1. Name Of The Medicinal Product
Eviplera 200 mg/25 mg/245 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride) and 245 mg of tenofovir disoproxil (as fumarate).
Excipients with known effect:
Each film-coated tablet contains 277 mg lactose monohydrate and 4 micrograms sunset yellow aluminium lake (E110).
For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Purplish-pink, capsule-shaped, film-coated tablet of dimensions 19 mm x 8.5 mm, debossed on one side with “GSI” and plain on the other side.
4. Clinical Particulars
4.1 Therapeutic Indications
Eviplera is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve adult patients with a viral load
The demonstration of the benefit of the combination emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate in antiretroviral therapy is based on week 48 safety and efficacy analyses from two randomised, double-blind, controlled Phase III studies in treatment-naïve patients (see section 5.1).
As with other antiretroviral medicinal products, genotypic resistance testing should guide the use of Eviplera (see sections 4.4 and 5.1).
4.2 Posology And Method Of Administration
Therapy should be initiated by a physician experienced in the management of HIV infection.
Posology
Adults: The recommended dose of Eviplera is one tablet, taken orally, once daily. Eviplera must be taken with a meal (see section 5.2).
Where discontinuation of therapy with one of the components of Eviplera is indicated or where dose modification is necessary, separate preparations of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal products.
If a patient misses a dose of Eviplera within 12 hours of the time it is usually taken, the patient should take Eviplera with a meal 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 a meal. 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.
Special populations
Elderly: Eviplera has not been studied in patients over the age of 65 years. Eviplera should be administered with caution to elderly patients (see sections 4.4 and 5.2).
Renal impairment: Treatment with Eviplera resulted in an early small increase of mean serum creatinine levels which remained stable over time and is not considered clinically relevant (see section 4.8).
Limited data from clinical studies support once daily dosing of Eviplera in patients with mild renal impairment (creatinine clearance 50-80 ml/min). However, long-term safety data for the emtricitabine and tenofovir disoproxil fumarate components of Eviplera have not been evaluated in patients with mild renal impairment. Therefore, in patients with mild renal impairment Eviplera should only be used if the potential benefits of treatment outweigh the potential risks (see sections 4.4 and 5.2).
Eviplera is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renal impairment require a dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.4 and 5.2).
Hepatic impairment: There is limited information regarding the use of Eviplera in patients with mild or moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Score A or B). No dose adjustment of Eviplera is required in patients with mild or moderate hepatic impairment. Eviplera should be used with caution in patients with moderate hepatic impairment. Eviplera has not been studied in patients with severe hepatic impairment (CPT Score C). Therefore, Eviplera is not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).
If Eviplera is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).
Paediatric population: The safety and efficacy of Eviplera in children under the age of 18 years have not been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.
Method of administration
Eviplera must be taken orally, once daily with a meal (see section 5.2). It is recommended that Eviplera be swallowed whole with water. The film-coated tablet should not be chewed or crushed as it may impact the absorption of Eviplera.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Eviplera should not be co-administered with the following medicinal products as significant decreases in rilpivirine plasma concentrations may occur (due to CYP3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of Eviplera:
• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifabutin, 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
Patients should be advised that current antiretroviral therapy does not cure HIV, and there is still a risk of passing HIV to others through sexual contact or contamination with blood when taking Eviplera. Appropriate precautions to prevent the transmission of HIV should continue to be employed.
Virologic failure and development of resistance
Eviplera has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. Eviplera should be avoided in patients with HIV-1 harbouring the K65R mutation. The list of rilpivirine-associated mutations presented in section 5.1 should only guide the use of Eviplera in the treatment-naïve population.
In the pooled analysis from the two Phase III clinical studies (C209 and C215), patients treated with emtricitabine/tenofovir disoproxil fumarate + rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (15.3% with rilpivirine versus 5.9% with efavirenz) compared to patients with a baseline viral load
As with other antiretroviral medicinal products, resistance testing should guide the use of Eviplera (see section 5.1).
Cardiovascular
At supra-therapeutic doses (75 mg and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, 4.8, and 5.2). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Eviplera should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.
Co-administration of other medicinal products
Eviplera should not be administered concomitantly with other medicinal products containing emtricitabine, rilpivirine hydrochloride, tenofovir disoproxil fumarate or other cytidine analogues, such as lamivudine (see section 4.5). Eviplera should not be administered concomitantly with adefovir dipivoxil.
Co-administration of Eviplera and didanosine: is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.
Renal impairment
Eviplera is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renal impairment require a dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.2 and 5.2). Use of Eviplera should be avoided with concurrent or recent use of a nephrotoxic medicinal product (see section 4.5). If concomitant use of Eviplera and nephrotoxic agents is unavoidable, renal function must be monitored weekly (see section 4.5).
