 
should be monitored according to standard practice.  If there is evidence of worsening liver disease in 
such patients, interruption or discontinuation of treatment must be considered. 
 



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Severe skin reactions 
 
Cases of severe skin reactions with systemic symptoms have been reported during post-marketing 
experience with Eviplera, including but not limited to rashes accompanied by fever, blisters, 
conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia.  These symptoms 
resolved after Eviplera was discontinued.  As soon as serious skin and/or mucosal reactions are 
observed, Eviplera must be discontinued and appropriate therapy should be initiated. 
 
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. 
 
Mitochondrial dysfunction following exposure in utero 
 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological 
disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such 
neurological disorders are transient or permanent is currently unknown.  These findings should be 
considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical 
findings of unknown etiology, particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV. 
 
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 first few weeks or months of initiation of CART.  Relevant examples are cytomegalovirus 
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) 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. 
 
Elderly 
 
Eviplera has not been studied in patients over the age of 65 years.  Elderly patients are more likely to 
have decreased renal function, therefore caution should be exercised when treating elderly patients 
with Eviplera (see sections 4.2 and 5.2). 



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Pregnancy 
 
Lower exposures of rilpivirine were observed when rilpivirine 25 mg once daily was taken during 
pregnancy.  In the Phase III studies (C209 and C215), lower rilpivirine exposure, similar to that seen 
during pregnancy, has been associated with an increased risk of virological failure, therefore viral load 
should be monitored closely (see sections 4.6, 5.1 and 5.2).  Alternatively, switching to another 
antiretroviral regimen could be considered. 
 
Excipients 
 
Eviplera contains lactose monohydrate.  Patients with rare hereditary problems of galactose 
intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal 
product. 
 
Eviplera contains a colourant called sunset yellow aluminium lake (E110), which may cause allergic 
reactions. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
As Eviplera contains emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil, any interactions 
that have been identified with these active substances individually may occur with Eviplera.  
Interaction studies with these active substances have only been performed in adults. 
 
Rilpivirine is primarily metabolised by CYP3A  Medicinal products that induce or inhibit CYP3A may 
thus affect the clearance of rilpivirine (see section 5.2). 
 
Concomitant use contraindicated 
 
Co-administration of Eviplera and medicinal products that induce CYP3A has been observed to 
decrease the plasma concentrations of rilpivirine which could potentially lead to loss of therapeutic 
effect of Eviplera (see section 4.3). 
 
Co-administration of Eviplera with proton pump inhibitors has been observed to decrease the plasma 
concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of 
therapeutic effect of Eviplera (see section 4.3). 
 
Concomitant use not recommended 
 
Eviplera should not be administered concomitantly with other medicinal products containing 
emtricitabine, tenofovir disoproxil or tenofovir alafenamide.  Eviplera should not be administered 
concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin (see 
section 4.2). 
 
Due to similarities with emtricitabine, Eviplera should not be administered concomitantly with other 
cytidine analogues, such as lamivudine (see section 4.4).  Eviplera should not be administered 
concomitantly with adefovir dipivoxil. 
 
Didanosine 
The co-administration of Eviplera and didanosine is not recommended (see section 4.4 and Table 1). 
 
Renally eliminated medicinal products 
Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of 
Eviplera with medicinal products that reduce renal function or compete for active tubular secretion 
(e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the 
co-administered medicinal products. 
 



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Use of Eviplera should be avoided with concurrent or recent use of a nephrotoxic medicinal product.  
Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, 
ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin). 
 
Other NNRTIs 
It is not recommended to co-administer Eviplera with other NNRTIs. 
 
Concomitant use where caution is recommended 
 
Cytochrome P450 enzyme inhibitors 
Co-administration of Eviplera with medicinal products that inhibit CYP3A enzyme activity has been 
observed to increase rilpivirine plasma concentrations. 
 
QT prolonging medicinal products 
Eviplera should be used with caution when co-administered with a medicinal product with a known 
risk of Torsade de Pointes.  There is limited information available on the potential for a 
pharmacodynamic interaction between rilpivirine and medicinal products that prolong the 
QTc interval of the electrocardiogram.  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 section 5.1). 
 
P-glycoprotein substrates 
Rilpivirine inhibits P-glycoprotein (P-gp) in vitro (IC50 is 9.2 µM).  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 medicinal products transported by P-gp that are more 
sensitive to intestinal P-gp inhibition (e.g. dabigatran etexilate). 
 
Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM.  The clinical 
implications of this finding are currently unknown. 
 
Other interactions 
 
Interactions between Eviplera or its individual component(s) and co-administered medicinal products 
are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”). 
 



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Table 1: Interactions between Eviplera or its individual component(s) and other medicinal 
products 
 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

ANTI-INFECTIVES 
Antiretrovirals 
Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs/N[t]RTIs) 
Didanosine/Emtricitabine Interaction not studied. Co-administration of Eviplera and 

didanosine is not recommended 
(see section 4.4). 

Didanosine (400 mg once daily)/ 
Rilpivirine1 

Didanosine: 
AUC: ↑ 12% 
Cmin: N/A 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

Didanosine/Tenofovir disoproxil Co-administration of tenofovir 
disoproxil and didanosine results in 
a 40-60% increase in systemic 
exposure to didanosine that may 
increase the risk of didanosine-
related adverse reactions.  Rarely, 
pancreatitis and lactic acidosis, 
sometimes fatal, have been reported.  
Co-administration of tenofovir 
disoproxil and didanosine at a dose 
of 400 mg daily has been associated 
with a significant decrease in 
CD4+ cell count, possibly due to an 
intracellular interaction increasing 
phosphorylated (i.e. active) 
didanosine.  A decreased dosage of 
250 mg didanosine co-administered 
with tenofovir disoproxil therapy 
has been associated with reports of 
high rates of virological failure 
within several tested combinations 
for the treatment of HIV-1 infection. 



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Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Protease inhibitors (PIs) - boosted (with co-administration of low-dose ritonavir) 
Atazanavir/Ritonavir/Emtricitabine Interaction not studied. Concomitant use of Eviplera with 

ritonavir-boosted PIs causes an 
increase in the plasma 
concentrations of rilpivirine 
(inhibition of CYP3A enzymes). 
 
No dose adjustment is required. 

Atazanavir/Ritonavir/Rilpivirine Interaction not studied. 
Atazanavir (300 mg once daily)/ 
Ritonavir (100 mg once daily)/ 
Tenofovir disoproxil (245 mg once 
daily) 

Atazanavir: 
AUC: ↓ 25% 
Cmax: ↓ 28% 
Cmin: ↓ 26% 
 
Tenofovir: 
AUC: ↑ 37% 
Cmax: ↑ 34% 
Cmin: ↑ 29% 

Darunavir/Ritonavir/Emtricitabine Interaction not studied. 
Darunavir (800 mg once daily)/ 
Ritonavir (100 mg once daily)/ 
Rilpivirine1 

Darunavir: 
AUC: ↔ 
Cmin: ↓ 11% 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↑ 130% 
Cmin: ↑ 178% 
Cmax: ↑ 79% 

Darunavir (300 mg once daily)/ 
Ritonavir (100 mg once daily)/ 
Tenofovir disoproxil 
(245 mg once daily) 

Darunavir: 
AUC: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 22% 
Cmin: ↑ 37% 

Lopinavir/Ritonavir/Emtricitabine Interaction not studied. 
Lopinavir (400 mg twice daily)/ 
Ritonavir (100 mg twice daily)/ 
Rilpivirine1 
(soft capsule) 

Lopinavir: 
AUC: ↔ 
Cmin: ↓ 11% 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↑ 52% 
Cmin: ↑ 74% 
Cmax: ↑ 29% 

Lopinavir (400 mg twice daily)/ 
Ritonavir (100 mg twice daily)/ 
Tenofovir disoproxil (245 mg once 
daily) 

Lopinavir/Ritonavir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 

CCR5 antagonists 
Maraviroc/Emtricitabine Interaction not studied. No clinically relevant drug-drug 

interaction is expected. 
 
No dose adjustment is required. 

Maraviroc/Rilpivirine Interaction not studied. 
Maraviroc (300 mg twice daily)/ 
Tenofovir disoproxil (245 mg once 
daily) 

AUC: ↔ 
Cmax: ↔ 
Tenofovir concentrations not 
measured, no effect is expected. 



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Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Integrase strand transfer inhibitors 
Raltegravir/Emtricitabine Interaction not studied. No clinically relevant drug-drug 

interaction is expected. 
 
No dose adjustment is required. 

Raltegravir/Rilpivirine Raltegravir: 
AUC: ↑ 9% 
Cmin: ↑ 27% 
Cmax: ↑ 10% 
 
Rilpivirine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

Raltegravir (400 mg twice daily)/ 
Tenofovir disoproxil 

Raltegravir: 
AUC: ↑ 49% 
C12h: ↑ 3% 
Cmax: ↑ 64% 
(mechanism of interaction unknown) 
 
Tenofovir: 
AUC: ↓ 10% 
C12h: ↓ 13% 
Cmax: ↓ 23% 

Other antiviral agents 
Ledipasvir/Sofosbuvir 
(90 mg/400 mg once daily)/ 
Emtricitabine/Rilpivirine/ 
Tenofovir disoproxil 
(200 mg/25 mg/245 mg once daily) 

Ledipasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310074: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↔ 
Cmin: ↑ 91% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



13 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Sofosbuvir/Velpatasvir 
(400 mg/100 mg once daily)/ 
Emtricitabine/Rilpivirine/Tenofovir 
disoproxil 
(200 mg/25 mg/245 mg once daily) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310074: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑ 40% 
Cmax: ↑ 44% 
Cmin: ↑ 84% 

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 



14 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Sofosbuvir/Velpatasvir/ 
Voxilaprevir (400 mg/100 mg/ 
100 mg + 100 mg once daily)5/ 
Rilpivirine/Emtricitabine 
(25 mg/200 mg once daily)6 

Interaction not studied with 
Eviplera. 
 
Expected: 
Sofosbuvir: 
AUC: ↔ 
Cmax: ↔ 
 
GS-3310074: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Voxilaprevir 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 
 
Tenofovir: 
AUC: ↑  
Cmax: ↑  
Cmin: ↑  

No dose adjustment is 
recommended.  The increased 
exposure of tenofovir could 
potentiate adverse reactions 
associated with tenofovir 
disoproxil, including renal 
disorders.  Renal function should 
be closely monitored (see 
section 4.4). 

Sofosbuvir/Emtricitabine Interaction not studied. No dose adjustment is required. 
Sofosbuvir (400 mg once daily)/ 
Rilpivirine (25 mg once daily) 

Sofosbuvir: 
AUC: ↔ 
Cmax: ↑ 21% 
 
GS-3310074: 
AUC: ↔ 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

Sofosbuvir/Tenofovir disoproxil Interaction not studied. 
Ribavirin/Tenofovir disoproxil Ribavirin: 

AUC: ↔ 
Cmax: ↔ 
Cmin: N/A 

No dose adjustment is required. 



15 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Simeprevir (150 mg once daily)/ 
Rilpivirine (25 mg once daily) 

Simeprevir:  
AUC: ↔ 
Cmax: ↑ 10% 
Cmin: ↔ 
 
Rilpivirine: 
AUC:  ↔ 
Cmax:  ↔ 
Cmin:  ↑ 25% 

No dose adjustment is required. 

Simeprevir (150 mg once daily)/ 
Tenofovir disoproxil 
(245 mg once daily) 

Simeprevir:  
AUC: ↓ 14% 
Cmax: ↓ 15% 
Cmin: ↓ 7% 
 
Tenofovir:  
AUC: ↔ 
Cmax: ↑ 19% 
Cmin: ↑ 24% 

Herpesvirus antiviral agents 
Famciclovir/Emtricitabine Famciclovir: 

AUC: ↔ 
Cmax: ↔ 
Cmin: N/A 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: N/A 

No dose adjustment is required. 

