4.1. Therapeutic indications

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see sections 4.4 and 5.1).

4.2. Posology and method of administration

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should be initiated by a physician experienced in the management of HIV infection.

Posology

Adults

The recommended dose of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is one tablet, taken orally, once daily. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead must be taken with food (see section 5.2).

Where discontinuation of therapy with one of the components of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead within 12 hours of the time it is usually taken, the patient should take Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead another Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead tablet should be taken with food. If a patient vomits more than 4 hours after taking Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead they do not need to take another dose of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead until the next regularly scheduled dose.

Dose adjustment

If Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is co-administered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, for the duration of the rifabutin co-administration (see section 4.5).

Special populations

Elderly

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead has not been studied in patients over the age of 65 years. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should be administered with caution to elderly patients (see sections 4.4 and 5.2).

Renal impairment

Treatment with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead have not been evaluated in patients with mild renal impairment. Therefore, in patients with mild renal impairment Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should only be used if the potential benefits of treatment outweigh the potential risks (see sections 4.4 and 5.2).

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead in patients with mild or moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Score A or B). No dose adjustment of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is required in patients with mild or moderate hepatic impairment. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should be used with caution in patients with moderate hepatic impairment. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead has not been studied in patients with severe hepatic impairment (CPT Score C). Therefore, Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).

If Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead) 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

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead must be taken orally, once daily with food (see section 5.2). It is recommended that Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead be swallowed whole with water. The film-coated tablet should not be chewed, crushed or split as it may impact the absorption of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead:

• 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

Virologic failure and development of resistance

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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). Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin (see sections 4.2 and 4.5). Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should not be administered concomitantly with adefovir dipivoxil (see section 4.5).

Co-administration of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead and didanosine is not recommended (see section 4.5).

Renal impairment

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should be avoided with concurrent or recent use of a nephrotoxic medicinal product (see section 4.5). If concomitant use of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is a combination product and the dosing interval of the individual components cannot be altered, treatment with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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.

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section 4.8).

Reductions of BMD have been observed with tenofovir disoproxil in randomized controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients. These BMD decreases generally improved after treatment discontinuation.

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). Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations of long term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or with a history of bone fractures.

If bone abnormalities are suspected or detected 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead in patients with mild or moderate hepatic impairment (see sections 4.2 and 5.2). Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, including but not limited to rashes accompanied by fever, blisters, conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia. These symptoms resolved after Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead was discontinued. As soon as serious skin and/or mucosal reactions are observed, Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead contains emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead. 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see section 4.3).

Co-administration of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see section 4.3).

Concomitant use not recommended

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil or tenofovir alafenamide. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin (see section 4.2).

Due to similarities with emtricitabine, Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4). Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead should not be administered concomitantly with adefovir dipivoxil.

Didanosine

The co-administration of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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.

Use of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead with other NNRTIs.

Concomitant use where caution is recommended

Cytochrome P450 enzyme inhibitors

Co-administration of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead with medicinal products that inhibit CYP3A enzyme activity has been observed to increase rilpivirine plasma concentrations.

QT prolonging medicinal products

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 “↔”).

Table 1: Interactions between Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead

ANTI-INFECTIVES

Antiretrovirals

Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs/N[t]RTIs)

Didanosine/Emtricitabine

Interaction not studied.

Co-administration of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead and didanosine is not recommended (see section 4.4).

Increased systemic exposure to didanosine may increase 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.

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.

Protease inhibitors (PIs) - boosted (with co-administration of low-dose ritonavir)

Atazanavir/Ritonavir/Emtricitabine

Interaction not studied.

Concomitant use of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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.

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).

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).

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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

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.

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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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.

Antimycobacterials

Rifabutin/Emtricitabine

Interaction not studied.

Co-administration is likely to cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). When Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is co-administered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, 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.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see section 4.3).

Macrolide antibiotics

Clarithromycin

Erythromycin

Interaction not studied with any components of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

The combination of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see section 4.3).

GLUCOCORTICOIDS

Dexamethasone (systemic, except for single dose use)

Interaction not studied with any components of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see section 4.3).

Alternatives should be considered, particularly for long-term use.

PROTON PUMP INHIBITORS

Omeprazole/Emtricitabine

Interaction not studied.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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.

H2-RECEPTOR ANTAGONISTS

Famotidine/Emtricitabine

Interaction not studied.

The combination of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

The combination of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

NARCOTIC ANALGESICS

Methadone/Emtricitabine

Interaction not studied.

No dose adjustments are required when initiating co-administration of methadone with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead. 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: ↔

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: N/A

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.

ANTICOAGULANTS

Dabigatran etexilate

Interaction not studied with any of the components of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

A risk for increases in dabigatran plasma concentrations cannot be excluded (inhibition of intestinal P-gp.

The combination of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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.

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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead must be accompanied by the use of effective contraception.

Pregnancy

There are no adequate and well-controlled studies of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead or its components in pregnant women. A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of rilpivirine (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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

The use of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead may be considered during pregnancy, if necessary.

Breast-feeding

Emtricitabine and tenofovir disoproxil are excreted in human milk. It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats.

There is insufficient information on the effects of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead in newborns/infants.

Because of the potential for adverse reactions in breastfed infants, women should be instructed not to breast-feed if they are receiving Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

Fertility

No human data on the effect of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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), Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, the most frequently reported adverse reactions considered possibly or probably related to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (see section 4.4).

Discontinuation of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead based on clinical study and post-marketing experience with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead and its individual components

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common:

neutropenia1, decreased white blood cell count2, decreased haemoglobin2, decreased platelet count2

Uncommon:

anaemia1, 4

Immune system disorders

Common:

allergic reaction1

Uncommon:

immune reactivation syndrome

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 rash1, 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

Common:

bone mineral density decreased3

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 syndrome3, 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (fixed-dose combination) but not observed in randomised controlled clinical studies for Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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).

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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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).

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead, 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. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead is not recommended in this population (see section 4.2).

When emtricitabine (one of the components of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead) 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 very common (31.8%) in paediatric patients (see section 4.8, Tabulated summary of adverse reactions).

Other special populations

Elderly

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead (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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

An increased risk of adverse reactions associated with Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead 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 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Gilead. 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.