Eviplera 200 mg/25 mg/245 mg film-coated tablets

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.

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.

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).

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 fumarate 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.

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 50-80 mL/min). However, long-term safety data for the emtricitabine and tenofovir disoproxil fumarate components of Eviplera have not been eva luated 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 (creatinine clearance < 50 mL/min). Patients with moderate or severe renal impairment require a dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate 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.

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 CYP3A 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).

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 eva luated 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 fumarate + 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 fumarate + 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 fumarate + 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 supra-therapeutic 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, 4.8, and 5.2). 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 fumarate, 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).

Co-administration of Eviplera and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate, 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 (creatinine clearance < 50 mL/min). Patients with moderate or severe renal impairment require a dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate 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 section 4.5).

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 fumarate 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 fumarate in clinical practice (see section 4.8).

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Eviplera and renal function (creatinine clearance 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 creatinine clearance is decreased to < 50 mL/min in any patient receiving Eviplera, renal function should be re-eva luated 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 creatinine clearance 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 fumarate are available.

Bone effects

A dual energy x-ray absorptiometry (DEXA) 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. DEXA 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 fumarate.

In a 144-week controlled clinical study that compared tenofovir disoproxil fumarate 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 fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. 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 fumarate as part of a regimen containing a boosted protease inhibitor. 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 have 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 have 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.

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 eva luated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

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).

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, the Lapp 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.