Antifungals 
Ketoconazole/Emtricitabine Interaction not studied. Concomitant use of Eviplera with 

azole antifungal agents may cause 
an increase in the plasma 
concentrations of rilpivirine 
(inhibition of CYP3A enzymes). 
 
At a dose of 25 mg of rilpivirine, 
no dose adjustment is required. 

Ketoconazole (400 mg once daily)/ 
Rilpivirine1 
 
 
 
Fluconazole2 
Itraconazole2 
Posaconazole2 
Voriconazole2 

Ketoconazole: 
AUC: ↓ 24% 
Cmin: ↓ 66% 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↑ 49% 
Cmin: ↑ 76% 
Cmax: ↑ 30% 

Ketoconazole/Tenofovir disoproxil Interaction not studied. 



16 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Antimycobacterials 
Rifabutin/Emtricitabine Interaction not studied. Co-administration is likely to 

cause significant decreases in 
rilpivirine plasma concentrations 
(induction of CYP3A enzymes).  
When Eviplera is co-administered 
with rifabutin, an additional 25 mg 
tablet of rilpivirine per day is 
recommended to be taken 
concomitantly with Eviplera, for 
the duration of the rifabutin co-
administration. 

Rifabutin (300 mg once daily)/ 
Rilpivirine3 
 
 
 
 
 
 
 
 
Rifabutin (300 mg once daily)/ 
Rilpivirine (25 mg once daily) 
 
 
 
Rifabutin (300 mg once daily)/ 
Rilpivirine (50 mg once daily) 

Rifabutin: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
25-O-desacetyl-rifabutin: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↓ 42% 
Cmin: ↓ 48% 
Cmax: ↓ 31% 
 
Rilpivirine: 
AUC: ↑ 16%* 
Cmin: ↔* 
Cmax: ↑ 43%* 
*compared to 25 mg once daily 
rilpivirine alone 

Rifabutin/Tenofovir disoproxil Interaction not studied. 
Rifampicin/Emtricitabine Interaction not studied. Eviplera must not be used in 

combination with rifampicin as 
co-administration is likely to cause 
significant decreases in rilpivirine 
plasma concentrations (induction 
of CYP3A enzymes).  This may 
result in loss of therapeutic effect 
of Eviplera (see section 4.3). 

Rifampicin (600 mg once daily)/ 
Rilpivirine1 

Rifampicin: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↔ 
 
25-desacetyl-rifampicin: 
AUC: ↓ 9% 
Cmin: N/A 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↓ 80% 
Cmin: ↓ 89% 
Cmax: ↓ 69% 

Rifampicin (600 mg once daily)/ 
Tenofovir disoproxil (245 mg once 
daily) 

Rifampicin: 
AUC: ↔ 
Cmax: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 

Rifapentine2 Interaction not studied with any 
components of Eviplera. 

Eviplera must not be used in 
combination with rifapentine as 
co-administration is likely to cause 
significant decreases in rilpivirine 
plasma concentrations (induction 
of CYP3A enzymes).  This may 
result in loss of therapeutic effect 
of Eviplera (see section 4.3). 



17 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

Macrolide antibiotics 
Clarithromycin 
Erythromycin 

Interaction not studied with any 
components of Eviplera. 

The combination of Eviplera with 
these macrolide antibiotics may 
cause an increase in the plasma 
concentrations of rilpivirine 
(inhibition of CYP3A enzymes). 
 
Where possible, alternatives such 
as azithromycin should be 
considered. 

ANTICONVULSANTS 
Carbamazepine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 

Interaction not studied with any 
components of Eviplera. 

Eviplera must not be used in 
combination with these 
anticonvulsants as 
co-administration may cause 
significant decreases in rilpivirine 
plasma concentrations (induction 
of CYP3A enzymes).  This may 
result in loss of therapeutic effect 
of Eviplera (see section 4.3). 

GLUCOCORTICOIDS 
Dexamethasone (systemic, except 
for single dose use) 

Interaction not studied with any 
components of Eviplera. 

Eviplera should not be used in 
combination with systemic 
dexamethasone (except as a single 
dose) as co-administration may 
cause significant dose dependent 
decreases in rilpivirine plasma 
concentrations (induction of 
CYP3A enzymes).  This may 
result in loss of therapeutic effect 
of Eviplera (see section 4.3). 
 
Alternatives should be considered, 
particularly for long-term use. 

PROTON PUMP INHIBITORS 
Omeprazole/Emtricitabine Interaction not studied. Eviplera must not be used in 

combination with proton pump 
inhibitors as co-administration is 
likely to cause significant 
decreases in rilpivirine plasma 
concentrations (reduced 
absorption, increase in gastric pH).  
This may result in loss of 
therapeutic effect of Eviplera (see 
section 4.3). 

Omeprazole (20 mg once daily)/ 
Rilpivirine1 
 
 
 
 
Lansoprazole2 
Rabeprazole2 
Pantoprazole2 
Esomeprazole2 

Omeprazole: 
AUC: ↓ 14% 
Cmin: N/A 
Cmax: ↓ 14% 
 
Rilpivirine: 
AUC: ↓ 40% 
Cmin: ↓ 33% 
Cmax: ↓ 40% 

Omeprazole/Tenofovir disoproxil Interaction not studied. 



18 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

H2-RECEPTOR ANTAGONISTS 
Famotidine/Emtricitabine Interaction not studied. The combination of Eviplera and 

H2-receptor antagonists should be 
used with particular caution as 
co-administration may cause 
significant decreases in rilpivirine 
plasma concentrations (reduced 
absorption, increase in gastric pH).  
Only H2-receptor antagonists that 
can be dosed once daily should be 
used.  A strict dosing schedule 
with intake of the H2-receptor 
antagonists at least 12 hours before 
or at least 4 hours after Eviplera 
should be used. 

Famotidine (40 mg single dose 
taken 12 hours before rilpivirine)/ 
Rilpivirine1 
 
Cimetidine2 
Nizatidine2 
Ranitidine2 

Rilpivirine: 
AUC: ↓ 9% 
Cmin: N/A 
Cmax: ↔ 

Famotidine (40 mg single dose 
taken 2 hours before rilpivirine)/ 
Rilpivirine1 

Rilpivirine: 
AUC: ↓ 76% 
Cmin: N/A 
Cmax: ↓ 85% 

Famotidine (40 mg single dose 
taken 4 hours after rilpivirine)/ 
Rilpivirine1 

Rilpivirine: 
AUC: ↑ 13% 
Cmin: N/A 
Cmax: ↑ 21% 

Famotidine/Tenofovir disoproxil Interaction not studied. 
ANTACIDS 
Antacids (e.g. aluminium or 
magnesium hydroxide, calcium 
carbonate) 

Interaction not studied with any of 
the components of Eviplera. 

The combination of Eviplera and 
antacids should be used with 
caution as co-administration may 
cause significant decreases in 
rilpivirine plasma concentrations 
(reduced absorption, gastric pH 
increase).  Antacids should only be 
administered either at least 2 hours 
before or at least 4 hours after 
Eviplera. 

NARCOTIC ANALGESICS 
Methadone/Emtricitabine Interaction not studied. No dose adjustments are required 

when initiating co-administration 
of methadone with Eviplera.  
However, clinical monitoring is 
recommended as methadone 
maintenance therapy may need to 
be adjusted in some patients. 

Methadone (60-100 mg once daily, 
individualised dose)/Rilpivirine 

R(-) methadone: 
AUC: ↓ 16% 
Cmin: ↓ 22% 
Cmax: ↓ 14% 
 
Rilpivirine: 
AUC: ↔* 
Cmin: ↔* 
Cmax: ↔* 
*based on historic controls 

Methadone/Tenofovir disoproxil Methadone: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 



19 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

ANALGESICS 
Paracetamol/Emtricitabine Interaction not studied. No dose adjustment is required. 
Paracetamol (500 mg single dose)/ 
Rilpivirine1 

Paracetamol: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmin: ↑ 26% 
Cmax: ↔ 

Paracetamol/Tenofovir disoproxil Interaction not studied. 
ORAL CONTRACEPTIVES 
Ethinylestradiol/Norethindrone/ 
Emtricitabine 

Interaction not studied. No dose adjustment is required. 

Ethinylestradiol (0.035 mg once 
daily)/Rilpivirine 
 
Norethindrone (1 mg once daily)/ 
Rilpivirine 

Ethinylestradiol: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↑ 17% 
 
Norethindrone: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↔* 
Cmin: ↔* 
Cmax: ↔* 
*based on historic controls 

Ethinylestradiol/Norethindrone/ 
Tenofovir disoproxil 

Ethinylestradiol: 
AUC: ↔ 
Cmax: ↔ 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 

Norgestimate/Ethinylestradiol/ 
Tenofovir disoproxil 

Norgestimate: 
AUC: ↔ 
Cmax: ↔ 
Cmin: NC 
 
Ethinylestradiol: 
AUC: ↔ 
Cmax: ↔ 
Cmin: ↔ 

No dose adjustment is required.  

ANTIARRHYTHMICS 
Digoxin/Emtricitabine Interaction not studied. No dose adjustment is required. 
Digoxin/Rilpivirine Digoxin: 

AUC: ↔ 
Cmin: N/A 
Cmax: ↔ 

Digoxin/Tenofovir disoproxil Interaction not studied. 



20 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

ANTICOAGULANTS 
Dabigatran etexilate Interaction not studied with any of 

the components of Eviplera. 
A risk for increases in dabigatran 
plasma concentrations cannot be 
excluded (inhibition of intestinal 
P-gp. 
 
The combination of Eviplera and 
dabigatran etexilate should be used 
with caution. 

IMMUNOSUPPRESSANTS 
Tacrolimus/Tenofovir disoproxil/ 
Emtricitabine 

Tacrolimus: 
AUC: ↔ 
Cmax: ↔ 
Cmin: N/A 
 
Emtricitabine: 
AUC: ↔ 
Cmax: ↔ 
Cmin: N/A 
 
Tenofovir: 
AUC: ↔ 
Cmax: ↔ 
Cmin: N/A 

No dose adjustment is required.  

ANTIDIABETICS 
Metformin/Emtricitabine Interaction not studied. No dose adjustment is required. 
Metformin (850 mg single dose)/ 
Rilpivirine 

Metformin: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↔ 

Metformin/Tenofovir disoproxil Interaction not studied. 
HERBAL PRODUCTS 
St. John’s wort 
(Hypericum perforatum) 

Interaction not studied with any of 
the components of Eviplera. 

Eviplera must not be used in 
combination with products 
containing St. John’s wort as co-
administration may cause 
significant decreases in rilpivirine 
plasma concentrations.  This may 
result in loss of therapeutic effect 
of Eviplera (see section 4.3). 

HMG CO-A REDUCTASE INHIBITORS 
Atorvastatin/Emtricitabine Interaction not studied. No dose adjustment is required. 
Atorvastatin (40 mg once daily)/ 
Rilpivirine1 

Atorvastatin: 
AUC: ↔ 
Cmin: ↓ 15% 
Cmax: ↑ 35% 
 
Rilpivirine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↓ 9% 

Atorvastatin/Tenofovir disoproxil Interaction not studied. 



21 

Medicinal product by therapeutic 
areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin 

Recommendation concerning 
co-administration with Eviplera 

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS 
Sildenafil/Emtricitabine Interaction not studied. No dose adjustment is required. 
Sildenafil (50 mg single dose)/ 
Rilpivirine1 
 
 
 
 
 
Vardenafil2 
Tadalafil2 

Sildenafil: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↔ 
 
Rilpivirine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

Sildenafil/Tenofovir disoproxil Interaction not studied. 
N/A = not applicable 
1 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine hydrochloride 

assessing the maximal effect on the co-administered medicinal product.  The dosing recommendation is applicable to the 
recommended dose of rilpivirine of 25 mg once daily. 

