Eviplera (Tablets) Instructions for Use

ATC Code

J05AR08 (Emtricitabine, Tenofovir disoproxil, and Rilpivirine)

Active Substances

Emtricitabine (Rec.INN registered by WHO)

Tenofovir (Rec.INN registered by WHO)

Rilpivirine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Eviplera is a fixed-dose combination drug of rilpivirine, tenofovir, and emtricitabine.

Mechanism of action

Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo to Tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Both Emtricitabine and Tenofovir have specific activity against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Rilpivirine is a diarylpyrimidine non-nucleoside inhibitor of HIV-1 reverse transcriptase. The activity of rilpivirine is mediated by non-competitive inhibition of HIV-1 reverse transcriptase.

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 phosphoryrated when present simultaneously in the cell. Emtricitabine triphosphate and tenofovir diphosphate inhibit HIV-1 reverse transcriptase by a competitive mechanism, leading to termination of viral DNA chain synthesis.

Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerase. There are no in vitro or in vivo data on their mitochondrial toxicity. Rilpivirine does not inhibit human cellular α and β DNA polymerase or mitochondrial γ DNA polymerase.

In vitro antiviral activity

The combination of emtricitabine, rilpivirine, and tenofovir exhibits 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, MAGI-CCR5 cell lines, and peripheral blood mononuclear cells. The 50% effective concentration (EC₅₀) values for emtricitabine ranged from 0.0013 to 0.64 µmol. Emtricitabine exhibits antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, and G (EC₅₀ value range from 0.007 to 0.075 µmol), as well as specific activity against HIV-2 strains (EC₅₀ value range from 0.007 to 1.5 µmol).

In studies of the combination of emtricitabine with nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, Tenofovir, and zidovudine), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine and Rilpivirine) and protease inhibitors (PIs) (amprenavir, nelfinavir, ritonavir and saquinavir), an additive or synergistic effect was observed.

Rilpivirine is active against laboratory wild-type HIV-1 strains in acutely infected T-cell lines with a median EC₅₀HIV-1/IIIB value of 0.73 nmol (0.27 ng/ml). Although in vitro Rilpivirine demonstrated limited activity against HIV-2 with EC₅₀ values ranging from 2,510 to 10,830 nmol (920 to 3970 ng/ml), in the absence of clinical data, treatment of HIV-2 infection with rilpivirine hydrochloride is not recommended.

Rilpivirine also demonstrated antiviral activity against a wide range of primary isolates of HIV-1 group M strains (subtypes A, B, C, D, F, G, H) with EC₅₀ values ranging from 0.07 to 1.01 nmol (0.03 to 0.37 ng/ml) and primary group O isolates with EC₅₀ values ranging from 2.88 to 8.45 nmol (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, primarily in monocytes/macrophages and peripheral blood lymphocytes. The EC₅₀ values for tenofovir ranged from 0.04 to 8.5 µmol.

Tenofovir demonstrated antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, G, and O (EC₅₀ value range from 0.5 to 2.2 µmol), as well as specific activity against HIV-2 strains (EC₅₀ value range from 1.6 µmol to 5.5 µmol).

In studies of the combination 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), an additive or synergistic effect was observed.

Resistance

Cell culture

Resistance to emtricitabine or tenofovir has been observed in vitro and in some HIV-1 infected patients due to substitutions at codons M184V or M184I of reverse transcriptase (RT) for emtricitabine or at codon K65R of reverse transcriptase for tenofovir. No other mechanisms for the development of resistance to emtricitabine or tenofovir have been identified. Emtricitabine-resistant viruses with the M184V/I mutation demonstrated cross-resistance to lamivudine but remained sensitive to didanosine, stavudine, tenofovir, zalcitabine, and zidovudine.

The mutation at codon K65R may also be associated with resistance to abacavir or didanosine and lead to reduced sensitivity to these drugs, as well as to lamivudine, emtricitabine, and tenofovir. Tenofovir should not be used in patients with HIV-1 K65R mutation. HIV-1 with mutations at codons K65R, M184V and K65R+M184V remains fully sensitive to rilpivirine.

Rilpivirine and NNRTI-resistant strains were isolated in cell cultures from wild-type HIV-1 of various origins and subtypes. The most frequently observed resistance-associated mutations were L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.

Based on all available in vitro and in vivo data in antiretroviral-naive patients, the activity of Eviplera may be affected by the following mutations: K65R, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, H221Y, F227C, M230I and M230L (if detected prior to initiation of therapy). These resistance-associated mutations should only be considered when using Eviplera for the treatment of antiretroviral-naive patients.

These resistance-associated mutations have been identified in vivo only in treatment-naive patients and therefore cannot be used to predict the activity of Eviplera in patients with virological failure of antiretroviral therapy.

As with other antiretroviral agents, genotypic resistance testing should be performed during treatment with Eviplera.

HIV-1 infected patients, antiretroviral-naive

In a pooled analysis of data from Phase III clinical trials (C209 and C215) in patients receiving Emtricitabine/Tenofovir+Rilpivirine, 62 patients had virological failure, with resistance development information available for 54 of the 62 patients. Amino acid substitutions associated with NNRTI resistance were identified and most commonly found in such patients: V90I, K101E, E138K/Q, Y181C, V189I and H221Y. However, the presence of mutations such as V90I and V189I did not affect treatment efficacy. In more than 3 patients, NRTI resistance-associated mutations were identified during therapy: K65R, K70E, M184V/I and K219E.

