Eviplera

/ Janssen

Adults: The recommended dose is one tablet taken orally once daily with food.
Renal Impairment: Because this product is a fixed-dose combination, it should not be prescribed for patients requiring dose reduction such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute).
Rifabutin Coadministration: If this product is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with this product and with a meal for the duration of the rifabutin coadministration. If a patient misses a dose of Eviplera within 12 hours of the time it is usually taken, the patient should take Eviplera with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Eviplera by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. If a patient vomits within 4 hours of taking Eviplera another Eviplera tablet should be taken with food . If a patient vomits more than 4 hours after taking Eviplera they do not need to take another dose of Eviplera until the next regularly scheduled dose.
For full details see prescribing information.

Indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naive adults. This indication is based on Week 48 safety and efficacy analyses from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naive subjects comparing rilpivirine to efavirenz . The following points should be considered when initiating therapy with this product: More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy. The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz . More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.

Hypersensitivity to the active substances or to any of the excipients.
this product should not be coadministered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to this product or to the class of NNRTIs: The anticonvulsants – carbamazepine, oxcarbazepine, phenobarbital, phenytoin. The antimycobacterials – rifabutin, rifampin, rifapentine. Proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, antoprazole, rabeprazole. The glucocorticoid systemic dexamethasone (more than a single dose). St. John’s wort (Hypericum perforatum).

Virologic failure and development of resistance
This medicinal product 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 this drug.
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). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. This medicinal product 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
This drug should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or other cytidine analogues, such as lamivudine. This drug should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin. This drug should not be administered concomitantly with adefovir dipivoxil.
Co-administration with didanosine is not recommended.
Renal impairment
This drug 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. Use should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use with nephrotoxic agents is unavoidable, renal function must be monitored weekly.
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 this drug 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.
It is recommended that CrCl is calculated in all patients prior to initiating therapy with Eviplera and renal function (CrCl and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required.
If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or CrCl is decreased to < 50 mL/min in any patient receiving this drug , renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations. Since this drug is a combination product and the dosing interval of the individual components cannot be altered, treatment with this drug 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 this drug 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 this drug is indicated or where dose modification is necessary, separate preparations of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil are available.
Bone effects
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.
Tenofovir disoproxil may also cause a reduction in BMD. In a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in BMD of the hip and spine were observed in both treatment groups. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks in this study.
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 that are at a high risk for 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.
Discontinuation 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 this drug 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 this drug 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 in patients with mild or moderate hepatic impairment. This drug 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, including but not limited to rashes accompanied by fever, blisters, conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia. These symptoms resolved after the drug was discontinued. As soon as serious skin and/or mucosal reactions are observed, this drug 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 and metabolic disorders. 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. 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, 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
This drug 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 this drug.
Excipients
This drug contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The drug contains a colourant called sunset yellow aluminium lake (E110), which may cause allergic reactions.
See prescribing information for full details.

Nausea, headache, dizziness, insomnia, abnormal dreams, diarrhea.
For full details see prescribing information.

As this medicinal product contains emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with this drug. 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.
Concomitant use contraindicated
Co-administration with 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 this drug.
Co-administration 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 this drug.
Concomitant use not recommended
This drug should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil or tenofovir alafenamide. This drug should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin.
Due to similarities with emtricitabine, Eviplera should not be administered concomitantly with other cytidine analogues, such as lamivudine. This drug should not be administered concomitantly with adefovir dipivoxil.
Didanosine: The co-administration with didanosine is not recommended.
Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration 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 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 this drug with other NNRTIs.
Concomitant use where caution is recommended.
Cytochrome P450 enzyme inhibitors: Co-administration with medicinal products that inhibit CYP3A enzyme activity has been observed to increase rilpivirine plasma concentrations.
QT prolonging medicinal products: this drug 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.
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.
See prescribing information for full details.

Pregnancy:
There are no adequate and well-controlled studies of this drug or its components in pregnant women. A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformative or foetal/neonatal toxicity of rilpivirine. 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 with the components of this drug.
The use 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 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 this drug.
In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with this product consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose. In one clinical pharmacology study, single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis. Rilpivirine: There is no specific antidote for overdose with rilpivirine. Human experience of overdose with rilpivirine is limited. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of rilpivirine. If indicated, elimination of unabsorbed active  substance may be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.