2 These are medicinal products within class where similar interactions could be predicted. 
3 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine hydrochloride 

assessing the maximal effect on the co-administered medicinal product. 
4 The predominant circulating metabolite of sofosbuvir. 
5 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in hepatitis C virus 

(HCV) infected patients. 
6 Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablet. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
The use of Eviplera must be accompanied by the use of effective contraception. 
 
Pregnancy 
 
There are no adequate and well-controlled studies of Eviplera or its components in pregnant women.  
There are a limited amount of data (less than 300 pregnancy outcomes) from the use of rilpivirine in 
pregnant women (see sections 4.4, 5.1 and 5.2).  Lower exposures of rilpivirine were observed during 
pregnancy; therefore viral load should be monitored closely.  A large amount of data on pregnant 
women (more than 1,000 pregnancy outcomes) indicate no malformative nor foetal/neonatal toxicity 
associated with emtricitabine and tenofovir disoproxil. 
 
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity 
(see section 5.3) with the components of Eviplera. 
 
As a precautionary measure, it is preferable to avoid the use of Eviplera during pregnancy. 
 
Breast-feeding 
 
Emtricitabine and tenofovir disoproxil are excreted in human milk.  It is not known whether rilpivirine 
is excreted in human milk. 
 
There is insufficient information on the effects of Eviplera in newborns/infants.  Breast-feeding should 
be discontinued during treatment with Eviplera. 
 
In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not 
breast-feed their infants under any circumstances. 
 



22 

Fertility 
 
No human data on the effect of Eviplera on fertility are available.  Animal studies do not indicate 
harmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir disoproxil on fertility. 
 
4.7 Effects on ability to drive and use machines 
 
Eviplera has no or negligible influence on the ability to drive and use machines.  However, patients 
should be informed that fatigue, dizziness and somnolence have been reported during treatment with 
the components of Eviplera (see section 4.8).  This should be considered when assessing a patient’s 
ability to drive or operate machinery. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The combination of emtricitabine, rilpivirine and tenofovir disoproxil has been studied as the 
component products in treatment-naïve patients (Phase III studies C209 and C215).  The single-tablet 
regimen (STR), Eviplera, has been studied in virologically suppressed patients who switched from a 
regimen containing a ritonavir-boosted PI (Phase III study GS-US-264-0106) or from 
efavirenz/emtricitabine/tenofovir disoproxil (Phase IIb study GS-US-264-0111).  In treatment-naïve 
patients, the most frequently reported adverse reactions considered possibly or probably related to 
rilpivirine hydrochloride and emtricitabine/tenofovir disoproxil were nausea (9%), dizziness (8%), 
abnormal dreams (8%), headache (6%), diarrhoea (5%) and insomnia (5%) (pooled data from the 
Phase III clinical studies C209 and C215, see section 5.1).  In virologically suppressed patients 
switching to Eviplera, the most frequently reported adverse reactions considered possibly or probably 
related to Eviplera were fatigue (3%), diarrhoea (3%), nausea (2%) and insomnia (2%) (48 week data 
from the Phase III study GS-US-264-0106).  The safety profile of emtricitabine and tenofovir 
disoproxil in these studies was consistent with the previous experience with these agents when each 
was administered with other antiretroviral agents. 
 
In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and 
uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to 
bone abnormalities (infrequently contributing to fractures) have been reported.  Monitoring of renal 
function is recommended for patients receiving Eviplera (see section 4.4). 
 
Discontinuation of Eviplera therapy in patients co-infected with HIV and HBV may be associated with 
severe acute exacerbations of hepatitis (see section 4.4). 
 
Tabulated summary of adverse reactions 
 
The adverse reactions considered at least possibly related to treatment with the components of 
Eviplera from clinical study and post-marketing experience are listed in Table 2, below, by body 
system organ class and frequency.  Within each frequency grouping, undesirable effects are presented 
in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), common 
(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
 
Table 2: Tabulated summary of adverse reactions to Eviplera based on clinical study and 
post-marketing experience with Eviplera and its individual components 
 

Frequency Adverse reaction 
Blood and lymphatic system disorders 

Common: neutropenia
1, decreased white blood cell count2, decreased haemoglobin2, decreased 

platelet count2 
Uncommon: anaemia1, 4 
Immune system disorders 
Common: allergic reaction1 
Uncommon: immune reactivation syndrome 



23 

Frequency Adverse reaction 
Metabolism and nutrition disorders 

Very common: increased total cholesterol (fasted)
2, increased LDL-cholesterol (fasted)2, 

hypophosphataemia3, 5 
Common: hypertriglyceridaemia1, 2, hyperglycaemia1, decreased appetite2 
Uncommon: hypokalaemia3, 5 
Rare: lactic acidosis3 
Psychiatric disorders 
Very common: insomnia1, 2 
Common: depression2, depressed mood2, sleep disorders2, abnormal dreams1, 2  
Nervous system disorders 
Very common: headache1, 2, 3, dizziness1, 2, 3 
Common: somnolence2 
Gastrointestinal disorders 
Very common: increased pancreatic amylase2, vomiting1, 2, 3, diarrhoea1, 3, nausea1, 2, 3  

Common: 
elevated amylase including elevated pancreatic amylase1, elevated serum lipase1, 2, 
abdominal pain1, 2, 3, abdominal discomfort2, abdominal distension3, dyspepsia1, 
flatulence3, dry mouth2 

Uncommon: pancreatitis3 
Hepatobiliary disorders 
Very common: increased transaminases (AST and/or ALT)1, 2, 3 
Common: increased bilirubin1, 2 
Rare: hepatitis3, hepatic steatosis3  
Skin and subcutaneous tissue disorders 
Very common: rash1, 2, 3 

Common: vesiculobullous rash
1, pustular rash1, urticaria1, skin discolouration (increased 

pigmentation)1, 4, maculopapular rash1, pruritus1 
Uncommon: angioedema1, 3, 6, severe skin reactions with systemic symptoms7 
Musculoskeletal and connective tissue disorders 
Very common: elevated creatine kinase1 
Uncommon: rhabdomyolysis3, 5, muscular weakness3, 5 

Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)
3, 5, 8, 

myopathy3, 5 
Renal and urinary disorders 

Uncommon: proximal renal tubulopathy including Fanconi syndrome
3, increased creatinine3, 

proteinuria3 

Rare: renal failure (acute and chronic)
3, acute tubular necrosis3, nephritis (including acute 

interstitial nephritis)3, 8, nephrogenic diabetes insipidus3 
General disorders and administration site conditions 
Very common: asthenia1, 3 
Common: pain1, fatigue2 

1 Adverse reaction identified for emtricitabine. 
2 Adverse reaction identified for rilpivirine hydrochloride. 
3 Adverse reaction identified for tenofovir disoproxil. 
4 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was 

administered to paediatric patients (see section 4.8, Paediatric population). 
5 This adverse reaction may occur as a consequence of proximal renal tubulopathy.  It is not considered to be causally 

associated with tenofovir disoproxil in the absence of this condition. 
6 This was a rare adverse reaction for tenofovir disoproxil.  It was also identified as an adverse reaction for emtricitabine 

through post-marketing surveillance but was not observed in randomised controlled clinical studies in adults or paediatric 
HIV clinical studies of emtricitabine.  The frequency category of uncommon was estimated from a statistical calculation 
based on the total number of patients exposed to emtricitabine in these clinical studies (n = 1,563). 

7 This adverse reaction was identified through post-marketing surveillance for Eviplera (fixed-dose combination) but not 
observed in randomised controlled clinical studies for Eviplera.  The frequency category was estimated from a statistical 
calculation based on the total number of patients exposed to Eviplera or all of its components in randomised controlled 
clinical studies (n = 1,261).  See section 4.8, Description of selected adverse reactions. 

8 This adverse reaction was identified through post-marketing surveillance for tenofovir disoproxil but not observed in 
randomised controlled clinical studies or the expanded access program for tenofovir disoproxil.  The frequency category 
was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil in 
randomised controlled clinical studies and the expanded access program (n = 7,319). 

 



24 

Laboratory abnormalities 
 
Lipids 
At 96 weeks in the pooled Phase III C209 and C215 studies of treatment-naïve patients, in the 
rilpivirine arm the mean change from baseline in total cholesterol (fasted) was 5 mg/dL, in 
high-density lipoprotein (HDL)-cholesterol (fasted) 4 mg/dL, in low density lipoprotein 
(LDL)-cholesterol (fasted) 1 mg/dL, and in triglycerides (fasted) -7 mg/dL.  At 48 weeks in Phase III 
study GS-US-264-0106 of virologically suppressed patients switching to Eviplera from a regimen 
containing a ritonavir-boosted PI, the mean change from baseline in total cholesterol (fasted) 
was -24 mg/dL, in HDL-cholesterol (fasted) -2 mg/dL, in LDL-cholesterol (fasted) -16 mg/dL, and in 
triglycerides (fasted) -64 mg/dL. 
 
Description of selected adverse reactions 
 
Renal impairment 
As Eviplera may cause renal damage, monitoring of renal function is recommended (see sections 4.4 
and 4.8, Summary of the safety profile).  Proximal renal tubulopathy generally resolved or improved 
after tenofovir disoproxil discontinuation.  However, in some patients, declines in CrCl did not 
completely resolve despite tenofovir disoproxil discontinuation.  Patients at risk of renal impairment 
(such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving 
concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of 
renal function despite tenofovir disoproxil discontinuation (see section 4.4). 
 
Interaction with didanosine 
Co-administration of Eviplera and didanosine is not recommended as it results in a 40-60% increase in 
systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see 
section 4.5).  Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
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.  Autoimmune 
disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the 
reported time to onset is more variable and these events can occur many months after initiation of 
treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART.  The frequency of this is unknown 
(see section 4.4). 
 
Severe skin reactions 
Severe skin reactions with systemic symptoms have been reported during post-marketing experience 
with Eviplera, including rashes accompanied by fever, blisters, conjunctivitis, angioedema, elevated 
liver function tests, and/or eosinophilia (see section 4.4). 
 
Paediatric population 
 
Insufficient safety data are available for children under the age of 18 years.  Eviplera is not 
recommended in this population (see section 4.2). 
 
When emtricitabine (one of the components of Eviplera) was administered to paediatric patients, the 
following adverse reactions were observed more frequently in addition to the adverse reactions 
reported in adults: anaemia was common (9.5%) and skin discolouration (increased pigmentation) was 



25 

very common (31.8%) in paediatric patients (see section 4.8, Tabulated summary of adverse 
reactions). 
 
Other special populations 
 
Elderly 
Eviplera has not been studied in patients over the age of 65 years.  Elderly patients are more likely to 
have decreased renal function, therefore caution should be exercised when treating elderly patients 
with Eviplera (see section 4.4). 
 
Patients with renal impairment 
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended 
in any patient with renal impairment treated with Eviplera (see sections 4.2, 4.4 and 5.2). 
 
HIV/HBV or HCV co-infected patients 
The adverse reaction profile of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil in 
patients co-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with 
HIV without co-infection.  However, as would be expected in this patient population, elevations in 
AST and ALT occurred more frequently than in the general HIV infected population. 
 
Exacerbations of hepatitis after discontinuation of treatment 
In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have 
occurred after discontinuation of treatment (see section 4.4). 
 
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 the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
An increased risk of adverse reactions associated with Eviplera and its individual components may be 
seen in the event of an overdose. 
 
If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and 
standard supportive treatment applied as necessary including observation of the clinical status of the 
patient and monitoring of vital signs and ECG (QT interval). 
 