Cross-resistance

When HIV-1 develops resistance to rilpivirine, cross-resistance to emtricitabine and tenofovir does not develop, and vice versa.

Resistance in cell culture

Emtricitabine emtricitabine-resistant strains with the M184V/I substitution demonstrated cross-resistance to lamivudine but remained sensitive to didanosine, stavudine, tenofovir and zidovudine. Virus strains with substitutions conferring reduced sensitivity to stavudine and with thymidine analogue mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine mutations (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution or other substitutions associated with resistance to rilpivirine and other NNRTIs remained sensitive to emtricitabine.

Rilpivirine in a group of 67 recombinant laboratory HIV-1 strains with a single RT codon NNRTI resistance mutation, including the most common K103N and Y181C mutations, Rilpivirine demonstrated antiviral activity against 64 (96%) of these strains. Single codon resistance mutations associated with loss of sensitivity to rilpivirine were: K101P and Y181V/I.

Tenofovir the mutation at codon K65R may also be associated with resistance to abacavir or didanosine and lead to reduced sensitivity to these drugs, as well as to lamivudine, emtricitabine and tenofovir, while maintaining sensitivity to zidovudine.

In patients with three or more HIV-1 thymidine analogue mutations, including M41L or L210W, a reduced response to Tenofovir was observed.

The virological response to Tenofovir was not reduced in patients with HIV-1 infection and the M184V mutation associated with resistance to abacavir/emtricitabine/lamivudine. Patients with K103N and Y181C mutations, or with substitutions associated with resistance to rilpivirine and NNRTIs, were sensitive to tenofovir.

HIV-1 infected patients, antiretroviral-naive

In a pooled analysis of data from Phase III clinical trials (C209 and C215) in patients receiving Emtricitabine/Tenofovir+Rilpivirine, phenotypic resistance development information was available for 54 patients with virological failure; 37 patients lost sensitivity to emtricitabine during treatment, 29 to rilpivirine and 2 to tenofovir, respectively. Among these patients, 37 were resistant to lamivudine, 28 to etravirine, 26 to efavirenz, and 12 to nevirapine. In some cases, reduced sensitivity to abacavir and/or didanosine was observed.

Pharmacokinetics

Absorption

The bioequivalence of one film-coated Eviplera tablet and the combination of one 200 mg emtricitabine capsule, one 25 mg rilpivirine (as hydrochloride) film-coated tablet, and one 245 mg tenofovir disoproxil (as fumarate) film-coated tablet was determined after single doses were administered with food to healthy volunteers. After oral administration of Eviplera with food, Emtricitabine was rapidly and extensively absorbed in the gastrointestinal tract, reaching C_max in plasma within 2.5 hours. The C_max of tenofovir in plasma is observed within 2 hours, and the C_max of rilpivirine in plasma is usually reached within 4-5 hours. After oral administration of tenofovir disoproxil fumarate to HIV-infected patients, it is rapidly absorbed and converted to Tenofovir. The absolute bioavailability of emtricitabine at a dose of 200 mg in solid capsules was 93%. Administration of 200 mg emtricitabine hard gelatin capsules with a high-fat meal did not affect the AUC of emtricitabine. The oral bioavailability of tenofovir when tenofovir disoproxil fumarate was administered fasting was approximately 25%. Concurrent administration of tenofovir disoproxil fumarate with a high-fat meal increased oral bioavailability (increase in tenofovir AUC by approximately 40% and C_max by approximately 14%). There are no data on the absolute bioavailability of rilpivirine. Rilpivirine exposure was approximately 40% lower when the drug was taken on an empty stomach than when taken concurrently with a normal-calorie meal (533 kcal) or a high-fat meal (928 kcal). When rilpivirine hydrochloride was taken only with a protein-enriched beverage, rilpivirine exposure was 50% lower than when taken with food. Taking rilpivirine hydrochloride on an empty stomach or only with a protein-enriched beverage reduces rilpivirine plasma concentrations, which may potentially reduce the therapeutic effect of Eviplera. For optimal absorption, Eviplera should be taken with food.

Distribution

After intravenous administration, the volume of distribution of the individual components emtricitabine and tenofovir was approximately 1400 ml/kg and 800 ml/kg, respectively. After oral administration, Emtricitabine and Tenofovir are widely distributed in the body. In vitro binding of emtricitabine to human plasma proteins was <4% and was concentration-independent in the range of 0.02 to 200 µg/ml.

In vitro binding of rilpivirine to plasma proteins is approximately 99.7%, mainly due to binding to albumin. In vitro binding of tenofovir to plasma and serum proteins was less than 0.7% and 7.2%, respectively, in the tenofovir concentration range of 0.01 to 25 µg/ml.

Metabolism

Emtricitabine undergoes incomplete metabolism in the body. The biotransformation of emtricitabine involves oxidation of the thiol group to form 3'-sulfoxide diastereomers (approximately 9% of the dose) and conjugation with glucuronic acid to form the 2'-O-glucuronide (approximately 4% of the dose). In vitro experiments show that rilpivirine hydrochloride undergoes primarily oxidative metabolism mediated by the cytochrome P450 isoenzyme system (CYP3A). In vitro studies have demonstrated that neither tenofovir disoproxil fumarate nor Tenofovir are substrates for CYP450 isoenzymes. Neither Emtricitabine nor Tenofovir inhibit in vitro drug metabolism mediated by any of the major CYP450 isoenzymes involved in biotransformation. In addition, Emtricitabine does not inhibit uridine-5-diphosphoglucuronyl transferase (the enzyme responsible for glucuronidation).

