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英文药名：EVIPLERA（emtricitabine/rilpivirine hydrochloride/tenofovir disoproxil fixed-dose tablet） 中文药名：替诺福韦酯/恩曲他滨/盐酸利匹韦林组成的复合片 生产厂家：Gilead
Eviplera 200mg/25mg/245mg film coated tablets
2 These are drugs within class where similar interactions could be predicted. 3 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine hydrochloride assessing the maximal effect on the co-administered medicinal product. Studies conducted with other medicinal products Emtricitabine: In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. There are no clinically significant pharmacokinetic interactions 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 clinically significant pharmacokinetic interaction. Emtricitabine/tenofovir disoproxil fumarate fixed dose combination: Co-administration of tacrolimus with emtricitabine/tenofovir disoproxil fumarate did not result in any clinically significant pharmacokinetic interaction. 4.6 Fertility, pregnancy and lactation Women of childbearing potential / contraception in males and females The use of Eviplera must be accompanied by the use of effective contraception (see section 4.5). Pregnancy There are no clinical data with Eviplera in pregnant women. However, a moderate amount of data in pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil fumarate. Studies in animals have shown no reproductive toxicity (see section 5.3) with the components of Eviplera. Studies in animals have shown limited placenta passage of rilpivirine. It is not known whether placental transfer of rilpivirine occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits. Eviplera should not be used during pregnancy unless clearly needed. Breast-feeding Emtricitabine and tenofovir have been shown to be excreted in human milk. It is not known whether rilpivirine is excreted in human milk. There is insufficient information on the effects of all of the components of Eviplera in newborns/infants. Therefore Eviplera should not be used during breast-feeding. In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breast-feed their infants under any circumstances. Fertility No human data on the effect of Eviplera on fertility are available. Animal studies do not indicate harmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir disoproxil fumarate on fertility. 4.7 Effects on ability to drive and use machines Eviplera has no or negligible influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of Eviplera (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery. 4.8 Undesirable effects Summary of the safety profile The combination of emtricitabine, rilpivirine and tenofovir disoproxil fumarate has been studied as the component products in treatment-naïve patients (Phase III studies C209 and C215). The single-tablet regimen (STR), Eviplera, has been studied in virologically suppressed patients who switched from a regimen containing a ritonavir-boosted protease inhibitor (Phase III study GS-US-264-0106) or from efavirenz/emtricitabine/tenofovir disoproxil fumarate (Phase IIb study GS-US-264-0111). In treatment-naïve patients, the most frequently reported adverse reactions considered possibly or probably related to rilpivirine hydrochloride and emtricitabine/tenofovir disoproxil fumarate were nausea (9%), dizziness (8%), abnormal dreams (8%), headache (6%), diarrhoea (5%) and insomnia (5%) (pooled data from the Phase III clinical studies C209 and C215, see section 5.1). No new adverse reaction terms were identified between 48 weeks and 96 weeks. In virologically suppressed patients switching to Eviplera, the most frequently reported adverse reactions considered possibly or probably related to Eviplera were fatigue (3%), diarrhoea (3%), nausea (2%) and insomnia (2%) (48 week data from the Phase III study GS-US-264-0106). No new adverse reactions to Eviplera were identified in virologically suppressed patients switching to Eviplera in clinical studies GS-US-264-0106 and GS-US-264-0111. The safety profile of emtricitabine and tenofovir disoproxil fumarate in these studies was consistent with the previous experience with these agents when each was administered with other antiretroviral agents. In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving Eviplera (see section 4.4). Lipodystrophy is associated with tenofovir disoproxil fumarate and emtricitabine (see sections 4.4 and 4.8 Description of selected adverse reactions). Discontinuation of Eviplera therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4). Tabulated summary of adverse reactions The adverse reactions considered at least possibly related to treatment with the components of Eviplera from clinical study and post-marketing experience are listed in Table 2, below, by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). Table 2: Tabulated summary of adverse reactions associated with the individual components of Eviplera based on clinical study and post-marketing experience