There is no specific antidote for overdose with Eviplera.  Up to 30% of the emtricitabine dose and 
approximately 10% of the tenofovir dose can be removed by haemodialysis.  It is not known whether 
emtricitabine or tenofovir can be removed by peritoneal dialysis.  Since rilpivirine is highly protein 
bound, dialysis is unlikely to result in significant removal of the active substance.  Further 
management should be as clinically indicated or as recommended by the national poisons centre, 
where available. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, 
combinations.  ATC code: J05AR08. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

Mechanism of action and pharmacodynamic effects 
 
Emtricitabine is a nucleoside analogue of cytidine.  Tenofovir disoproxil is converted in vivo to 
tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate.  Both 
emtricitabine and tenofovir have activity that is specific to HIV-1, HIV-2 and, HBV. 
 
Rilpivirine is a diarylpyrimidine NNRTI of HIV-1.  Rilpivirine activity is mediated by 
non-competitive inhibition of HIV-1 reverse transcriptase (RT). 
 
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate 
and tenofovir diphosphate, respectively.  In vitro studies have shown that both emtricitabine and 
tenofovir can be fully phosphorylated when combined together in cells.  Emtricitabine triphosphate 
and tenofovir diphosphate competitively inhibit HIV-1 RT, resulting in DNA chain termination. 
 
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA 
polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.  Rilpivirine 
does not inhibit the human cellular DNA polymerases α, β and mitochondrial DNA polymerase γ. 
 
Antiviral activity in vitro 
 
The triple combination of emtricitabine, rilpivirine, and tenofovir demonstrated synergistic antiviral 
activity in cell culture. 
 
The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells.  The 
50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013 to 0.64 µM. 
 
Emtricitabine displayed antiviral activity in cell culture against HIV-1 subtype A, B, C, D, E, F, and G 
(EC50 values ranged from 0.007 to 0.075 µM) and showed strain specific activity against HIV-2 
(EC50 values ranged from 0.007 to 1.5 µM). 
 
In combination studies of emtricitabine with NRTIs (abacavir, didanosine, lamivudine, stavudine, 
tenofovir, and zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine), and PIs 
(amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. 
 
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 2,510 to 
10,830 nM (920 to 3,970 ng/mL), treatment of HIV-2 infection with rilpivirine hydrochloride 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 to 1.01 nM (0.03 to 0.37 ng/mL) 
and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL). 
 
The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes.  
The EC50 values for tenofovir were in the range of 0.04 to 8.5 µM. 
 
Tenofovir displayed antiviral activity in cell culture against HIV-1 subtype A, B, C, D, E, F, G, and O 
(EC50 values ranged from 0.5 to 2.2 µM) and strain specific activity against HIV-2 (EC50 values 
ranged from 1.6 to 5.5 µM). 
 
In combination studies of tenofovir with NRTIs (abacavir, didanosine, emtricitabine, lamivudine, 
stavudine, and zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine), and PIs 
(amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were 
observed. 



27 

 
Resistance 
 
Considering all of the available in vitro data and data generated in previously untreated patients, the 
following resistance-associated mutations in HIV-1 RT, when present at baseline, may affect the 
activity of Eviplera: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, 
Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and the 
combination of L100I and K103N. 
 
A negative impact by NNRTI mutations other than those listed above (e.g. mutations K103N or L100I 
as single mutations) cannot be excluded, since this was not studied in vivo in a sufficient number of 
patients. 
 
As with other antiretroviral medicinal products, resistance testing and/or historical resistance data 
should guide the use of Eviplera (see section 4.4). 
 
In cell culture 
Resistance to emtricitabine or tenofovir has been seen in vitro and in some HIV-1 infected patients due 
to the development of the M184V or M184I substitution in RT with emtricitabine, or the K65R 
substitution in RT with tenofovir.  In addition, a K70E substitution in HIV-1 RT has been selected by 
tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir and 
lamivudine.  No other pathways of resistance to emtricitabine or tenofovir have been identified.  
Emtricitabine-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine, but 
retained sensitivity to didanosine, stavudine, tenofovir, zalcitabine and zidovudine.  The K65R 
mutation can also be selected by abacavir or didanosine and results in reduced susceptibility to these 
agents plus to lamivudine, emtricitabine, and tenofovir.  Tenofovir disoproxil should be avoided in 
patients with HIV-1 harbouring the K65R mutation.  The K65R, M184V, and K65R+M184V mutants 
of HIV-1 remain fully susceptible to rilpivirine. 
 
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. 
 
In treatment-naïve HIV-1 infected patients 
For the resistance analyses, a broader definition of virologic failure was used than in the primary 
efficacy analysis.  In the cumulative week 96 pooled resistance analysis for patients receiving 
rilpivirine in combination with emtricitabine/tenofovir disoproxil, a greater risk of virologic failure for 
patients in the rilpivirine arm was observed within the first 48 weeks of these studies (11.5% in the 
rilpivirine arm and 4.2% in the efavirenz arm) while low rates of virologic failure, similar between the 
treatment arms, were observed from the week 48 to week 96 analysis (15 patients or 2.7% in the 
rilpivirine arm and 14 patients or 2.6% in the efavirenz arm).  Of these virologic failures 5/15 
(rilpivirine) and 5/14 (efavirenz) were in patients with a baseline viral load of ≤ 100,000 copies/mL. 
 
In the week 96 pooled resistance analysis for patients receiving emtricitabine/tenofovir disoproxil + 
rilpivirine hydrochloride in the Phase III clinical studies C209 and C215, there were 78 virologic 
failure patients with genotypic resistance information available for 71 of those patients.  In this 
analysis, the NNRTI resistance-associated mutations that developed most commonly in these patients 
were: V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y and F227C.  The most common 
mutations were the same in the week 48 and week 96 analyses.  In the studies, the presence of the 
mutations V90I and V189I at baseline did not affect the response.  The E138K substitution emerged 
most frequently during rilpivirine treatment, commonly in combination with the M184I substitution.  
52% of patients with virologic failure in the rilpivirine arm developed concomitant NNRTI and NRTI 
mutations.  The mutations associated with NRTI resistance that developed in 3 or more patients were: 
K65R, K70E, M184V/I and K219E during the treatment period. 
 



28 

Through week 96, fewer patients in the rilpivirine arm with baseline viral load ≤ 100,000 copies/mL 
had emerging resistance-associated substitutions and/or phenotypic resistance to rilpivirine (7/288) 
than patients with baseline viral load > 100,000 copies/mL (30/262).  Among those patients who 
developed resistance to rilpivirine, 4/7 patients with baseline viral load ≤ 100,000 copies/mL and 
28/30 patients with baseline viral load > 100,000 copies/mL had cross-resistance to other NNRTIs. 
 
In virologically suppressed HIV-1 infected patients 
Study GS-US-264-0106 
Of the 469 Eviplera-treated patients [317 patients who switched to Eviplera at baseline (Eviplera arm) 
and 152 patients who switched at week 24 (Delayed Switch arm)], a total of 7 patients were analysed 
for resistance development and all had genotypic and phenotypic data available.  Through week 24, 
two patients who switched to Eviplera at baseline (2 of 317 patients, 0.6%) and one patient who 
maintained their ritonavir-boosted PI-based regimen [Stayed on Baseline Regimen (SBR) arm] (1 of 
159 patients, 0.6%) developed genotypic and/or phenotypic resistance to study drugs.  After week 24, 
the HIV-1 from 2 additional patients in the Eviplera arm developed resistance by week 48 (total of 4 
of 469 patients, 0.9%).  The remaining 3 Eviplera-treated patients did not have emergent resistance. 
 
The most common emergent resistance mutations in Eviplera-treated patients were M184V/I and 
E138K in RT.  All patients remained susceptible to tenofovir.  Of the 24 patients treated with Eviplera 
who had the NNRTI-associated K103N substitution pre-existing at baseline in their HIV-1, 17 of 
18 patients in the Eviplera arm and 5 of 6 patients in the SBR arm maintained virologic suppression 
after switching to Eviplera through 48 weeks and 24 weeks of treatment, respectively.  One patient 
with pre-existing K103N at baseline had virologic failure with additional emergent resistance by 
week 48. 
 
Study GS-US-264-0111 
Through week 48, no emergent resistance developed in the 2 patients who failed virologically among 
patients who switched to Eviplera from efavirenz/emtricitabine/tenofovir disoproxil (0 of 49 patients). 
 
Cross-resistance 
 
No significant cross-resistance has been demonstrated between rilpivirine-resistant HIV-1 variants and 
emtricitabine or tenofovir, or between emtricitabine- or tenofovir-resistant variants and rilpivirine. 
 
In cell culture 
Emtricitabine 
Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but 
retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine. 
 
Viruses harbouring substitutions conferring reduced susceptibility to stavudine and 
zidovudine-thymidine analogue-associated mutations-TAMs (M41L, D67N, K70R, L210W, T215Y/F, 
K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine.  HIV-1 containing the K103N 
substitution or other substitutions associated with resistance to rilpivirine and other NNRTIs was 
susceptible to emtricitabine. 
 
Rilpivirine hydrochloride 
In a panel of 67 HIV-1 recombinant laboratory strains with one 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 and Y181V/I.  The 
K103N substitution alone did not result in reduced susceptibility to rilpivirine, but the combination of 
K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.  In another study, the 
Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9-fold for clinical isolates and 
6-fold for site-directed mutants. 
 



29 

Tenofovir disoproxil 
The K65R and also the K70E substitution result in reduced susceptibility to abacavir, didanosine, 
lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine. 
 
Patients with HIV-1 expressing three or more TAMs that included either the M41L or L210W RT 
substitution showed reduced response to tenofovir disoproxil. 
 
Virologic response to tenofovir disoproxil was not reduced in patients with HIV-1 that expressed the 
abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. 
 
HIV-1 containing the K103N, Y181C, or rilpivirine-associated substitutions with resistance to 
NNRTIs were susceptible to tenofovir. 
 
In treatment-naïve patients 
Resistance outcomes, including cross-resistance to other NNRTIs, in patients receiving rilpivirine 
hydrochloride in combination with emtricitabine/tenofovir disoproxil in Phase III studies (C209 and 
C215 pooled data) and experiencing virological failure, are shown in Table 3 below. 
 
Table 3: Phenotypic resistance and cross-resistance outcomes from studies C209 and C215 
(pooled data) for patients receiving rilpivirine hydrochloride in combination with 
emtricitabine/tenofovir disoproxil at week 96 (based on resistance analysis) 
 

 In patients with 
phenotypic data 
(n = 66) 

In patients with 
BL VL1 ≤ 100,000 
copies/mL (n = 22) 

In patients with BL 
VL1 > 100,000 
copies/mL (n = 44) 

Resistance to rilpivirine2 
Cross-resistance3 to 
          etravirine 
          efavirenz 
          nevirapine 

31/66 
 

28/31 
27/31 
13/31 

4/22 
 

3/4 
3/4 
1/4 

27/44 
 

25/27 
24/27 
12/27 

Resistance to 
emtricitabine/lamivudine 
(M184I/V) 

40/66 9/22 31/44 

Resistance to tenofovir 
(K65R) 

2/66 0/22 2/44 

1 BL VL = Baseline viral load. 
2 Phenotypic resistance to rilpivirine (> 3.7-fold change compared to control). 
3 Phenotypic resistance (Antivirogram). 
 
In virologically suppressed HIV-1 infected patients 
In study GS-US-264-0106, 4 of the 469 patients who switched from a ritonavir-PI-based regimen to 
Eviplera had HIV-1 with reduced susceptibility to at least one component of Eviplera through 
week 48.  De novo resistance to emtricitabine/lamivudine was seen in 4 cases, and also to rilpivirine in 
2 cases, with a consequent cross-resistance to efavirenz (2/2), nevirapine (2/2) and etravirine (1/2). 
 
Effects on electrocardiogram 
 
The effect of rilpivirine hydrochloride 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 hours at steady-state.  
Rilpivirine hydrochloride at the recommended dose of 25 mg once daily is not associated with a 
clinically relevant effect on QTc. 
 