Elimination

Emtricitabine is primarily excreted by the kidneys (approximately 86%) and through the intestines (approximately 14%). 13% of the emtricitabine dose was found in the urine as three metabolites. The systemic clearance of emtricitabine averaged 307 ml/min. T_1/2 after oral administration of emtricitabine is approximately 10 hours.

The terminal T_1/2 of rilpivirine is approximately 45 hours. After administration of a single oral dose of ¹⁴C-rilpivirine, radioactive doses were detected in feces and urine on average at 85% and 6.1%, respectively. In feces, unchanged Rilpivirine accounted for an average of 25% of the administered dose. Only minor concentrations of rilpivirine (<1% of the dose) were detected in urine.

Tenofovir is primarily excreted by the kidneys, both by filtration and by an active tubular transport system (human organic anion transporter 1 [hOAT1]). Approximately 70-80% of the administered dose is excreted unchanged in the urine after intravenous administration. The apparent clearance of tenofovir averaged approximately 307 ml/min. Renal clearance should be approximately 210 ml/min, which exceeds the glomerular filtration rate. This indicates that active tubular secretion is an important part of the tenofovir elimination process. After oral administration, the T_1/2 of tenofovir averages from 12 to 18 hours.

Special patient groups

Elderly patients

A population pharmacokinetic analysis of data from HIV-1-infected patients showed that the pharmacokinetics of rilpivirine remain comparable across all age groups (from 18 to 78 years).

Gender

No clinically significant differences in the pharmacokinetic parameters of rilpivirine were observed between men and women.

Race

No clinically significant differences in pharmacokinetic parameters were observed in patients of different ethnic origins.

Children

In general, the pharmacokinetic parameters of emtricitabine in neonates, children and adolescents (aged 4 months to 18 years) are similar to those observed in adults. The pharmacokinetic parameters of rilpivirine and tenofovir in children and adolescents are currently under investigation. Due to insufficient clinical data, dosing recommendations for children cannot be provided.

Renal impairment

Limited clinical trial data support the possibility of taking Eviplera once daily in patients with mild renal impairment (CrCl 50-80 ml/min). However, the safety of the individual components of the drug, emtricitabine and tenofovir disoproxil fumarate, has not been assessed in patients with mild renal impairment. Therefore, Eviplera should be used in such patients only if the potential benefit of treatment outweighs the possible risk.

Eviplera is contraindicated in patients with moderate or severe renal impairment (CrCl <50 ml/min). This group of patients requires adjustment of the dosing interval for emtricitabine and tenofovir, which is not feasible when using the combination drug.

Pharmacokinetic parameters were determined mainly after single doses of 200 mg emtricitabine or 245 mg tenofovir disoproxil were administered to non-HIV-infected patients with varying degrees of renal failure. The severity of renal impairment was determined according to baseline CrCl (normal renal function at CrCl>80 ml/min; mild renal impairment at CrCl=50-79 ml/min; moderate renal impairment at CrCl=30-49 ml/min and severe renal impairment at CrCl=10-29 ml/min).

The mean exposure (%CV) of emtricitabine 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 exposure (%CV) of tenofovir increased from 2185 (12%) ng×h/ml in patients with normal renal function to 3064 (30%) ng×h/ml, 6009 (42%) ng×h/ml and 15985 (45%) ng×h/ml in patients with mild, moderate and severe renal impairment, respectively.

In patients with end-stage renal disease requiring hemodialysis, exposure between dialysis sessions steadily increased over 72 hours to 53 µg×h/ml (19%) for emtricitabine, and over 48 hours to 42857 ng×h/ml (29%) for tenofovir.

The pharmacokinetics of rilpivirine have not been studied in patients with renal impairment. Renal excretion of rilpivirine is negligible. In patients with severe or end-stage renal impairment, plasma concentrations of the drug may increase due to secondary changes in absorption, distribution and/or metabolism as a result of renal impairment. Since Rilpivirine is highly bound to plasma proteins, it is unlikely to be significantly removed from the body by hemodialysis or peritoneal dialysis.

Hepatic impairment

No dose adjustment of Eviplera is required for patients with moderate hepatic impairment, but it should be prescribed with caution to this group of patients. Eviplera has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Therefore, its use is contraindicated in patients with severe hepatic insufficiency.

The pharmacokinetics of emtricitabine have not been studied in patients with varying degrees of hepatic impairment.

Rilpivirine hydrochloride is metabolized and eliminated primarily by the liver. The exposure level of multiple doses of rilpivirine was 47% higher in patients with mild hepatic impairment (Child-Pugh class A) and 5% higher in patients with moderate hepatic impairment (Child-Pugh class B) compared to the respective control groups. The use of rilpivirine has not been studied in patients with severe hepatic impairment (Child-Pugh class C). However, it cannot be ruled out that the exposure to pharmacologically active, unbound rilpivirine is significantly increased in moderate hepatic impairment.