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Eviplera and renal function (creatinine clearance and serum phosphate) is also monitored every four weeks during the first year and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving Eviplera, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Since Eviplera is a combination product and the dosing interval of the individual components cannot be altered, treatment with Eviplera must be interrupted in patients with confirmed creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Where discontinuation of therapy with one of the components of Eviplera is indicated or where dose modification is necessary, separate preparations of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate are available.
Bone effects
A dual energy x-ray absorptiometry (DEXA) substudy for both the Phase III studies (C209 and C215) investigated the effect of rilpivirine as compared with control, overall and by background regimen on changes in whole body bone mineral density (BMD) and bone mineral content (BMC) at week 48 and week 96. DEXA substudies showed that small but statistically significant decreases from baseline in whole body BMD and BMC were similar for rilpivirine and control at week 48 and week 96. There was no difference in the change from baseline in whole body BMD or BMC for rilpivirine compared with control, in the overall population or in those patients treated with a backbone regimen including tenofovir disoproxil fumarate.
In a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in BMD of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8). If bone abnormalities are suspected then appropriate consultation should be obtained.
Patients with HIV and hepatitis B or C virus co-infection
Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV.
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.
The safety and efficacy of Eviplera have not been established for the treatment of chronic HBV infection. Emtricitabine and tenofovir individually and in combination have shown activity against HBV in pharmacodynamic studies (see section 5.1).
Discontinuation of Eviplera therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Eviplera should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Liver disease
The safety and efficacy of Eviplera have not been established in patients with significant underlying liver disorders. The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment. Emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited. No dose adjustment is required for rilpivirine hydrochloride in patients with mild or moderate hepatic impairment (CPT Score A or B). Rilpivirine hydrochloride has not been studied in patients with severe hepatic impairment (CPT Score C). The pharmacokinetics of tenofovir have been studied in patients with hepatic impairment and no dose adjustment is required in these patients.
It is unlikely that a dose adjustment would be required for Eviplera in patients with mild or moderate hepatic impairment (see sections 4.2 and 5.2). Eviplera should be used with caution in patients with moderate hepatic impairment (CPT Score B) and is not recommended in patients with severe hepatic impairment (CPT Score C).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy 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.
Lactic acidosis
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Lipodystrophy
Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Mitochondrial dysfunction
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. 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 combination antiretroviral therapy (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.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Elderly
Eviplera has not been studied in patients over the age of 65 years. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with Eviplera (see sections 4.2 and 5.2).
Excipients
Eviplera contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Eviplera contains a colourant called sunset yellow aluminium lake (E110), this may cause allergic reactions in some people.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No drug interaction studies have been conducted using Eviplera. As Eviplera contains emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate, any interactions that have been identified with these agents individually may occur with Eviplera. Interaction studies with these agents have only been performed in adults.
Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2).
Concomitant use contraindicated
Co-administration of Eviplera and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine which could potentially lead to loss of therapeutic effect of Eviplera (see section 4.3).
Co-administration of Eviplera with proton pump inhibitors has been observed to decrease the plasma concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of therapeutic effect of Eviplera (see section 4.3).
Concomitant use not recommended
As a fixed combination, Eviplera should not be administered concomitantly with other medicinal products containing any of the components emtricitabine, rilpivirine hydrochloride or tenofovir disoproxil fumarate.
Due to similarities with emtricitabine, Eviplera should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4). Eviplera should not be administered concomitantly with adefovir dipivoxil.
Didanosine: The co-administration of Eviplera and didanosine is not recommended (see section 4.4 and Table 1).
Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Eviplera with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.
Use of Eviplera should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin).
Other NNRTIs: It is not recommended to co-administer Eviplera with other NNRTIs.
Concomitant use where caution is recommended
Cytochrome P450 enzyme inhibitors: Co-administration of Eviplera with medicinal products that inhibit CYP3A enzyme activity has been observed to increase rilpivirine plasma concentrations.
QT prolonging medicinal products: Eviplera should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes. There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1).
P-glycoprotein substrates: Eviplera should be administered with caution when co-administered with medicinal products that are substrates for P-glycoprotein (e.g. digoxin and dabigatran). Rilpivirine inhibits P-glycoprotein in vitro. The clinical relevance of this inhibition is unknown. Rilpivirine may inhibit intestinal P-glycoprotein and affect medicinal products that are transported by P-glycoprotein in the intestine, such as dabigatran. This may lead to increased plasma concentrations of such medicinal products.
Rilpivirine inhibits the active renal tubular secretion of creatinine. Via the same mechanism exposure to metformin may be increased. Patients should be carefully monitored when initiating or stopping the concomitant administration of rilpivirine and metformin.
Other interactions
Interactions between the components of Eviplera and co-administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “
Table 1: Interactions between the individual components of Eviplera and other medicinal products
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