When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine hydrochloride 
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) ms, respectively.  Steady-state administration of rilpivirine hydrochloride 75 mg once daily 
and 300 mg once daily resulted in a mean Cmax approximately 2.6-fold and 6.7-fold, respectively, 



30 

higher than the mean steady-state Cmax observed with the recommended 25 mg once daily dose of 
rilpivirine hydrochloride. 
 
Clinical experience 
 
Treatment-naïve HIV-1 infected patients 
The efficacy of Eviplera is based on the analyses of 96 week data from two randomised, double-blind, 
controlled studies C209 and C215.  Antiretroviral treatment-naïve HIV-1 infected patients were 
enrolled (n = 1,368) who had a plasma HIV-1 RNA ≥ 5,000 copies/mL and were screened for 
susceptibility to N(t)RTI and for absence of specific NNRTI resistance-associated mutations.  The 
studies are identical in design with the exception of the background regimen (BR).  Patients were 
randomised in a 1:1 ratio to receive either rilpivirine hydrochloride 25 mg (n = 686) once daily or 
efavirenz 600 mg (n = 682) once daily in addition to a BR.  In study C209 (n = 690), the BR was 
emtricitabine/tenofovir disoproxil.  In study C215 (n = 678), the BR consisted of 2 investigator 
selected N(t)RTIs: emtricitabine/tenofovir disoproxil (60%, n = 406) or lamivudine/zidovudine (30%, 
n = 204) or abacavir plus lamivudine (10%, n = 68). 
 
In the pooled analysis for C209 and C215 of patients who received a background regimen of 
emtricitabine/tenofovir disoproxil, demographic and baseline characteristics were balanced between 
the rilpivirine and efavirenz arm.  Table 4 displays selected demographic and baseline disease 
characteristics.  Median plasma HIV-1 RNA was 5.0 and 5.0 log10 copies/mL and median CD4+ count 
was 247 x 106 cells/L and 261 x 106 cells/L for patients randomised to rilpivirine and efavirenz arm, 
respectively. 
 
Table 4: Demographic and baseline characteristics of antiretroviral treatment-naïve HIV-1 
infected adult patients in studies C209 and C215 (pooled data for patients receiving rilpivirine 
hydrochloride or efavirenz in combination with emtricitabine/tenofovir disoproxil) at week 96 
 

 
 

Rilpivirine + 
Emtricitabine/Tenofovir 

disoproxil 
n = 550 

Efavirenz + 
Emtricitabine/Tenofovir 

disoproxil 
n = 546 

Demographic Characteristics 
Median age (range), years 36.0 

(18-78) 
36.0 

(19-69) 
Sex   
 Male 78% 79% 
 Female 22% 21% 
Ethnicity   
 White 64% 61% 
 Black/African American 25% 23% 
 Asian 10% 13% 
 Other 1% 1% 
 Not allowed to ask per local 

regulations 
1% 1% 

Baseline disease characteristics 
Median baseline plasma 
HIV-1 RNA (range), 
log10 copies/mL 

5.0 
(2-7) 

5.0 
(3-7) 

Median baseline CD4+ cell count 
(range), x 106 cells/L 

247 
(1-888) 

261 
(1-857) 

Percentage of patients with 
HBV/HCV co-infection 

7.7% 8.1% 

 
A subgroup analysis of the virologic response (< 50 HIV-1 RNA copies/mL) at both 48 weeks and 
96 weeks, and virologic failure by baseline viral load (pooled data from the two Phase III clinical 
studies, C209 and C215, for patients receiving the emtricitabine/tenofovir disoproxil background 
regimen) is presented in Table 5.  The response rate (confirmed undetectable viral load 
< 50 HIV-1 RNA copies/mL) at week 96 was comparable between the rilpivirine arm and the 



31 

efavirenz arm.  The incidence of virologic failure was higher in the rilpivirine arm than in 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 in 
the rilpivirine arm. 
 
Table 5: Virologic outcomes of randomised treatment of studies C209 and C215 (pooled data for 
patients receiving rilpivirine hydrochloride or efavirenz in combination with 
emtricitabine/tenofovir disoproxil) at week 48 (primary) and week 96 
 

 Rilpivirine + 
Emtricitabine/ 

Tenofovir disoproxil 
n = 550 

Efavirenz + 
Emtricitabine/ 

Tenofovir disoproxil 
n = 546 

Rilpivirine + 
Emtricitabine/ 

Tenofovir 
disoproxil 

n = 550 

Efavirenz + 
Emtricitabine/ 

Tenofovir 
disoproxil 

n = 546 
 Week 48 Week 96 
Overall response 
(HIV-1 RNA 
< 50 copies/mL 
(TLOVRa))b 

83.5% (459/550) 
(80.4, 86.6) 

82.4% (450/546) 
(79.2, 85.6) 

76.9% (423/550) 77.3% (422/546) 

By baseline viral load (copies/mL) 
    ≤ 100,000 89.6% (258/288) 

(86.1, 93.1) 
84.8% (217/256) 

(80.4, 89.2) 
83.7% (241/288) 80.8% (206/255) 

    > 100,000 76.7% (201/262) 
(71.6, 81.8) 

80.3% (233/290) 
(75.8, 84.9) 

69.5% (182/262) 74.2% (216/291) 

By baseline CD4+ cell count (x 106 cells/L) 
    < 50 51.7% (15/29) 

(33.5, 69.9) 
79.3% (23/29) 

(64.6, 94.1) 
48.3% 

(28.9, 67.6) 
72.4% 

(55.1, 89.7) 
    ≥ 50-200 80.9% (123/152) 

(74.7, 87.2) 
80.7% (109/135) 

(74.1, 87.4) 
71.1% 

(63.8, 78.3) 
72.6% 

(65.0, 80.2) 
    ≥ 200-350 86.3% (215/249) 

(82.1, 90.6) 
82.3% (205/249) 

(77.6, 87.1) 
80.7% 

(75.8, 85.7) 
78.7% 

(73.6, 83.8) 
    ≥ 350 89.1% (106/119) 

(83.5, 94.7) 
85.0% (113/133) 

(78.9, 91.0) 
84.0% 

(77.4, 90.7) 
80.5% 

(73.6, 87.3) 
Non-response 
Virologic failure 
(all patients) 

9.5% (52/550) 4.2% (23/546) 11.5% (63/550)c 5.1% (28/546)d 

By baseline viral load (copies/mL) 
    ≤ 100,000 4.2% (12/288) 2.3% (6/256) 5.9% (17/288) 2.4% (6/255) 
    > 100,000 15.3% (40/262) 5.9% (17/290) 17.6% (46/262) 7.6% (22/291) 
Death 0 0.2% (1/546) 0 0.7% (4/546) 
Discontinued due 
to adverse event 
(AE) 

2.2% (12/550) 7.1% (39/546) 3.6% (20/550) 8.1% (44/546) 

Discontinued for 
non-AE reasone 

4.9% (27/550) 6.0% (33/546) 8% (44/550) 8.8% (48/546) 

n = total number of patients per treatment group 
a ITT TLOVR = Intention to treat time to loss of virologic response 
b The difference of response rate is 1% (95% confidence interval -3% to 6%) using normal approximation. 
c There were 17 new virologic failures between the week 48 primary analysis and week 96 (6 patients with baseline viral 

load ≤ 100,000 copies/mL and 11 patients with baseline viral load > 100,000 copies/mL).  There were also 
reclassifications in the week 48 primary analysis with the most common being reclassification from virologic failure to 
discontinued for non-AE reasons. 

d There were 10 new virologic failures between the week 48 primary analysis and week 96 (3 patients with baseline viral 
load ≤ 100,000 copies/mL and 7 patients with baseline viral load > 100,000 copies/mL).  There were also 
reclassifications in the week 48 primary analysis with the most common being reclassification from virologic failure to 
discontinued for non-AE reasons. 

e e.g. lost to follow up, non-compliance, withdrew consent. 
 
Emtricitabine/tenofovir disoproxil + rilpivirine hydrochloride has been shown to be non-inferior in 
achieving HIV-1 RNA < 50 copies/mL compared to emtricitabine/tenofovir disoproxil + efavirenz. 
 



32 

At week 96 the mean changes in CD4+ cell count from baseline were +226 x 106 cells/L and 
+222 x 106 cells/L for the rilpivirine and efavirenz treatment arms, respectively, of patients receiving 
the emtricitabine/tenofovir disoproxil background regimen. 
 
There were no new cross-resistance patterns at week 96 compared to week 48.  The resistance 
outcome for patients with protocol defined virological failure and phenotypic resistance at week 96 are 
shown in Table 6: 
 
Table 6: Phenotypic resistance outcomes from studies C209 and C215 (pooled data for patients 
receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine/tenofovir 
disoproxil) at week 96 (based on resistance analysis) 
 

 Rilpivirine + 
Emtricitabine/Tenofovir 

disoproxil  
n = 550 

Efavirenz + 
Emtricitabine/Tenofovir 

disoproxil  
n = 546 

Resistance to 
emtricitabine/lamivudine 

7.3% (40/550) 0.9% (5/546) 

Resistance to rilpivirine 5.6% (31/550) 0 
Resistance to efavirenz 5.1% (28/550) 2.2% (12/546) 

 
For those patients failing therapy with Eviplera and who developed resistance to Eviplera 
cross-resistance to other approved NNRTIs (etravirine, efavirenz, nevirapine) was generally seen. 
 
Virologically suppressed HIV-1 infected patients 
Study GS-US-264-0106 
The efficacy and safety of switching from a ritonavir-boosted PI in combination with two NRTIs to 
Eviplera STR was evaluated in a randomised, open-label study in virologically suppressed HIV-1 
infected adults.  Patients had to be on either their first or second antiretroviral regimen with no history 
of virologic failure, have no current or past history of resistance to any of the three components of 
Eviplera, and must have been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months 
prior to screening.  Patients were randomised in a 2:1 ratio to either switch to Eviplera at baseline 
(Eviplera arm, n = 317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, 
n = 159) before switching to Eviplera for an additional 24 weeks (Delayed Switch arm, n = 152).  
Patients had a mean age of 42 years (range 19-73), 88% were male, 77% were White, 17% were 
Black, and 17% were Hispanic/Latino.  The mean baseline CD4 cell count was 584 x 106 cells/L 
(range 42-1,484).  Randomisation was stratified by use of tenofovir disoproxil and/or 
lopinavir/ritonavir in the baseline regimen. 
 
Treatment outcomes through 24 weeks are presented in Table 7. 
 
Table 7: Outcomes of randomised treatment in study GS-US-264-0106 at week 24a 
 

 Eviplera arm 
n = 317 

Stayed on Baseline 
Regimen (SBR) arm 

n = 159 
Virologic success after 24 weeks of treatmentb 
HIV-1 RNA < 50 copies/mL 

94% (297/317) 90% (143/159) 

Virologic failurec 1% (3/317) 5% (8/159) 
No virologic data in week 24 window   

Discontinued study drug due to AE or 
deathd 

2% (6/317) 0% 

Discontinued study drug due to other 
reasons and last available 
HIV-1 RNA < 50 copies/mLe 

3% (11/317) 3% (5/159) 

Missing data during window but on study 
drug 

0% 2% (3/159) 



33 

 Eviplera arm 
n = 317 

Stayed on Baseline 
Regimen (SBR) arm 

n = 159 
CD4+ median increase from baseline 
(x 106 cells/L) 

+10 +22 

a Week 24 window is between day 127 and 210 (inclusive). 
b Snapshot analysis. 
c Includes patients who had HIV-1 RNA ≥ 50 copies/mL in the week 24 window, patients who discontinued early due to 

lack or loss of efficacy, patients who discontinued for reasons other than an adverse event (AE) or death, and at the time 
of discontinuation had a viral value of ≥ 50 copies/mL. 

d Includes patients who discontinued due to AE or death at any time point from day 1 through the week 24 window 
resulting in no virologic data on treatment during the specified window. 

e Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, 
loss to follow-up, etc. 