A single 245 mg dose of tenofovir disoproxil was administered to HIV-infected patients with varying degrees of hepatic impairment, as determined by the Child-Pugh score. The pharmacokinetic parameters of tenofovir did not change significantly in patients with hepatic impairment, indicating no need for dose adjustment in these patients. The mean values (%CV) for tenofovir C_max and AUC_0-∞ were 223 (34.8%) ng/mL and 2050 (50.8%) ng×h/mL, respectively, in patients with normal liver function, compared to 289 (46.0%) ng/mL and 2310 (43.5%) ng×h/mL in patients with moderate hepatic impairment, and 305 (24.8%) ng×h/mL and 2740 (44.0%) ng×h/mL in patients with severe hepatic impairment.

Concomitant Hepatitis B and/or Hepatitis C Infection

Overall, the pharmacokinetic parameters of emtricitabine in patients with hepatitis B were similar to those observed in healthy volunteers and HIV-infected patients.

According to population pharmacokinetic analysis, concomitant infection with hepatitis B and/or C virus does not have a significant effect on the exposure level of rilpivirine.

Indications

• Treatment of HIV-1 infection as first-line therapy in adult patients with HIV-1 RNA levels not exceeding 100,000 copies/mL.

ICD codes

Dosage Regimen

Tablets

Orally.

Treatment should be administered by a physician experienced in the management of HIV infection.

Adults

Eviplera is for oral use only, one tablet once daily with a meal. The tablet should be swallowed whole with water. Tablets should not be chewed or broken, as this may affect drug absorption. If discontinuation or dose adjustment of one of the components of Eviplera is required, other available separate medicinal forms of emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate should be used (see the prescribing information for these drugs).

If a dose is delayed by less than 12 hours, the missed dose should be taken as soon as possible with food and the regular dosing schedule should be resumed. If a dose is delayed by more than 12 hours, the missed dose should not be taken; the next tablet should be taken at the usual time.

If a patient vomits within 4 hours after taking Eviplera, another Eviplera tablet should be taken with food. If a patient vomits more than 4 hours after taking Eviplera, there is no need to take another Eviplera tablet until the next scheduled dose.

Special patient groups

Elderly patients

The use of Eviplera has not been studied in patients over 65 years of age. Eviplera should be used with caution in elderly patients.

Renal impairment

Treatment with Eviplera caused a slight increase in mean serum creatinine concentration in the early stages of therapy. This parameter remained stable over time and is not considered clinically significant.

Limited clinical trial data support the dosing regimen of Eviplera once daily in patients with mild renal impairment (CrCl 50-80 mL/min). However, the safety of the individual components of Eviplera (emtricitabine and tenofovir disoproxil fumarate) has not been evaluated in patients with mild renal impairment. Therefore, Eviplera should be used in patients with mild renal impairment only if the potential benefit of treatment outweighs the possible risk.

Eviplera is contraindicated in patients with moderate or severe renal impairment (CrCl <50 mL/min), as such patients require dose interval adjustment for emtricitabine and tenofovir disoproxil fumarate, which is not possible with the use of the fixed-dose combination product.

Hepatic impairment

There is limited information regarding the use of Eviplera in patients with mild and moderate hepatic impairment (Child-Pugh class A and B). No dose adjustment of Eviplera is required for patients with mild and moderate hepatic impairment. However, Eviplera should be used with caution in patients with moderate hepatic impairment. Eviplera has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Therefore, its use in this group of patients is contraindicated.

If the drug is discontinued in patients with HIV infection and concomitant hepatitis B, patients should be closely monitored for signs of hepatitis flare.

Children

The safety and efficacy of Eviplera in children under 18 years of age have not been established.

Adverse Reactions

The most frequently reported adverse reactions, probably related to the intake of rilpivirine hydrochloride, emtricitabine, tenofovir disoproxil fumarate, were nausea (9%), dizziness (8%), abnormal dreams (7%), headache (6%), diarrhea (5%), and insomnia (5%). The safety profile of emtricitabine and tenofovir disoproxil fumarate in these studies was consistent with the previous experience of using these drugs when each was administered with other antiretroviral drugs.

Rare cases of renal failure and proximal tubulopathy (including Fanconi syndrome) have been reported in patients receiving tenofovir disoproxil fumarate, sometimes leading to bone disorders (occasionally contributing to fractures). Monitoring of renal function is recommended for patients receiving Eviplera.

The use of tenofovir disoproxil fumarate and emtricitabine may be accompanied by the development of lactic acidosis, severe hepatomegaly with steatosis, and lipodystrophy.

Discontinuation of Eviplera in HIV-infected patients with concomitant hepatitis B may be accompanied by severe exacerbation of hepatitis.

Adverse reactions of the drug are systematized by organ system according to frequency of occurrence, using the following classification: very common (>1/10); common (≥1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), including isolated cases.

¹ This adverse reaction may occur as a complication of proximal tubulopathy. In the absence of this condition, it is not considered associated with the use of tenofovir disoproxil fumarate.

² When emtricitabine was used in children, anemia was common, and skin discoloration (hyperpigmentation) was very common.

³ This adverse reaction was identified during post-marketing surveillance but was not reported in randomized, controlled clinical trials. The frequency category was estimated based on statistical calculations from the total number of patients exposed to emtricitabine in randomized, controlled clinical trials (n=1563) or in randomized, controlled clinical trials of tenofovir disoproxil fumarate and in the expanded access program (n=7319).