2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients. 3 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical studies in adults or paediatric HIV clinical studies for emtricitabine or in randomised controlled clinical studies or the tenofovir disoproxil fumarate expanded access program for tenofovir disoproxil fumarate. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical studies (n = 1,563) or tenofovir disoproxil fumarate in randomised controlled clinical studies and the expanded access program (n = 7,319). Laboratory abnormalities Lipids: At 96 weeks in the pooled Phase III C209 and C215 trials of treatment-naïve patients, in the rilpivirine arm the mean change from baseline in total cholesterol (fasted) was 5 mg/dL, in HDL cholesterol (fasted) 4 mg/dL, in LDL cholesterol (fasted) 1 mg/dL, and in triglycerides (fasted) -7 mg/dL. At 48 weeks in Phase III study GS-US-264-0106 of virologically suppressed patients switching to Eviplera from a regimen containing a ritonavir-boosted protease inhibitor, the mean change from baseline in total cholesterol (fasted) was -24 mg/dL, in HDL cholesterol (fasted) -2 mg/dL, in LDL cholesterol (fasted) -16 mg/dL, and in triglycerides (fasted) -64 mg/dL. Creatinine: The pooled data from the Phase III C209 and C215 trials of treatment-naïve patients also demonstrate that serum creatinine increased and estimated glomerular filtration rate (eGFR) decreased over 96 weeks of treatment with rilpivirine. Most of this increase in creatinine and decrease in eGFR occurred within the first four weeks of treatment. Over 96 weeks of treatment with rilpivirine mean changes of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) for creatinine and -13.3 mL/min/1.73 m2 (range: -63.7 mL/min/1.73 m2 to 40.1 mL/min/1.73 m2) for eGFR were observed. In patients who entered the studies with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in patients with normal renal function. These changes are not considered to be clinically relevant since they do not reflect a change in actual glomerular filtration rate. Changes in creatinine and eGFR observed at 48 weeks in Phase III study GS-US-264-0106 of virologically suppressed patients switching to Eviplera from a regimen containing a ritonavir-boosted protease inhibitor were consistent with those observed in studies C209 and C215. Cortisol: In the pooled Phase III C209 and C215 trials of treatment-naïve patients, at week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the rilpivirine arm and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz arm. At week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine arm (+18.4 ± 8.36 nmol/L) than in the efavirenz arm (+54.1 ± 7.24 nmol/L). Mean values for the rilpivirine arm for both basal and ACTH-stimulated cortisol at week 96 were within the normal range. These changes in adrenal safety parameters were not clinically relevant. There were no clinical signs or symptoms suggestive of adrenal or gonadal dysfunction in adults. Description of selected adverse reactions Renal impairment: As Eviplera may cause renal damage, monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil fumarate discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil fumarate discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil fumarate discontinuation (see section 4.4). Interaction with didanosine: Co-administration of Eviplera and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Lipids, lipodystrophy and metabolic abnormalities: CART has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4). CART has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4). Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4). Paediatric population Insufficient safety data are available for children under the age of 18 years. Eviplera is not recommended in this population (see section 4.2). Other special population(s) Older people: Eviplera has not been studied in patients over the age of 65 years. Older patients are more likely to have decreased renal function, therefore caution should be exercised when treating older patients with Eviplera (see section 4.4). Patients with renal impairment: Since tenofovir disoproxil fumarate can cause renal toxicity, close monitoring of renal function is recommended in any patient with renal impairment treated with Eviplera (see sections 4.2, 4.4 and 5.2). HIV/HBV or HCV co-infected patients: The adverse reaction profile of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate in patients co-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without co-infection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV infected population. Exacerbations of hepatitis after discontinuation of treatment: In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have occurred after discontinuation of treatment (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reportin Website: www.medicinesauthority.gov.mt/adrportal 4.9 Overdose If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary including observation of the clinical status of the patient and monitoring of vital signs and ECG (QT interval). There is no specific antidote for overdose with Eviplera. Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by haemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis. Since rilpivirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance. Administration of activated charcoal may also be used to aid in removal of unabsorbed rilpivirine hydrochloride. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations. ATC code: J05AR08. Mechanism of action and pharmacodynamic effects 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 activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus. Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). 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 phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 RT, resulting in DNA chain termination. Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo. Rilpivirine does not inhibit the human cellular DNA polymerases α, β and mitochondrial DNA polymerase γ. Antiviral activity in vitro The triple combination of emtricitabine, rilpivirine, and tenofovir demonstrated 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, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013 to 0.64 µM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 subtype A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 µM). In drug combination studies of emtricitabine with NRTIs (abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Although rilpivirine demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2,510 to 10,830 nM (920 to 3,970 ng/mL), treatment of HIV-2 infection with rilpivirine hydrochloride is not recommended in the absence of clinical data. Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL) and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (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, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04 to 8.5 µM. Tenofovir displayed antiviral activity in cell culture against HIV-1 subtype A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 to 2.2 µM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM). In drug combination studies 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), additive to synergistic effects were observed. Resistance Considering all of the available in vitro data and data generated in previously untreated patients, the following resistance-associated mutations in HIV-1 reverse transcriptase, when present at baseline, may affect the activity of Eviplera: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and the combination of L100I and K103N. A negative impact by NNRTI mutations other than those listed above (e.g. mutations K103N or L100I as single mutations) cannot be excluded, since this was not studied in vivo in a sufficient number of patients. As with other antiretroviral medicinal products, resistance testing and/or historical resistance data should guide the use of Eviplera (see section 4.4). In cell culture Resistance to emtricitabine or tenofovir has been seen in vitro and in some HIV-1 infected patients due to the development of the M184V or M184I substitution in RT with emtricitabine, or the K65R substitution in RT with tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir and lamivudine. No other pathways of resistance to emtricitabine or tenofovir have been identified. Emtricitabine-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, zalcitabine and zidovudine. The K65R mutation can also be selected by abacavir or didanosine and results in reduced susceptibility to these agents plus to lamivudine, emtricitabine, and tenofovir. Tenofovir disoproxil fumarate should be avoided in patients with HIV-1 harbouring the K65R mutation. The K65R, M184V, and K65R+M184V mutants of HIV-1 remain fully susceptible to rilpivirine. Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The most commonly observed resistance-associated mutations that emerged included L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I. In treatment-naïve HIV-1 infected patients For the resistance analyses, a broader definition of virologic failure was used than in the primary efficacy analysis. In the cumulative week 96 pooled resistance analysis for patients receiving rilpivirine in combination with emtricitabine/tenofovir disoproxil fumarate, a greater risk of virologic failure for patients in the rilpivirine arm was observed within the first 48 weeks of these trials (11.5% in the rilpivirine arm and 4.2% in the efavirenz arm) while low rates of virologic failure, similar between the treatment arms, were observed from the week 48 to week 96 analysis (15 patients or 2.7% in the rilpivirine arm and 14 patients or 2.6% in the efavirenz arm). Of these virologic failures 5/15 (rilpivirine) and 5/14 (efavirenz) were in patients with a baseline viral load of ≤ 100,000 copies/mL. In the week 96 pooled resistance analysis for patients receiving emtricitabine/tenofovir disoproxil fumarate + rilpivirine hydrochloride in the Phase III clinical studies C209 and C215, there were 78 virologic failure patients with genotypic resistance information available for 71 of those patients. In this analysis, the NNRTI resistance-associated mutations that developed most commonly in these patients were: V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y and F227C. The most common mutations were the same in the week 48 and week 96 analyses. In the studies, the presence of the mutations V90I and V189I at baseline did not affect the response. The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. 