 
Switching to Eviplera was non-inferior in maintaining HIV-1 RNA < 50 copies/mL when compared to 
patients who stayed on a ritonavir-boosted PI in combination with two NRTIs [treatment difference 
(95% CI): + 3.8% (-1.6% to 9.1%)]. 
 
Among patients in the SBR arm who maintained their baseline regimen for 24 weeks and then 
switched to Eviplera, 92% (140/152) of patients had HIV-1 RNA < 50 copies/mL after 24 weeks of 
Eviplera, consistent with the week 24 results for patients who switched to Eviplera at baseline. 
 
At week 48, 89% (283/317) of patients randomised to switch to Eviplera at baseline (Eviplera) had 
HIV-1 RNA < 50 copies/mL, 3% (8/317) were considered virologic failures 
(HIV RNA ≥ 50 copies/mL), and 8% (26/317) did not have data available in the week 48 window.  Of 
the 26 patients without data available in the week 48 window, 7 patients discontinued due to adverse 
event (AE) or death, 16 patients discontinued for other reasons, and 3 patients were missing data but 
remained on study drug.  The median change in CD4+ cell count at week 48 was +17 x 106 cells/L, in 
the on-treatment analysis. 
 
There were 7/317 patients (2%) in the Eviplera arm and 6/152 patients (4%) in the Delayed Switch 
arm who permanently discontinued study drug due to a treatment-emergent adverse event (TEAE).  
No patients discontinued from the study due to a TEAE in the SBR arm. 
 
Study GS-US-264-0111 
The efficacy, safety, and pharmacokinetics of switching from efavirenz/emtricitabine/tenofovir 
disoproxil STR to Eviplera STR were evaluated in an open-label study in virologically suppressed 
HIV-1 infected adults.  Patients had to have previously only received efavirenz/emtricitabine/tenofovir 
disoproxil as their first antiretroviral regimen for at least three months, and wished to switch regimens 
due to efavirenz intolerance.  Patients had to be stably suppressed for at least 8 weeks prior to study 
entry, have no current or past history of resistance to any of the three components of Eviplera, and 
have HIV-1 RNA < 50 copies/mL at screening.  Patients were switched from 
efavirenz/emtricitabine/tenofovir disoproxil to Eviplera without a washout period.  Among 49 patients 
who received at least one dose of Eviplera, 100% of patients remained suppressed 
(HIV-1 RNA < 50 copies/mL) at week 12 and week 24.  At week 48, 94% (46/49) of patients 
remained suppressed, and 4% (2/49) were considered virologic failures (HIV-1 RNA ≥ 50 copies/mL).  
One patient (2%) did not have data available in the week 48 window; study drug was discontinued due 
to a protocol violation (i.e. reason other than AE or death) and the last available HIV-1 RNA was 
< 50 copies/mL. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Eviplera in all subsets of the paediatric population in the treatment of HIV-1 (see section 4.2 for 
information on paediatric use). 
 



34 

Pregnancy 
 
Rilpivirine (taken as Eviplera in 16 of 19 patients and another background regimen in 3 of 19 patients) 
was evaluated in study TMC114HIV3015 in pregnant women during the 2nd and 3rd trimesters, and 
postpartum.  The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part 
of an antiretroviral regimen was approximately 30% lower during pregnancy compared with 
postpartum (6-12 weeks).  The virologic response was generally preserved throughout the study: of the 
12 patients that completed the study, 10 patients were suppressed at the end of the study; in the other 
2 patients an increase in viral load was observed only postpartum, for at least 1 patient due to 
suspected suboptimal adherence.  No mother to child transmission occurred in all 10 infants born to 
the mothers who completed the study and for whom the HIV status was available.  Rilpivirine was 
well tolerated during pregnancy and postpartum.  There were no new safety findings compared with 
the known safety profile of rilpivirine in HIV-1 infected adults (see sections 4.2, 4.4 and 5.2). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
The bioequivalence of one Eviplera film-coated tablet with one emtricitabine 200 mg hard capsule, 
one rilpivirine (as hydrochloride) 25 mg film-coated tablet and one tenofovir disoproxil 245 mg 
film-coated tablet was established following single dose administration to fed, healthy subjects.  
Following oral administration of Eviplera with food emtricitabine is rapidly and extensively absorbed 
with maximum plasma concentrations occurring within 2.5 hours post-dose.  Maximum tenofovir 
concentrations are observed in plasma within 2 hours and maximum plasma concentrations of 
rilpivirine are generally achieved within 4-5 hours.  Following oral administration of tenofovir 
disoproxil to HIV infected patients, tenofovir disoproxil is rapidly absorbed and converted to 
tenofovir.  The absolute bioavailability of emtricitabine from 200 mg hard capsules was estimated to 
be 93%.  The oral bioavailability of tenofovir from tenofovir disoproxil tablets in fasted patients was 
approximately 25%.  The absolute bioavailability of rilpivirine is unknown.  The administration of 
Eviplera to healthy adult subjects with either a light meal (390 kcal) or a standard meal (540 kcal) 
resulted in increased exposures of rilpivirine and tenofovir relative to fasting conditions.  The Cmax and 
AUC of rilpivirine increased by 34% and 9% (light meal) and 26% and 16% (standard meal), 
respectively.  The Cmax and AUC for tenofovir increased by 12% and 28% (light meal) and 32% and 
38% (standard meal), respectively.  Emtricitabine exposures were not affected by food.  Eviplera must 
be administered with food to ensure optimal absorption (see section 4.2). 
 
Distribution 
 
Following intravenous administration the volume of distribution of the single components 
emtricitabine and tenofovir was approximately 1,400 mL/kg and 800 mL/kg, respectively.  After oral 
administration of the single components emtricitabine and tenofovir disoproxil, emtricitabine and 
tenofovir are widely distributed throughout the body.  In vitro binding of emtricitabine to human 
plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 µg/mL.  
In vitro binding of rilpivirine to human plasma proteins is approximately 99.7%, primarily to albumin.  
In vitro binding of tenofovir to plasma or serum protein was less than 0.7% and 7.2%, respectively, 
over the tenofovir concentration range 0.01 to 25 µg/mL. 
 
Biotransformation 
 
There is limited metabolism of emtricitabine.  The biotransformation of emtricitabine includes 
oxidation of the thiol moiety to form the 3’-sulphoxide diastereomers (approximately 9% of dose) and 
conjugation with glucuronic acid to form 2’-O-glucuronide (approximately 4% of dose).  In vitro 
experiments indicate that rilpivirine hydrochloride primarily undergoes oxidative metabolism 
mediated by the CYP3A system.  In vitro studies have determined that neither tenofovir disoproxil nor 
tenofovir are substrates for the CYP450 enzymes.  Neither emtricitabine nor tenofovir inhibited 
in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug 



35 

biotransformation.  Also, emtricitabine did not inhibit uridine-5’-diphosphoglucuronyl transferase, the 
enzyme responsible for glucuronidation. 
 
Elimination 
 
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in 
urine (approximately 86%) and faeces (approximately 14%).  Thirteen percent of the emtricitabine 
dose was recovered in urine as three metabolites.  The systemic clearance of emtricitabine averaged 
307 mL/min.  Following oral administration, the elimination half-life of emtricitabine is approximately 
10 hours. 
 
The terminal elimination half-life of rilpivirine is approximately 45 hours.  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. 
 
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system 
(human organic anion transporter 1 [hOAT1]) with approximately 70-80% of the dose excreted 
unchanged in urine following intravenous administration.  The apparent clearance of tenofovir 
averaged approximately 307 mL/min.  Renal clearance has been estimated to be approximately 
210 mL/min, which is in excess of the glomerular filtration rate.  This indicates that active tubular 
secretion is an important part of the elimination of tenofovir.  Following oral administration, the 
elimination half-life of tenofovir is approximately 12 to 18 hours. 
 
Pharmacokinetics in special populations 
 
Elderly 
Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokinetics 
is not different across the age range (18 to 78 years) evaluated, with only 2 patients aged 65 years of 
age or older. 
 
Gender 
Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.  No clinically 
relevant differences in pharmacokinetics of rilpivirine have been observed between men and women. 
 
Ethnicity 
No clinically important pharmacokinetic differences due to ethnicity have been identified. 
 
Paediatric population 
In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months 
up to 18 years) is similar to those seen in adults.  The pharmacokinetics of rilpivirine and tenofovir 
disoproxil in children and adolescents are under investigation.  Dosing recommendations for paediatric 
patients cannot be made due to insufficient data (see section 4.2). 
 
Renal impairment 
Limited data from clinical studies support once daily dosing of Eviplera in patients with mild renal 
impairment (CrCl 50-80 mL/min).  However, long-term safety data for the emtricitabine and tenofovir 
disoproxil components of Eviplera have not been evaluated in patients with mild renal impairment.  
Therefore, in patients with mild renal impairment Eviplera should only be used if the potential benefits 
of treatment are considered to outweigh the potential risks (see sections 4.2 and 4.4). 
 
Eviplera is not recommended for patients with moderate or severe renal impairment (CrCl 
< 50 mL/min).  Patients with moderate or severe renal impairment require a dose interval adjustment 
of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet (see 
sections 4.2 and 4.4). 
 



36 

Pharmacokinetic parameters were mainly determined following administration of single doses of 
emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected patients with varying 
degrees of renal impairment.  The degree of renal impairment was defined according to baseline CrCl 
(normal renal function when CrCl > 80 mL/min; mild impairment with CrCl = 50-79 mL/min; 
moderate impairment with CrCl = 30-49 mL/min and severe impairment with CrCl = 10-29 mL/min). 
 
The mean (%CV) emtricitabine drug exposure increased from 12 (25%) µg•h/mL in patients with 
normal renal function, to 20 (6%) µg•h/mL, 25 (23%) µg•h/mL and 34 (6%) µg•h/mL, in patients with 
mild, moderate and severe renal impairment, respectively. 
 
The mean (%CV) tenofovir drug exposure increased from 2,185 (12%) ng•h/mL in patients with 
normal renal function, to 3,064 (30%) ng•h/mL, 6,009 (42%) ng•h/mL and 15,985 (45%) ng•h/mL, in 
patients with mild, moderate and severe renal impairment, respectively. 
 
In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug 
exposures substantially increased over 72 hours to 53 µg•h/mL (19%) of emtricitabine, and over 
48 hours to 42,857 ng•h/mL (29%) of tenofovir. 
 
A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics of 
tenofovir disoproxil in combination with emtricitabine in HIV infected patients with renal impairment.  
A subgroup of patients with baseline CrCl between 50 and 60 mL/min, receiving once daily dosing, 
had a 2- to 4-fold increase in tenofovir exposure and worsening renal function. 
 
The pharmacokinetics of rilpivirine has not been studied in patients with renal insufficiency.  Renal 
elimination of rilpivirine is negligible.  In patients with severe renal impairment or ESRD, plasma 
concentrations may be increased due to alteration of drug absorption, distribution and/or metabolism 
secondary to renal dysfunction.  As rilpivirine is highly bound to plasma proteins, it is unlikely that it 
will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.9). 
 
Hepatic impairment 
No dose adjustment of Eviplera is suggested but caution is advised in patients with moderate hepatic 
impairment.  Eviplera has not been studied in patients with severe hepatic impairment (CPT Score C).  
Therefore, Eviplera is not recommended in patients with severe hepatic impairment (see sections 4.2 
and 4.4). 
 
The pharmacokinetics of emtricitabine has not been studied in patients with varying degrees of hepatic 
insufficiency. 
 
Rilpivirine hydrochloride is primarily metabolised and eliminated by the liver.  In a study comparing 
8 patients with mild hepatic impairment (CPT Score A) to 8 matched controls and 8 patients with 
moderate hepatic impairment (CPT 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.  Rilpivirine has not been studied in patients with severe hepatic 
impairment (CPT Score C) (see section 4.2).  However, it may not be excluded that the 
pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate 
impairment. 
 