The mean change in fasting total cholesterol concentration was 2 mg/dL, fasting high-density lipoprotein – 4 mg/dL, fasting low-density lipoprotein – 1 mg/dL, and fasting triglycerides – 7 mg/dL.

Serum creatinine concentration

In Phase III clinical trials, an increase in serum creatinine concentration was observed during the first four weeks of rilpivirine therapy, with creatinine concentration remaining stable up to week 48. After 48 weeks of therapy, the mean values were 0.09 mg/dL (range: from 0.20 mg/dL to 0.62 mg/dL). In patients with mild or moderate renal impairment, the increase in serum creatinine concentration was comparable to the increase in serum creatinine concentration in patients with normal renal function. These changes were considered clinically insignificant, and no patient discontinued therapy due to increased serum creatinine concentration.

Description of selected adverse reactions

Renal impairment

Since Eviplera can cause kidney damage, monitoring of renal function parameters is recommended.

Interaction with didanosine

Concomitant use of Eviplera and didanosine is contraindicated, as it leads to a 40-60% increase in the systemic exposure of didanosine, which may increase the risk of didanosine-related adverse reactions. Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported. Dyslipidemia, lipodystrophy and metabolic disorders

Combination antiretroviral therapy is associated with metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia. Combination antiretroviral therapy causes redistribution of subcutaneous fat (lipodystrophy) in HIV-infected patients, manifested by loss of subcutaneous fat in the periphery (upper and lower limbs) and facial area, accumulation of visceral fat, breast hypertrophy, and accumulation of subcutaneous fat in the dorsocervical area (“buffalo hump”).

Immune reconstitution syndrome

At the initiation of combination antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to opportunistic infections, manifesting as the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome), which may require further careful monitoring and additional treatment. Such reactions are usually observed within the first few weeks after initiation of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported particularly frequently in patients with generally recognized risk factors, with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy. The frequency of this adverse reaction is unknown.

Lactic acidosis and severe hepatomegaly with steatosis

Lactic acidosis, usually accompanied by hepatic steatosis, has been reported with the use of nucleoside analogues. Nucleoside analogue therapy should be discontinued in the event of hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapid elevation of liver transaminases.

Hepatitis flare upon treatment discontinuation

Clinical and laboratory parameters of patients with HIV infection and concomitant hepatitis B should be closely monitored after discontinuation of Eviplera.

HIV/HBV or HIV/HCV co-infection

The safety profile of emtricitabine, rilpivirine, and tenofovir disoproxil fumarate in patients with HIV/HBV and HIV/HCV co-infection was similar to the safety profile observed in HIV-infected patients without co-infection. However, as expected, elevated ALT and AST were more common in this group of patients than in the general HIV-infected population.

Contraindications

• Hypersensitivity to rilpivirine, tenofovir, emtricitabine and/or other components of the drug;
• Children under 18 years of age;
• Moderate and severe renal impairment (creatinine clearance <50 mL/min);
• Severe hepatic impairment (Child-Pugh class C);
• Breastfeeding period;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Eviplera should not be used concomitantly with the following drugs: drugs containing the individual components of Eviplera; NNRTIs; anticonvulsants – carbamazepine, oxcarbazepine, phenobarbital, phenytoin; antituberculosis drugs – rifabutin, rifampicin, rifapentine; proton pump inhibitors – such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole; systemic glucocorticosteroids – dexamethasone (when taking more than a single dose); preparations based on St. John’s wort (Hypericum perforatum); didanosine; cytidine analogues (lamivudine); adefovir dipivoxil; nephrotoxic drugs (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin) or soon after their discontinuation.

With caution

• Moderate hepatic impairment (Child-Pugh class B);
• Age over 65 years;
• Renal impairment (CrCl 50-80 mL/min);
• Concomitant use with drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type; H₂-histamine receptor blockers; antacids (e.g., magnesium or aluminum hydroxide, calcium carbonate); inhibitors of CYP450 isoenzymes; P-glycoprotein substrates (digoxin, metformin, dabigatran).

Use in Pregnancy and Lactation

Pregnancy

There are no clinical data on the use of Eviplera in pregnant women. However, a moderate amount of data (300-1000 pregnancy outcomes) indicates no congenital malformations or neonatal toxicity with the use of emtricitabine and tenofovir disoproxil fumarate. Animal studies have shown no reproductive toxicity (with the components of Eviplera), as well as a small number of cases of rilpivirine crossing the placenta. It is not known whether rilpivirine crosses the placenta in pregnant women. No signs of teratogenicity were observed when rilpivirine was used in rats and rabbits.

The drug Eviplera should not be used during pregnancy, except in cases where the potential benefit of treatment for the mother outweighs the possible risk to the fetus.

Lactation

Emtricitabine and Tenofovir have been shown to be excreted in human milk in women. There are no data on the excretion of Rilpivirine in human milk in women. There are insufficient data on the effects of the components of the drug Eviplera on newborns/infants. Therefore, the drug Eviplera should not be used by women during breastfeeding.

To prevent transmission of HIV to the newborn, it is recommended that HIV-infected women completely refrain from breastfeeding.

Use in Hepatic Impairment

No dose adjustment of Eviplera is required for patients with moderate hepatic impairment, but it should be prescribed with caution to this group of patients. The use of the drug is contraindicated in patients with severe hepatic insufficiency.