52% of patients with virologic failure in the rilpivirine arm developed concomitant NNRTI and NRTI mutations. The mutations associated with NRTI resistance that developed in 3 or more patients were: K65R, K70E, M184V/I and K219E during the treatment period. Through week 96, fewer patients in the rilpivirine arm with baseline viral load ≤ 100,000 copies/mL had emerging resistance-associated substitutions and/or phenotypic resistance to rilpivirine (7/288) than patients with baseline viral load > 100,000 copies/mL (30/262). Among those patients who developed resistance to rilpivirine, 4/7 patients with baseline viral load ≤ 100,000 copies/mL and 28/30 patients with baseline viral load > 100,000 copies/mL had cross-resistance to other NNRTIs. In virologically suppressed HIV-1 infected patients Study GS-US-264-0106: Of the 469 Eviplera-treated patients [317 patients who switched to Eviplera at baseline (Eviplera arm) and 152 patients who switched at week 24 (Delayed Switch arm)], a total of 7 patients were analysed for resistance development and all had genotypic and phenotypic data available. Through week 24, two patients who switched to Eviplera at baseline (2 of 317 patients, 0.6%) and one patient who maintained their ritonavir-boosted protease inhibitor-based regimen [Stayed on Baseline Regimen (SBR) arm] (1 of 159 patients, 0.6%) developed genotypic and/or phenotypic resistance to study drugs. After week 24, the HIV-1 from 2 additional patients in the Eviplera arm developed resistance by week 48 (total of 4 of 469 patients, 0.9%). The remaining 3 Eviplera-treated patients did not have emergent resistance. The most common emergent resistance mutations in Eviplera-treated patients were M184V/I and E138K in reverse transcriptase. All patients remained susceptible to tenofovir. Of the 24 patients treated with Eviplera that had the NNRTI-associated K103N substitution pre-existing at baseline in their HIV-1, 17 of 18 patients in the Eviplera arm and 5 of 6 patients in the SBR arm maintained virologic suppression after switching to Eviplera through 48 weeks and 24 weeks of treatment, respectively. One patient with pre-existing K103N at baseline had virologic failure with additional emergent resistance by week 48. Study GS-US-264-0111: Through week 48, no emergent resistance developed in the 2 patients that failed virologically among patients that switched to Eviplera from efavirenz/emtricitabine/tenofovir disoproxil (0 of 49 patients). Cross-resistance No significant cross-resistance has been demonstrated between rilpivirine-resistant HIV-1 variants and emtricitabine or tenofovir, or between emtricitabine- or tenofovir-resistant variants and rilpivirine. In cell culture Emtricitabine: Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine. Viruses harbouring substitutions conferring reduced susceptibility to stavudine and zidovudine-thymidine analogue-associated mutations-TAMs (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution or other substitutions associated with resistance to rilpivirine and other NNRTIs was susceptible to emtricitabine. Rilpivirine hydrochloride: In a panel of 67 HIV-1 recombinant laboratory strains with one resistance-associated mutation at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity against 64 (96%) of these strains. The single resistance-associated mutations associated with a loss of susceptibility to rilpivirine were: K101P and Y181V/I. The K103N substitution alone did not result in reduced susceptibility to rilpivirine, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9-fold for clinical isolates and 6-fold for site-directed mutants. Tenofovir disoproxil fumarate: The K65R and also the K70E substitution result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine. Patients with HIV-1 expressing three or more TAMs that included either the M41L or L210W reverse transcriptase substitution showed reduced response to tenofovir disoproxil fumarate. Virologic response to tenofovir disoproxil fumarate was not reduced in patients with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 containing the K103N, Y181C, or rilpivirine-associated substitutions with resistance to NNRTIs were susceptible to tenofovir. In treatment-naïve patients Resistance outcomes, including cross resistance to other NNRTIs, in patients receiving rilpivirine hydrochloride in combination with emtricitabine/tenofovir disoproxil fumarate in Phase III studies (C209 and C215 pooled data) and experiencing virological failure, are shown in Table 3 below. Table 3: Phenotypic resistance and cross-resistance outcomes from studies C209 and C215 (pooled data) for patients receiving rilpivirine hydrochloride in combination with emtricitabine/tenofovir disoproxil fumarate at week 96 (based on resistance analysis)