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected subjects with 
varying degrees of hepatic impairment defined according to CPT classification.  Tenofovir 
pharmacokinetics was not substantially altered in subjects with hepatic impairment suggesting that no 
dose adjustment is required in these subjects.  The mean (%CV) tenofovir Cmax and AUC0-∞ values 
were 223 (34.8%) ng/mL and 2,050 (50.8%) ng•h/mL, respectively, in normal subjects compared with 
289 (46.0%) ng/mL and 2,310 (43.5%) ng•h/mL in subjects with moderate hepatic impairment, and 
305 (24.8%) ng/mL and 2,740 (44.0%) ng•h/mL in subjects with severe hepatic impairment. 
 



37 

Hepatitis B and/or hepatitis C virus co-infection 
In general, emtricitabine pharmacokinetics in HBV infected patients was similar to those in healthy 
subjects and in HIV infected patients. 
 
Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no 
clinically relevant effect on the exposure to rilpivirine. 
 
Switching from an efavirenz-based regimen 
The efficacy data from study GS-US-264-0111 (see section 5.1) indicates that the brief period of lower 
rilpivirine exposure does not impact antiviral efficacy of Eviplera.  Due to the decline in efavirenz 
plasma levels, the inductive effect decreased and rilpivirine concentrations started to normalise.  
During the time period of declining efavirenz plasma levels and increasing rilpivirine plasma levels 
after switching, none of the patients had efavirenz or rilpivirine levels below their respective IC90 
levels at the same time.  No dose adjustment is required following the switch from an 
efavirenz-containing regimen. 
 
Pregnancy and postpartum 
After taking rilpivirine 25 mg once daily as part of an antiretroviral regimen, the total exposure of 
rilpivirine was lower during pregnancy (similar for the 2nd and 3rd trimester) compared with 
postpartum.  The decrease in the unbound free fraction of rilpivirine exposure (i.e. active) during 
pregnancy compared to postpartum was less pronounced than for total exposure of rilpivirine. 
 
In women receiving rilpivirine 25 mg once daily during the 2nd trimester of pregnancy, mean intra-
individual values for total rilpivirine Cmax, AUC24h and Cmin values were 21%, 29% and 35% lower, 
respectively, as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cmin 
values were 20%, 31% and 42% lower, respectively, as compared to postpartum. 
 
5.3 Preclinical safety data 
 
Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies 
of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to 
reproduction and development. 
 
Non-clinical data on rilpivirine hydrochloride reveal no special hazard for humans based on studies of 
safety pharmacology, drug disposition, genotoxicity, carcinogenic potential, and toxicity to 
reproduction and development.  Liver toxicity associated with liver enzyme induction was observed in 
rodents.  In dogs cholestasis-like effects were noted. 
 
Carcinogenicity studies with rilpivirine in mice and rats revealed tumorigenic potential specific for 
these species, but are regarded as of no relevance for humans. 
 
Studies in animals have shown limited placenta passage of rilpivirine.  It is not known whether 
placental transfer of rilpivirine occurs in pregnant women.  There was no teratogenicity with 
rilpivirine in rats and rabbits. 
 
Non-clinical data on tenofovir disoproxil reveal no special hazard for humans based on conventional 
studies of safety pharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction and 
development.  Findings in repeated dose toxicity studies in rats, dogs and monkeys at exposure levels 
greater than or equal to clinical exposure levels and with possible relevance to clinical use included 
kidney and bone changes and a decrease in serum phosphate concentration.  Bone toxicity was 
diagnosed as osteomalacia (monkeys) and reduced BMD (rats and dogs). 
 
Genotoxicity and repeated dose toxicity studies of one month or less with the combination of 
emtricitabine and tenofovir disproxil found no exacerbation of toxicological effects compared to 
studies with the separate components. 
 
 



38 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Microcrystalline cellulose 
Polysorbate 20 
Povidone 
Pregelatinised maize starch 
 
Film-coating 
 
Hypromellose 
Indigo carmine aluminium lake 
Lactose monohydrate 
Polyethylene glycol 
Red iron oxide 
Sunset yellow aluminium lake (E110) 
Titanium dioxide 
Triacetin 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 
30 film-coated tablets and a silica gel desiccant. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 



39 

 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/737/001 
EU/1/11/737/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 November 2011 
Date of latest renewal: 22 July 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



41 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
  



42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



44 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Eviplera 200 mg/25 mg/245 mg film-coated tablets 
emtricitabine/rilpivirine/tenofovir disoproxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride) and 
245 mg of tenofovir disoproxil (as fumarate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate and sunset yellow aluminium lake (E110), see leaflet for further 
information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 (3 bottles of 30) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 



45 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/737/001 30 film-coated tablets. 
EU/1/11/737/002 90 (3 bottles of 30) film-coated tablets. 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Eviplera [outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 

  



46 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



47 

Package leaflet: Information for the user 
 

Eviplera 200 mg/25 mg/245 mg film-coated tablets 
emtricitabine/rilpivirine/tenofovir disoproxil 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet: 
 
1. What Eviplera is and what it is used for 
2. What you need to know before you take Eviplera 
3. How to take Eviplera 
4. Possible side effects 
5. How to store Eviplera 
6. Contents of the pack and other information 
 
 
1. What Eviplera is and what it is used for 
 
Eviplera contains three active substances that are used to treat Human Immunodeficiency Virus 
(HIV) infection: 
 
• Emtricitabine, a nucleoside reverse transcriptase inhibitor (NRTI). 
• Rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). 
• Tenofovir disoproxil, a nucleotide reverse transcriptase inhibitor (NtRTI). 
 
Each of these active substances, also known as antiretroviral medicines, works by interfering with an 
enzyme (a protein called ‘reverse transcriptase’) that is essential for the virus to multiply. 
 
Eviplera reduces the amount of HIV in your body.  This, will improve your immune system and 
reduces the risk of developing illnesses linked to HIV infection. 
 
Eviplera is a treatment for Human Immunodeficiency Virus (HIV) infection in adults aged 
18 years and over. 
 
 
2. What you need to know before you take Eviplera 
 
Do not take Eviplera 
 
• If you are allergic to emtricitabine, rilpivirine, tenofovir disoproxil, or any of the other 

ingredients of this medicine (listed in section 6 of this leaflet). 
 
 If this applies to you, tell your doctor immediately. 

 
• If you are currently taking any of the following medicines 

• carbamazepine, oxcarbazepine, phenobarbital and phenytoin (medicines to treat 
epilepsy and prevent seizures) 

• rifampicin and rifapentine (used to treat some bacterial infections such as tuberculosis) 



48 

• omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole (proton 
pump inhibitors that are medicines used to prevent and treat stomach ulcers, heartburn, 
acid reflux disease) 

• dexamethasone (a corticosteroid used to treat inflammation and suppress the immune 
system) when taken by mouth or injected (except as a single dose treatment) 

• products that contain St. John’s wort (Hypericum perforatum) (a herbal remedy used 
for depression and anxiety) 

 
Warnings and precautions 
 
You must remain under the care of your doctor while taking Eviplera. 
 
• You can still pass on HIV when taking this medicine, although the risk is lowered by effective 

antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid infecting other 
people.  This medicine is not a cure for HIV infection.  While taking Eviplera you may still 
develop infections or other illnesses associated with HIV infection. 

 
• Tell your doctor if you had kidney disease, or if tests have shown kidney problems.  Eviplera 

may affect your kidneys.  Before and during treatment, your doctor may order blood tests to 
measure kidney function.  Eviplera is not recommended if you have moderate to severe kidney 
disease. 
 
Eviplera is not usually taken with other medicines that can damage your kidneys (see Other 
medicines and Eviplera).  If this is unavoidable, your doctor will monitor your kidney function 
once a week. 

 
• Talk to your doctor if you have a history of liver disease, including hepatitis.  HIV patients 

with liver disease (including chronic hepatitis B or C), who are treated with antiretrovirals, have 
a higher risk of severe and potentially fatal liver complications.  If you have hepatitis B, your 
doctor will carefully consider the best treatment regimen for you.  Two of the active substances 
in Eviplera (tenofovir disoproxil and emtricitabine) show some activity against hepatitis B virus.  
If you have a history of liver disease, or chronic hepatitis B infection, your doctor may conduct 
blood tests in order to monitor liver function. 

 
If you have hepatitis B infection, liver problems may become worse after you stop taking 
Eviplera.  It is important not to stop taking Eviplera without talking to your doctor: see 
section 3, Do not stop taking Eviplera. 

 
• Tell your doctor immediately and stop taking Eviplera if you develop a skin rash with the 

following symptoms: fever, blisters, redness in your eyes and swelling of your face, mouth 
or body.  This may become severe or potentially life-threatening. 

 
• Talk to your doctor if you are over 65 years of age.  Not enough patients over the age of 65 

have been studied.  If you are over 65 years of age and are prescribed Eviplera, your doctor will 
monitor you carefully. 

 
While you take Eviplera 
Once you start taking Eviplera, look out for: 
 
• any signs of inflammation or infection 
• bone problems 
 
 If you notice any of these symptoms, tell your doctor immediately. 
 



49 

Children and adolescents 
 
Do not give this medicine to children and adolescents under 18 years of age. 
 
Other medicines and Eviplera 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  This includes medicines and herbal medicines obtained without a prescription. 
 
Tell your doctor if you are taking any of the following: 
 
• Any other medicines containing: 

• emtricitabine 
• rilpivirine 
• tenofovir disoproxil 
• tenofovir alafenamide 
• any other antiviral medicines that contain lamivudine or adefovir dipivoxil 

 
Eviplera may interact with other medicines.  As a result, the amounts of Eviplera or other medicines in 
your blood may be affected.  This may stop your medicines from working properly, or may make any 
side effects worse.  In some cases, your doctor may need to adjust your dose or check your blood 
levels. 
 
• Medicines that may damage your kidneys, examples include: 

• aminoglycosides (such as streptomycin, neomycin and gentamicin), vancomycin (for 
bacterial infections) 

• foscarnet, ganciclovir, cidofovir (for viral infections) 
• amphotericin B, pentamidine (for fungal infections) 
• interleukin-2, also called aldesleukin (to treat cancer) 
• non-steroidal anti-inflammatory drugs (NSAIDs, to relieve bone or muscle pains) 

 
• Medicines containing didanosine (for HIV infection): Taking Eviplera with other antiviral 

medicines that contain didanosine can raise the levels of didanosine in your blood and may 
reduce CD4+ cell counts.  Inflammation of the pancreas and lactic acidosis (excess lactic acid in 
the blood), which sometimes caused death, have been reported rarely when medicines 
containing tenofovir disoproxil and didanosine were taken together.  Your doctor will carefully 
consider whether to treat you with other medicines used for treating HIV infection (see Other 
medicines used for HIV infection). 

 
• Other medicines used for HIV infection: Non-nucleoside reverse transcriptase inhibitors 

(NNRTIs).  Eviplera contains an NNRTI (rilpivirine) and so Eviplera is not to be combined with 
other medicines of this type.  Your doctor will discuss a different medicine if required. 

 
• Rifabutin, a medicine to treat some bacterial infections.  This medicine can decrease the 

amount of rilpivirine (a component of Eviplera) in your blood.  Your doctor may need to give 
you an additional dose of rilpivirine to treat your HIV infection (see section 3, How to take 
Eviplera). 

 
• Antibiotics used to treat bacterial infections including tuberculosis containing: 

• clarithromycin 
• erythromycin 
These medicines can increase the amount of rilpivirine (a component of Eviplera) in your blood.  
Your doctor may need to change the dose of the antibiotic or give you a different antibiotic. 

 



50 

• Medicines for stomach ulcers, heartburn or acid reflux such as: 
• antacids (aluminium/magnesium hydroxide or calcium carbonate) 
• H2-antagonists (famotidine, cimetidine, nizatidine or ranitidine) 
These medicines can decrease the amount of rilpivirine (a component of Eviplera) in your 
blood.  If you are taking one of these medicines your doctor will either give you a different 
medicine for stomach ulcers, heartburn or acid reflux, or recommend how and when you take 
that medicine. 