Use in Renal Impairment

The drug Eviplera is contraindicated in patients with moderate or severe renal impairment (CrCl <50 ml/min).

Geriatric Use

The drug Eviplera should be used with caution in elderly patients.

Special Precautions

Patients should be warned that modern antiretroviral drugs do not cure HIV infection, nor can they prevent the transmission of HIV through blood or sexual contact. Necessary precautions should be taken to prevent acquiring HIV infection.

Virological failure and development of resistance

Eviplera has not been evaluated in patients with a history of virological failure on any antiretroviral therapy. Eviplera should not be prescribed to patients with HIV-1 infection who have the K65R codon mutation. The list of rilpivirine-associated mutations should only be used when prescribing Eviplera to treatment-naive patients.

In study participants receiving Emtricitabine+Tenofovir in combination with Rilpivirine with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy, lack of virological response was observed more frequently compared to patients whose HIV-1 RNA levels at the start of therapy were no more than 100,000 copies/mL. Observed virological failure in patients with HIV-1 RNA levels greater than 100,000 copies/mL at the start of therapy when treated with the combination of Emtricitabine+Tenofovir and Rilpivirine led to a higher frequency of resistance development to NNRTI class drugs. In patients with observed virological failure on rilpivirine, resistance to lamivudine/emtricitabine developed more frequently compared to patients with observed virological failure receiving efavirenz. Therefore, the use of Eviplera is indicated for the treatment of HIV-1 infection as first-line therapy in patients with HIV-1 RNA levels not exceeding 100,000 copies/mL.

As with other antiretroviral drugs, genotypic resistance should be analyzed before starting therapy with Eviplera.

Effect on the cardiovascular system

Administration of Rilpivirine at supratherapeutic doses (75 mg and 300 mg once daily) is associated with QTc interval prolongation on the ECG. Use of the recommended dose of Rilpivirine 25 mg once daily is not associated with a clinically significant effect on the QTc interval length. Eviplera should be used with caution when co-administered with drugs known for their potential to cause torsades de pointes ventricular tachycardia.

Co-administration with other medicinal products

Eviplera should not be co-administered with other medicinal products containing Emtricitabine, rilpivirine hydrochloride, tenofovir disoproxil fumarate, or other cytidine analogues, for example, lamivudine. Eviplera should not be used concomitantly with adefovir dipivoxil.

Co-administration of Eviplera and didanosine

Co-administration of these drugs is contraindicated, as the systemic exposure of didanosine is significantly increased after co-administration with tenofovir disoproxil fumarate, which may increase the risk of adverse reactions associated with didanosine. Rare cases of pancreatitis and lactic acidosis, sometimes with fatal outcome, have been reported.

Renal impairment

Eviplera is contraindicated in patients with moderate or severe renal impairment (CrCl <50 ml/min). These patients require adjustment of the dosing interval for emtricitabine and tenofovir disoproxil fumarate, which cannot be achieved with the use of the combined product. Eviplera should not be taken concomitantly with nephrotoxic medicinal products, or soon after their discontinuation. The use of tenofovir disoproxil fumarate in clinical practice has been associated with reports of renal impairment, renal failure, increased serum creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome).

It is recommended to assess CrCl in all patients before starting treatment with Eviplera, and to assess renal function (CrCl and plasma phosphate concentration) every 4 weeks during the first year of drug use, and then every 3 months. In patients at risk of developing renal impairment, including those with a history of renal impairment while taking adefovir dipivoxil, renal function should be monitored more frequently. If any patient receiving Eviplera has a serum phosphate concentration of <1.5 mg/dL (0.48 mmol/L) or CrCl decreases to <50 ml/min, renal function should be reassessed within one week, including determination of blood glucose and potassium levels and urine glucose. Since Eviplera is a combined medicinal product and the dosing intervals of its individual components cannot be changed, treatment with Eviplera should be discontinued in patients with a confirmed decrease in CrCl to <50 ml/min or a decrease in serum phosphate concentration to <1.0 mg/dL (0.32 mmol/L). If discontinuation of one of the components of Eviplera is indicated or dose adjustment is necessary, the available individual formulations of emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate can be used.

Effect on bone tissue

Dual-energy X-ray absorptiometry (DXA) revealed a small but statistically significant decrease in bone mineral density (BMD) and bone mineral content (BMC) from baseline, which was the same for the rilpivirine group and the control group.

There are data on decreased BMD in the spine and changes in bone biomarker levels from baseline in patients receiving treatment with tenofovir disoproxil fumarate. However, no increased risk of fractures or signs of clinically significant bone disorders were observed.

Bone disorders (sometimes contributing to the development of fractures) may be associated with proximal renal tubulopathy. If bone disorders are suspected, appropriate consultation with a specialist physician should be sought.

Patients with HIV and co-infection with hepatitis B or C virus

Patients with chronic hepatitis B or C receiving antiretroviral therapy have an increased risk of developing severe and potentially fatal adverse reactions associated with impaired liver function.

For the selection of the optimal treatment method for patients with HIV infection and concomitant hepatitis B, physicians should refer to current HIV treatment guidelines.

When co-administering drugs for the treatment of hepatitis B or C, see also the prescribing information for those drugs.

The safety and efficacy of Eviplera in the treatment of chronic hepatitis B have not been evaluated. Emtricitabine and Tenofovir individually and in combination have demonstrated activity against hepatitis B virus in pharmacodynamic studies.

Discontinuation of Eviplera in patients with HIV infection and concomitant hepatitis B may result in severe exacerbation of hepatitis. Clinical and laboratory parameters of patients with HIV infection and concomitant hepatitis B who have discontinued Eviplera should be carefully monitored for at least several months after treatment cessation. In such cases, resumption of hepatitis B treatment may be warranted. In patients with severe liver disease or cirrhosis, discontinuation of therapy is not recommended, as post-withdrawal hepatitis flare may lead to decompensation.

Liver disease

The safety and efficacy of Eviplera in patients with significant underlying liver disease have not been evaluated. The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment. Emtricitabine is not significantly metabolized by liver enzymes, so the presence of hepatic impairment should not significantly affect the drug’s activity. No dose adjustment of rilpivirine hydrochloride is required for patients with mild or moderate hepatic impairment (Child-Pugh class A and B). The use of rilpivirine hydrochloride has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A study of the pharmacokinetics of tenofovir in patients with hepatic impairment showed that no dose adjustment is required in these patients.

It is unlikely that patients with mild to moderate hepatic impairment will require a dose adjustment of Eviplera. Eviplera should be used with caution in patients with moderate hepatic impairment (Child-Pugh class B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Patients with a history of liver impairment also have an increased frequency of liver function abnormalities during combination antiretroviral therapy. These patients should be monitored closely according to standard practice. If such patients show signs of worsening liver disease, consideration should be given to interrupting or discontinuing treatment.

Lactic acidosis

Lactic acidosis, usually accompanied by hepatic steatosis, has been reported with the use of nucleoside analogues. Early manifestations of this condition (symptomatic hyperlactatemia) include mild digestive symptoms (nausea, vomiting, abdominal pain), nonspecific symptoms (malaise, loss of appetite, weight loss), respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including muscle weakness). Lactic acidosis is associated with a high mortality rate and may be accompanied by pancreatitis, hepatic and renal failure. Lactic acidosis usually occurs after several months of therapy.

Treatment with nucleoside analogues should be discontinued in the event of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase activity.

Nucleoside analogues should be prescribed with caution to all patients (especially obese women) with hepatomegaly, hepatitis, or other known risk factors (including certain medicinal products and alcohol). Patients with concomitant HCV infection receiving alpha-interferon and ribavirin may be at particular risk.

Patients at increased risk should be closely monitored.

Redistribution of subcutaneous adipose tissue (SAT)

Combined antiretroviral therapy may cause redistribution of SAT (lipodystrophy) in HIV-infected patients. The exact mechanism of occurrence and long-term consequences of this phenomenon are currently unknown. An association is suggested between the development of visceral lipomatosis and the use of protease inhibitors (PIs), and between lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs). An increased risk of developing lipodystrophy is associated with individual factors such as older age, as well as drug-related factors, such as a longer duration of antiretroviral therapy and associated metabolic disorders. Clinical examination of patients should include assessment of physical signs of subcutaneous fat redistribution. The need to monitor fasting serum lipid levels and blood glucose concentration should be considered. If clinically indicated, lipid disorders should be treated.

Mitochondrial dysfunction

Nucleosides and nucleoside analogues have been shown to cause in vitro and in vivo mitochondrial dysfunction of varying degrees. Mitochondrial dysfunction has been reported in HIV-negative newborns exposed in utero and/or postnatally to nucleoside analogues. The main reported adverse reactions include hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These changes are often transient. Some long-term neurological disorders (hypertension, convulsions, behavioral disorders) have been recorded. It is currently unknown whether the neurological disorders are transient or permanent. All children exposed in utero to nucleosides or nucleoside analogues, even HIV-negative newborns, in the event of relevant signs or symptoms, should be under close clinical and laboratory observation and undergo a thorough examination for possible mitochondrial changes.

Immune reconstitution syndrome

At the initiation of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to the presence of asymptomatic opportunistic infections in the form of the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome), which may require further careful monitoring and treatment. Such reactions are usually observed within the first few weeks after starting treatment. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis pneumonia. Any symptoms of inflammation should be assessed and, if necessary, treatment should be initiated promptly.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher BMI), cases of osteonecrosis have been reported particularly frequently in patients with advanced HIV infection and/or with long-term exposure to combination antiretroviral therapy. Patients should be advised to seek medical advice if they experience joint aches or pain, joint stiffness, or difficulty moving.

Elderly patients

Eviplera has not been studied in patients over 65 years of age. Elderly patients are more likely to have decreased renal function, so the drug should be prescribed with caution in this group of patients.

Information about certain excipients in Eviplera

Eviplera contains lactose monohydrate. Therefore, patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

Eviplera contains a dye called aluminum lake “sunset yellow” (E110), which may cause allergic reactions in some patients.

Contraception in men and women

Effective contraceptive measures should be used during treatment with Eviplera.

Reproductive function

There are no data on the effect of Eviplera on fertility in humans. Animal studies do not indicate harmful effects of emtricitabine, rilpivirine hydrochloride, or tenofovir disoproxil fumarate on fertility.

Effect on driving and operating machinery

Eviplera has no or negligible influence on the ability to drive and use machines. Studies on the effect of the drug on the ability to drive and use machines have not been conducted. However, patients should be informed about the possibility of fatigue, dizziness, and drowsiness during treatment with Eviplera. This should be taken into account when assessing the patient’s ability to drive and operate machinery. If the described adverse events occur, one should refrain from performing these activities.

Overdose

In case of overdose, the patient’s condition should be carefully monitored for signs of toxicity. Also, if necessary, standard supportive therapy should be administered, including monitoring of clinical status, vital signs, and ECG data (QT interval length).

There is no specific antidote. Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed from the body by hemodialysis. There are no data on the removal of emtricitabine or tenofovir from the body by peritoneal dialysis. Since Rilpivirine is highly bound to plasma proteins, dialysis is ineffective in case of overdose. Activated charcoal may also be used to remove unabsorbed rilpivirine hydrochloride from the gastrointestinal tract.

Drug Interactions

Drug interaction studies with Eviplera have not been conducted. Since Eviplera contains Emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate, all drug interactions identified with these active substances may occur with the use of Eviplera. Drug interaction studies with these drugs have only been conducted in adult patients.

Rilpivirine is metabolized primarily by the cytochrome P450 (CYP3A) isoenzyme. Therefore, drugs that induce or inhibit the activity of the CYP3A isoenzyme may affect the clearance of rilpivirine.

Drugs contraindicated for co-administration

A decrease in rilpivirine plasma concentrations was observed when Eviplera was co-administered with drugs that induce the activity of CYP3A isoenzymes, which may lead to a reduction in the therapeutic effect of Eviplera.

A decrease in rilpivirine plasma concentrations was observed when Eviplera was co-administered with proton pump inhibitors (due to increased gastric pH), which may lead to a reduction in the therapeutic effect of Eviplera.

Didanosine: concomitant administration of Eviplera and didanosine is contraindicated.

Eviplera is a combined medicinal product, therefore it is contraindicated to use it concomitantly with other drugs containing any of its components: Emtricitabine, rilpivirine hydrochloride, or tenofovir disoproxil fumarate.

Eviplera is contraindicated for concomitant use with other cytidine analogues, for example, lamivudine. Eviplera should not be prescribed concomitantly with adefovir dipivoxil.

Drug substances that are eliminated by the kidneys Since Emtricitabine and Tenofovir are primarily eliminated by the kidneys, co-administration of Eviplera with drugs that reduce renal function or compete for active tubular secretion (e.g., cidofovir) may increase the serum concentration of emtricitabine, tenofovir, and/or the co-administered drugs. Eviplera should not be used concurrently with nephrotoxic drugs, or soon after their discontinuation. Such drugs include, among others, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (also called aldesleukin).

Other NNRTIs Co-administration of Eviplera with other NNRTIs is contraindicated.

Drugs recommended for co-administration with caution

Cytochrome P450 isoenzyme inhibitors When Eviplera is co-administered with drugs that inhibit the activity of the CYP3A isoenzyme, an increase in the plasma concentration of rilpivirine was observed.

Drugs that prolong the QT interval Eviplera should be used with caution when co-administered with drugs known for their potential to cause torsades de pointes ventricular tachycardia. There is limited information regarding the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval on the electrocardiogram. In a study on healthy volunteers, administration of supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) was associated with QTc interval prolongation on the ECG.

P-glycoprotein substrates Eviplera should be prescribed with caution with drugs that are substrates of P-glycoprotein (e.g., digoxin and dabigatran). Rilpivirine inhibits the activity of P-glycoprotein in vitro. The clinical significance of this inhibition is unknown. Rilpivirine may suppress the activity of P-glycoprotein in the intestine and affect the metabolism of drugs transported by P-glycoproteins in the intestine, for example, the concentration of dabigatran. This may lead to an increase in the plasma concentration of such drugs. Rilpivirine inhibits the active tubular secretion of creatinine in the kidneys. Through this same mechanism, the blood exposure of metformin may be increased. When initiating or discontinuing co-administration of rilpivirine and metformin, the patient’s condition should be carefully monitored.

Other types of interactions

Interactions between the components of Eviplera and co-administered drugs are described below in Table 1 (an increase in drug concentration is indicated by an “↑” arrow, a decrease by “↓”, and no change by “↔”).

Table 1. Interaction between individual components of Eviplera and other medicinal products.

¹ A drug interaction study used a dose higher than recommended to assess the maximum effect of rilpivirine hydrochloride on the concentration of the co-administered drug. Dosing instructions apply to the recommended dose of rilpivirine 25 mg once daily.

² Drugs of the same class for which a similar drug interaction can be predicted.

Studies conducted with other drugs

Emtricitabine

In vitro, Emtricitabine does not inhibit metabolism mediated by any of the following human CYP450 isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 3A4. Emtricitabine does not inhibit the activity of the enzyme responsible for glucuronidation.

There is no clinically significant pharmacokinetic interaction when emtricitabine is co-administered with indinavir, zidovudine, stavudine, or famciclovir.

Tenofovir disoproxil fumarate

Co-administration of lamivudine, indinavir, efavirenz, nelfinavir, or saquinavir (ritonavir-boosted), ribavirin, or adefovir dipivoxil with tenofovir disoproxil fumarate did not result in any significant pharmacokinetic interaction.

Combined drug Emtricitabine+Tenofovir

Co-administration of tacrolimus with emtricitabine/tenofovir disoproxil fumarate did not result in any significant pharmacokinetic interaction.

Storage Conditions

Store the drug in the original packaging, in a place inaccessible to children, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.