2 Phenotypic resistance to rilpivirine (> 3.7-fold change compared to control). 3 Phenotypic resistance (Antivirogram). In virologically suppressed HIV-1 infected patients In study GS-US-264-0106, 4 of the 469 patients who switched from a ritonavir-boosted protease inhibitor-based regimen to Eviplera had HIV-1 with reduced susceptibility to at least one component of Eviplera through week 48. De novo resistance to emtricitabine/lamivudine was seen in 4 cases, and also to rilpivirine in 2 cases, with a consequent cross resistance to efavirenz (2/2), nevirapine (2/2) and etravirine (1/2). Effects on electrocardiogram The effect of rilpivirine hydrochloride at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady-state. Rilpivirine hydrochloride at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine hydrochloride were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) ms, respectively. Steady-state administration of rilpivirine hydrochloride 75 mg once daily and 300 mg once daily resulted in a mean Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 25 mg once daily dose of rilpivirine hydrochloride. Clinical experience Treatment-naïve HIV-1 infected patients The efficacy of Eviplera is based on the analyses of 96 week data from two randomised, double-blind, controlled studies C209 and C215. Antiretroviral treatment-naïve HIV-1 infected patients were enrolled (n = 1,368) who had a plasma HIV-1 RNA ≥ 5,000 copies/mL and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI resistance-associated mutations. The studies are identical in design with the exception of the background regimen (BR). Patients were randomised in a 1:1 ratio to receive either rilpivirine hydrochloride 25 mg (n = 686) once daily or efavirenz 600 mg (n = 682) once daily in addition to a BR. In study C209 (n = 690), the BR was emtricitabine/tenofovir disoproxil fumarate. In study C215 (n = 678), the BR consisted of 2 investigator selected N(t)RTIs: emtricitabine/tenofovir disoproxil fumarate (60%, n = 406) or lamivudine/zidovudine (30%, n = 204) or abacavir plus lamivudine (10%, n = 68). In the pooled analysis for C209 and C215 of patients who received a background regimen of emtricitabine/tenofovir disoproxil fumarate, demographic and baseline characteristics were balanced between the rilpivirine and efavirenz arm. Table 4 displays selected demographic and baseline disease characteristics. Median plasma HIV-1 RNA was 5.0 and 5.0 log10 copies/mL and median CD4 count was 247 x 106 cells/L and 261 x 106 cells/L for patients randomised to rilpivirine and efavirenz arm, respectively. Table 4: Demographic and baseline characteristics of antiretroviral treatment-naïve HIV-1 infected adult patients in studies C209 and C215 (pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine/tenofovir disoproxil fumarate) at week 96
Table 5: Virologic outcomes of randomised treatment of studies C209 and C215 (pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine/tenofovir disoproxil fumarate) at week 48 (primary) and week 96
a ITT TLOVR = Intention to treat time to loss of virologic response. b The difference of response rate is 1% (95% confidence interval -3% to 6%) using normal approximation. c There were 17 new virologic failures between the week 48 primary analysis and week 96 (6 patients with baseline viral load ≤ 100,000 copies/mL and 11 patients with baseline viral load > 100,000 copies/mL). There were also reclassifications in the week 48 primary analysis with the most common being reclassification from virologic failure to discontinued for non-AE reasons. d There were 10 new virologic failures between the week 48 primary analysis and week 96 (3 patients with baseline viral load ≤ 100,000 copies/mL and 7 patients with baseline viral load > 100,000 copies/mL). There were also reclassifications in the week 48 primary analysis with the most common being reclassification from virologic failure to discontinued for non-AE reasons. e e.g. lost to follow up, non-compliance, withdrew consent. Emtricitabine/tenofovir disoproxil fumarate + rilpivirine hydrochloride has been shown to be non-inferior in achieving HIV-1 RNA < 50 copies/mL compared to emtricitabine/tenofovir disoproxil fumarate + efavirenz. At week 96 the mean changes in CD4 cell count from baseline were +226 x 106 cells/L and + 222 x 106 cells/L for the rilpivirine and efavirenz treatment arms, respectively, of patients receiving the emtricitabine/tenofovir disoproxil fumarate background regimen. There were no new cross resistance patterns at week 96 compared to week 48. The resistance outcome for patients with protocol defined virological failure and phenotypic resistance at week 96 are shown in Table 6: Table 6: Phenotypic resistance outcomes from studies C209 and C215 (pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine/tenofovir disoproxil fumarate) at week 96 (based on resistance analysis)
Virologically suppressed HIV-1 infected patients Study GS-US-264-0106: The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination with two NRTIs to Eviplera STR was evaluated in a randomised, open-label study in virologically suppressed HIV-1 infected adults. Patients had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of Eviplera, and must have been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Eviplera at baseline (Eviplera arm, n = 317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, n = 159) before switching to Eviplera for an additional 24 weeks (Delayed Switch arm, n = 152). Patients had a mean age of 42 years (range 19-73), 88% were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino. The mean baseline CD4 cell count was 584 x 106 cells/L (range 42-1,484). Randomisation was stratified by use of tenofovir disoproxil fumarate and/or lopinavir/ritonavir in the baseline regimen. Treatment outcomes through 24 weeks are presented in Table 7. Table 7: Outcomes of randomised treatment in study GS-US-264-0106 at week 24a
b Snapshot analysis. c Includes patients who had HIV-1 RNA ≥ 50 copies/mL in the week 24 window, patients who discontinued early due to lack or loss of efficacy, patients who discontinued for reasons other than an adverse event or death, and at the time of discontinuation had a viral value of ≥ 50 copies/mL. d Includes patients who discontinued due to adverse event or death at any time point from day 1 through the week 24 window resulting in no virologic data on treatment during the specified window. e Includes patients who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. Switching to Eviplera was non-inferior in maintaining HIV-1 RNA < 50 copies/mL when compared to patients who stayed on a ritonavir-boosted protease inhibitor in combination with two NRTIs [Treatment difference (95% CI): + 3.8% (-1.6% to 9.1%)]. Among patients in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to Eviplera, 92% (140/152) of patients had HIV-1 RNA < 50 copies/mL after 24 weeks of Eviplera, consistent with the week 24 results for patients who switched to Eviplera at baseline. At week 48, 89% (283/317) of patients randomised to switch to Eviplera at baseline (Eviplera) had HIV-1 RNA < 50 copies/mL, 3% (8/317) were considered virologic failures (HIV RNA ≥ 50 copies/mL), and 8% (26/317) did not have data available in the week 48 window. Of the 26 patients without data available in the week 48 window, 7 patients discontinued due to adverse event or death, 16 patients discontinued for other reasons, and 3 patients were missing data but remained on study drug. The median change in CD4 cell count at week 48 was +17 x 106 cells/L, in the on-treatment analysis. There were 7/317 patients (2%) in the Eviplera arm and 6/152 patients (4%) in the Delayed Switch arm who permanently discontinued study drug due to a treatment-emergent adverse events (TEAE). No patients discontinued from the study due to a TEAE in the SBR arm. Study GS-US-264-0111: The efficacy, safety, and pharmacokinetics of switching from efavirenz/emtricitabine/tenofovir disoproxil STR to Eviplera STR was evaluated in an open-label study in virologically suppressed HIV-1 infected adults. Patients had to have previously only received efavirenz/emtricitabine/tenofovir disoproxil as their first antiretroviral regimen for at least three months, and wished to switch regimens due to efavirenz intolerance. Patients had to be stably suppressed for at least 8 weeks prior to study entry, have no current or past history of resistance to any of the three components of Eviplera, and have HIV-1 RNA < 50 copies/mL at screening. Patients were switched from efavirenz/emtricitabine/tenofovir disoproxil to Eviplera without a washout period. Among 49 patients who received at least one dose of Eviplera, 100% of patients remained suppressed (HIV-1 RNA < 50 copies/mL) at week 12 and week 24. At week 48, 94% (46/49) of patients remained suppressed, and 4% (2/49) were considered virologic failures (HIV-1 RNA ≥ 50 copies/mL). One patient (2%) did not have data available in the week 48 window; study drug was discontinued due to a protocol violation (i.e. reason other than AE or death) and the last available HIV-1 RNA was < 50 copies/mL. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Eviplera in one or more subsets of the paediatric population in the treatment of HIV-1 (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption The bioequivalence of one Eviplera film-coated tablet with one emtricitabine 200 mg hard capsule, one rilpivirine (as hydrochloride) 25 mg film-coated tablet and one tenofovir disoproxil (as fumarate) 245 mg film-coated tablet was established following single dose administration to fed, healthy subjects. Following oral administration of Eviplera with food emtricitabine is rapidly and extensively absorbed with maximum plasma concentrations occurring within 2.5 hours post dose. Maximum tenofovir concentrations are observed in plasma within 2 hours and maximum plasma concentrations of rilpivirine are generally achieved within 4-5 hours. Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. The absolute bioavailability of emtricitabine from 200 mg hard capsules was estimated to be 93%. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate tablets in fasted patients was approximately 25%. The absolute bioavailability of rilpivirine is unknown. The administration of Eviplera to healthy adult subjects with either a light meal (390 kcal) or a standard meal (540 kcal) resulted in increased exposures of rilpivirine and tenofovir relative to fasting conditions. The Cmax and AUC of rilpivirine increased by 34% and 9% (light meal) and 26% and 16% (standard meal), respectively. The Cmax and AUC for tenofovir increased by 12% and 28% (light meal) and 32% and 38% (standard meal), respectively. Emtricitabine exposures were not affected by food. Eviplera must be administered with food to ensure optimal absorption (see section 4.2). Distribution Following intravenous administration the volume of distribution of the single components emtricitabine and tenofovir was approximately 1,400 mL/kg and 800 mL/kg, respectively. After oral administration of the single components emtricitabine and tenofovir disoproxil fumarate, emtricitabine and tenofovir are widely distributed throughout the body. In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 µg/mL. In vitro binding of rilpivirine to human plasma proteins is approximately 99.7%, primarily to albumin. In vitro binding of tenofovir to plasma or serum protein was less than 0.7% and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL. Biotransformation There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitro experiments indicate that rilpivirine hydrochloride primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP)3A system. In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation. Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation. Elimination Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours. The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine. Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system (human organic anion transporter 1 [hOAT1]) with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. The apparent clearance of tenofovir averaged approximately 307 mL/min. Renal clearance has been estimated to be approximately 210 mL/min, which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours. Older people Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokinetics are not different across the age range (18 to 78 years) evaluated, with only 2 patients aged 65 years of age or older. Gender Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients. No clinically relevant differences in pharmacokinetics of rilpivirine have been observed between men and women. Ethnicity No clinically important pharmacokinetic differences due to ethnicity have been identified. Paediatric population In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months up to 18 years) are similar to those seen in adults. The pharmacokinetics of rilpivirine and tenofovir disoproxil fumarate in children and adolescents are under investigation. Dosing recommendations for paediatric patients cannot be made due to insufficient data (see section 4.2). Renal impairment 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 are considered to outweigh the potential risks (see sections 4.2 and 4.4). 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 4.4). Pharmacokinetic parameters were mainly determined following administration of single doses of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected patients with varying degrees of renal impairment. The degree of renal impairment was defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 mL/min; mild impairment with CrCl = 50-79 mL/min; moderate impairment with CrCl = 30-49 mL/min and severe impairment with CrCl = 10-29 mL/min). The mean (%CV) emtricitabine drug exposure 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 (%CV) tenofovir drug exposure increased from 2,185 (12%) ng•h/mL in patients with normal renal function, to 3,064 (30%) ng•h/mL, 6,009 (42%) ng•h/mL and 15,985 (45%) ng•h/mL, in patients with mild, moderate and severe renal impairment, respectively. In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug exposures substantially increased over 72 hours to 53 µg•h/mL (19%) of emtricitabine, and over 48 hours to 42,857 ng•h/mL (29%) of tenofovir. A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics of tenofovir disoproxil fumarate in combination with emtricitabine in HIV infected patients with renal impairment. A subgroup of patients with baseline creatinine clearance between 50 and 60 mL/min, receiving once daily dosing, had a 2-4-fold increase in tenofovir exposure and worsening renal function. The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. In patients with severe renal impairment or ESRD, plasma concentrations may be increased due to alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.9). Hepatic impairment No dose adjustment of Eviplera is suggested but caution is advised 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 4.2 and 4.4). The pharmacokinetics of emtricitabine have not been studied in patients with varying degrees of hepatic insufficiency. Rilpivirine hydrochloride is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (CPT Score A) to 8 matched controls and 8 patients with moderate hepatic impairment (CPT Score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. Rilpivirine has not been studied in patients with severe hepatic impairment (CPT Score C) (see section 4.2). However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate impairment. A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected subjects with varying degrees of hepatic impairment defined according to CPT classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/mL and 2,050 (50.8%) ng•h/mL, respectively, in normal subjects compared with 289 (46.0%) ng/mL and 2,310 (43.5%) ng•h/mL in subjects with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ng•h/mL in subjects with severe hepatic impairment. Hepatitis B and/or hepatitis C virus co-infection In general, emtricitabine pharmacokinetics in HBV infected patients were similar to those in healthy subjects and in HIV infected patients. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine. Switching from an efavirenz-based regimen The efficacy data from study GS-US-264-0111 (see section 5.1) indicates that the brief period of lower rilpivirine exposure does not impact antiviral efficacy of Eviplera. Due to the decline in efavirenz plasma levels, the inductive effect decreased and rilpivirine concentrations started to normalise. During the time period of declining efavirenz plasma levels and increasing rilpivirine plasma levels after switching, none of the patients had efavirenz or rilpivirine levels below their respective IC90 levels at the same time.No dose adjustment is required following the switch from an efavirenz-containing regimen. 5.3 Preclinical safety data Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Non-clinical data on rilpivirine hydrochloride reveal no special hazard for humans based on studies of safety pharmacology, drug disposition, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs cholestasis-like effects were noted. Carcinogenicity studies with rilpivirine in mice and rats revealed tumorigenic potential specific for these species, but are regarded as of no relevance for humans. Non-clinical data on tenofovir disoproxil fumarate reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Findings in repeat-dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use included kidney and bone changes and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (rats and dogs). Genotoxicity and repeat-dose toxicity studies of one month or less with the combination of emtricitabine and tenofovir disproxil fumarate found no exacerbation of toxicological effects compared to studies with the separate components. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Croscarmellose sodium Lactose monohydrate Magnesium stearate (E470b) Microcrystalline cellulose (E460(i)) Polysorbate 20 (E432) Povidone (E1201) Pregelatinised maize starch Film-coating Hypromellose (E464) Indigo carmine aluminium lake (E132) Lactose monohydrate Polyethylene glycol Red iron oxide (E172) Sunset yellow aluminium lake (E110) Titanium dioxide (E171) Triacetin (E1518) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in the original package in order to protect from moisture. Keep the bottle tightly closed. 6.5 Nature and contents of container High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 30 film-coated tablets and a silica gel desiccant. The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Gilead Sciences International Ltd Cambridge CB21 6GT United Kingdom 8. Marketing authorisation number(s) EU/1/11/737/001 EU/1/11/737/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 28 November 2011 10. Date of revision of the text 05/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.
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EVIPLERA Tablet（替诺福韦酯/恩曲他滨/盐酸利匹韦林复合片）简介：
英文药名：EVIPLERA（emtricitabine/rilpivirine hydrochloride/tenofovir disoproxil fixed-dose tablet）
中文药名：替诺福韦酯/恩曲他滨/盐酸利匹韦林组成的复合片
生产厂家：Gilead药品说明通用 ... 责任编辑：admin |
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