 
• If you are taking an antacid (such as medicines containing magnesium or potassium), take it 

at least 2 hours before or at least 4 hours after Eviplera (see section 3, How to take Eviplera). 
 
• If you are taking an H2-antagonist (also used to treat stomach acid or acid reflux disease), 

take it at least 12 hours before or at least 4 hours after Eviplera.  H2-antagonists can only be 
taken once a day if you take Eviplera.  H2-antagonists should not be taken in a twice a day 
regimen.  Talk to your doctor about an alternative regimen (see section 3, How to take 
Eviplera). 

 
• Methadone, a medicine used to treat opiate addiction, as your doctor may need to change your 

methadone dose. 
 
• Dabigatran etexilate, a medicine used to treat heart conditions, as your doctor may need to 

monitor the levels of this medicine in your blood. 
 
 Tell your doctor if you are taking any of these medicines.  Do not stop your treatment without 

contacting your doctor. 
 
Pregnancy and breast-feeding 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
• Women must not get pregnant while taking Eviplera. 
• Use effective contraception while taking Eviplera. 
• Tell your doctor immediately if you become pregnant or if you plan to become pregnant.  

Pregnant women should not take Eviplera unless you and your doctor decide it is clearly 
needed.  Your doctor will discuss the potential benefits and risks of taking Eviplera to you and 
your child. 

• If you have taken Eviplera during your pregnancy, your doctor may request regular blood tests 
and other diagnostic tests to monitor the development of your child.  In children whose mothers 
took NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk 
of side effects. 

 
Do not breast-feed during treatment with Eviplera: 
• This is because the active substances in this medicine pass into human breast milk. 
• If you are a woman with HIV it is recommended that you do not breast-feed, to avoid passing 

the virus to the baby in breast milk. 
 
Driving and using machines 
 
Do not drive or operate machines if you feel tired, sleepy or dizzy after taking your medicine. 
 
Eviplera contains lactose and sunset yellow aluminium lake (E110) 
 
• If you have been told by your doctor that you have an intolerance to some sugars, contact your 

doctor before taking this medicine. 
• Tell your doctor if you have an allergy to sunset yellow aluminium lake (E110).  Eviplera 

contains sunset yellow aluminium lake also called “E110” which may cause allergic reactions. 



51 

 
 
3. How to take Eviplera 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure. 
 
The usual dose is one tablet taken each day by mouth.  The tablet must be taken with food.  This 
is important to get the right levels of active substance in your body.  A nutritional drink alone does not 
replace food. 
 
Swallow the tablet whole with water. 
 
Do not chew, crush or split the tablet – if you do it may affect the way the medicine is released into 
your body. 
 
If your doctor decides to stop one of the components of Eviplera or change the dose of Eviplera, you 
may be given emtricitabine, rilpivirine and/or tenofovir disoproxil separately or with other medicines 
for the treatment of HIV infection. 
 
If you are taking an antacid such as medicines containing magnesium or potassium.  Take it at least 
2 hours before or at least 4 hours after Eviplera. 
 
If you are taking an H2-antagonist such as famotidine, cimetidine, nizatidine or ranitidine.  Take it at 
least 12 hours before or at least 4 hours after Eviplera.  H2-antagonists can only be taken once a day if 
you take Eviplera.  H2-antagonists should not be taken twice a day.  Talk to your doctor about an 
alternative regimen. 
 
If you are taking rifabutin.  Your doctor may need to give you an additional dose of rilpivirine.  
Take the rilpivirine tablet at the same time you take Eviplera.  Check with your doctor or pharmacist if 
you are not sure. 
 
If you take more Eviplera than you should 
 
If you accidentally take more than the recommended dose of Eviplera you may be at increased risk of 
experiencing possible side effects with this medicine (see section 4, Possible side effects). 
 
Contact your doctor or nearest emergency department immediately for advice.  Keep the tablet bottle 
with you so that you can easily describe what you have taken. 
 
If you forget to take Eviplera 
 
It is important not to miss a dose of Eviplera. 
 
If you do miss a dose: 
• If you notice within 12 hours of the time you usually take Eviplera, you must take the tablet as 

soon as possible.  Always take the tablet with food.  Then take the next dose as usual. 
• If you notice after 12 hours or more of the time you usually take Eviplera, then do not take 

the missed dose.  Wait and take the next dose, with food, at your usual time. 
 
If you vomit less than 4 hours after taking Eviplera, take another tablet with food.  If you vomit 
more than 4 hours after taking Eviplera you do not need to take another tablet until your next 
regularly scheduled tablet. 
 



52 

Do not stop taking Eviplera 
 
Do not stop taking Eviplera without talking to your doctor.  Stopping Eviplera can seriously affect 
your response to future treatment.  If Eviplera for any reason is stopped, speak to your doctor before 
you restart taking Eviplera tablets.  Your doctor may consider giving you the components of Eviplera 
separately if you are having problems or need your dose adjusted. 
 
When your supply of Eviplera starts to run low, get more from your doctor or pharmacist.  This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time.  The virus may then become harder to treat. 
 
If you have HIV infection and hepatitis B, it is especially important not to stop your Eviplera 
treatment without talking to your doctor first.  Some patients have had blood tests or symptoms 
indicating that their hepatitis has got worse after stopping emtricitabine or tenofovir disoproxil (two of 
the three active substances of Eviplera).  If Eviplera is stopped your doctor may recommend that you 
resume hepatitis B treatment.  You may need blood tests to check how your liver is working for 
4 months after stopping treatment.  In some patients with advanced liver disease or cirrhosis, stopping 
treatment is not recommended as this may lead to worsening of your hepatitis, which may be life-
threatening. 
 
 Tell your doctor immediately about new or unusual symptoms after you stop treatment, 

particularly symptoms you associate with hepatitis B infection. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Possible side effects: tell a doctor immediately 
• Lactic acidosis (excess lactic acid in the blood) is a rare but potentially life-threatening side 

effect of some HIV medicines.  Lactic acidosis occurs more often in women – particularly if 
they are overweight, and in people with liver disease.  The following may be signs of lactic 
acidosis: 
• Deep, rapid breathing 
• Tiredness or drowsiness 
• Feeling sick (nausea), being sick (vomiting) 
• Stomach pain 

 If you think you may have lactic acidosis, tell your doctor immediately. 
 
Any signs of inflammation or infection.  In some patients with advanced HIV infection (AIDS) and 
a history of opportunistic infections (infections that occur in people with a weak immune system), 
signs and symptoms of inflammation from previous infections may occur soon after anti-HIV 
treatment is started.  It is thought that these symptoms are due to an improvement in the body’s 
immune response, enabling the body to fight infections that may have been present with no obvious 
symptoms. 
 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection.  Autoimmune disorders may occur many months after the start of 
treatment.  If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment. 
 If you notice any symptoms of inflammation or infection, tell your doctor immediately. 
 



53 

Very common side effects 
(may affect more than 1 in 10 people) 
• Diarrhoea, being sick (vomiting), feeling sick (nausea) 
• Difficulty sleeping (insomnia) 
• Dizziness, headache 
• Rash 
• Feeling weak 
 
Tests may also show: 
• Decreases in phosphate levels in the blood 
• Increased levels of creatine kinase in the blood that may result in muscle pain and weakness 
• Increased levels of cholesterol and/or pancreatic amylase in the blood 
• Increased levels of liver enzymes in the blood 
 If any of the side effects get serious tell your doctor. 
 
Common side effects 
(may affect up to 1 in 10 people) 
• Decreased appetite 
• Depression and depressed mood 
• Tiredness, feeling sleepy (somnolence) 
• Drowsiness 
• Pain, stomach pain or discomfort, feeling bloated, dry mouth 
• Abnormal dreams, sleep disorders 
• Problems with digestion resulting in discomfort after meals, wind (flatulence) 
• Rashes (including red spots or blotches sometimes with blistering and swelling of the skin), 

which may be allergic reactions, itching, changes in skin colour including darkening of the skin 
in patches 

• Other allergic reactions, such as wheezing, swelling or feeling light-headed 
 
Tests may also show: 
• Low white blood cell count (a reduced white blood cell count can make you more prone to 

infection) 
• Low platelet count (a type of blood cell involved in clotting blood) 
• Decrease in haemoglobin in your blood (low red blood cell count) 
• Increased fatty acids (triglycerides), bilirubin or sugar in the blood 
• Pancreas problems 
 If any of the side effects get serious tell your doctor. 
 
Uncommon side effects 
(may affect up to 1 in 100 people) 
• Anaemia (low red blood cell count) 
• Pain in the abdomen (tummy) caused by inflammation of the pancreas 
• Breakdown of muscle, muscle pain or weakness 
• Swelling of the face, lips, tongue or throat 
• Signs or symptoms of inflammation or infection 
• Severe skin reactions including rash accompanied by fever, swelling and liver problems 
• Damage to kidney tubule cells 
 
Tests may also show: 
• Decreases in potassium in the blood 
• Increases in creatinine in your blood 
• Changes to your urine 
 If any of the side effects get serious tell your doctor. 
 



54 

Rare side effects 
(may affect up to 1 in 1,000 people) 
• Lactic acidosis (see Possible side effects: tell a doctor immediately) 
• Back pain caused by kidney problems, including kidney failure.  Your doctor may do blood 

tests to see if your kidneys are working properly 
• Fatty liver 
• Yellow skin or eyes, itching or pain in the abdomen (tummy) caused by inflammation of the 

liver 
• Inflammation of the kidney, passing a lot of urine and feeling thirsty 
• Softening of the bones (with bone pain and sometimes resulting in fractures) 
 
The breakdown of muscle, softening of the bones (with bone pain and sometimes resulting in 
fractures), muscle pain, muscle weakness and decreases in potassium or phosphate in the blood may 
occur due to damage to kidney tubule cells. 
 
 If any of the side effects get serious tell your doctor. 
 
Other effects that may be seen during HIV treatment 
 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
 
• Bone problems.  Some patients taking combination antiretroviral medicines such as Eviplera 

may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood 
supply to the bone).  Taking this type of medicine for a long time, taking corticosteroids, 
drinking alcohol, having a very weak immune system, and being overweight, may be some of 
the many risk factors for developing this disease.  Signs of osteonecrosis are: 
• Joint stiffness 
• Joint aches and pains (especially of the hip, knee and shoulder) 
• Difficulty with movement 

 If you notice any of these symptoms tell your doctor. 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 
effects not listed in this leaflet.  You can also report side effects directly via the national reporting 
system listed in Appendix V.  By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Eviplera 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


55 

6. Contents of the pack and other information 
 
What Eviplera contains 
 
• The active substances are emtricitabine, rilpivirine and tenofovir disoproxil.  Each Eviplera 

film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride) and 
245 mg of tenofovir disoproxil (as fumarate). 

 
• The other ingredients are: 

Tablet core: 
 Microcrystalline cellulose, lactose monohydrate, povidone, pregelatinised maize starch, 

polysorbate 20, croscarmellose sodium, and magnesium stearate. 
 

Film-coating: 
 Hypromellose, indigo carmine aluminium lake, lactose monohydrate, polyethylene glycol, red 

iron oxide, sunset yellow aluminium lake (E110), titanium dioxide, and triacetin. 
 
What Eviplera looks like and contents of the pack 
 
Eviplera is a purplish-pink, capsule-shaped, film-coated tablet debossed on one side with “GSI” and 
plain on the other side.  Eviplera comes in bottles of 30 tablets and in packs made up of 3 bottles, each 
containing 30 tablets.  Each bottle contains a silica gel desiccant that must be kept in the bottle to help 
protect your tablets.  The silica gel desiccant is contained in a separate sachet or canister and should 
not be swallowed. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 



56 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in . 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET